In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epithelium.

Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6-12% and SAP > or = 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P-value < 1(E)- 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell-cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function.

Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3).

OBJECTIVES: Visceral hypersensitivity is involved in the etiology of reflux symptoms. Familial clustering and twin studies demonstrated a genetic predisposition to gastroesophageal reflux disease (GERD). G-protein-coupled receptors (GPCRs) mediate the response to acid, neurotransmitters and humoral factors modulating esophageal sensory function. Thus, polymorphisms in G-proteins are putative genetic factors contributing to GERD manifestation. A functional polymorphism in the G-protein beta3 subunit gene (GNB3) is associated with functional dyspepsia (FD), in which visceral hypersensitivity is implicated in symptom generation. We evaluated the association of the GNB3 C825T polymorphism with GERD and GERD subgroups classified according to esophageal acid exposure time, symptom-reflux correlation, or coexistence of FD and/or irritable bowel syndrome (IBS) symptoms. METHODS: In total, 363 GERD patients, defined as having esophageal pH < 4 > or = 6% of time and/or symptom index (SI) > or = 50% or symptom association probability (SAP) > or = 95%, participated. In addition, 373 healthy controls free of gastrointestinal symptoms were studied. Genotyping was performed by molecular beacon assay. RESULTS: The CT genotype was more prevalent in GERD patients relative to healthy controls (adjusted odds ratio (OR)=1.43, 95% CI 1.04-1.98). GERD patients sensitive to physiological amounts of reflux displayed a higher OR (1.59), as did GERD patients with a positive symptom association score (1.50). The strongest association was detected in patients without concomitant FD and/or IBS symptoms (OR=1.66). CONCLUSIONS: GERD is associated with GNB3 C825T. The results for GERD subgroups support the hypothesis that enhanced perception of reflux events, as a consequence of the increased signal transduction upon GPCR activation associated with the 825T allele, underlies this association.

High prevalence of esophageal involvement in lichen planus: a study using magnification chromoendoscopy.

BACKGROUND AND STUDY AIMS: The first cases of squamous cell carcinoma in esophageal lichen planus were recently described. We performed a study to establish the prevalence of endoscopic and histopathologic abnormalities consistent with lichen planus and (pre-) malignancy in a cohort of patients with lichen planus. PATIENTS AND METHODS: A total of 24 patients with lichen planus were prospectively studied using high-magnification chromoendoscopy. Focal esophageal abnormalities were mapped, classified, and biopsied. Biopsies were also taken from normal-appearing esophageal mucosa at three levels (proximal, middle, and distal). The presence of a lymphohistiocytic interface inflammatory infiltrate and Civatte bodies (i. e. apoptotic basal keratinocytes) at histopathologic examination was considered diagnostic for esophageal lichen planus. Symptoms were assessed using validated questionnaires. RESULTS: A total of 38 focal abnormalities were biopsied. These consisted of: layers of mucosa peeling off, hyperemic lesions, papular lesions, submucosal plaques/papules, a flat polypoid lesion, and segments of cylindrical epithelium. No endoscopic signs of dysplasia were present. Esophagitis consistent with gastroesophageal reflux disease was noted in 12 / 24 patients. Histopathology showed chronic inflammation of the esophageal mucosa in the majority (18 / 24) of patients. In 50 % (12 / 24), the diagnosis of esophageal lichen planus was made. Dysplasia was not present. There were no differences in symptoms between patients with and without esophageal lichen planus. CONCLUSIONS: At screening endoscopy a high prevalence (50 %) of esophageal lichen planus was found in patients with orocutaneous lichen planus. No dysplasia was found.

High frequency of early colorectal cancer in inflammatory bowel disease.

BACKGROUND AND AIMS: To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8-10 years of extensive colitis, or after 15-20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence. METHODS: A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD-associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months. RESULTS: 149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn's disease n = 59/indeterminate colitis n = 1). Taking date of diagnosis as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using onset of symptoms to calculate the time interval, 17-22% of patients would present with cancer prior to the surveillance starting points. CONCLUSIONS: These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17-28%) when conducting surveillance strictly according to formal guidelines.

Validation of a disease-specific quality-of-life questionnaire in a large sample of Dutch achalasia patients.

SUMMARY: The aim of this study was to validate a translated version of an achalasia-specific quality-of-life questionnaire (achalasia-DSQoL) by examining its psychometric properties in a Dutch cohort of achalasia patients. The achalasia-DSQoL was administered to 171 treated achalasia patients together with a clinical symptom score and the RAND-36. Validation methods included factor analysis, known-group techniques, Cronbach's alpha and Spearman rank correlation with other questionnaires and feasibility. About 72.5% of the achalasia patients completed the questionnaires. The achalasia-DSQoL showed evidence of an underlying construct and seems reliable with a Cronbach's alpha of 0.77. The question concerning heartburn did not correlate with the other items on the questionnaire. Known-group techniques demonstrated that the achalasia-DSQoL discriminates between achalasia patients in clinical remission and patients who are not. There was a moderate correlation between the achalasia-DSQoL and the RAND-36 subscales. The questionnaire was easy in use. The translated version of the achalasia-DSQoL is a valid and reliable instrument to compare groups of achalasia patients although the question concerning heartburn should be excluded.

Air swallowing, belching, acid and non-acid reflux in patients with functional dyspepsia.

BACKGROUND: Frequent belching is a common symptom in patients with functional dyspepsia with a reported incidence up to 80%. We hypothesized that patients with functional dyspepsia possibly have a higher frequency of belching than healthy subjects secondary to frequent air swallowing. AIM: To assess air swallowing, belching, acid and non-acid reflux patterns of patients with functional dyspepsia. METHODS: Combined 24-h oesophageal impedance and pH monitoring was performed in 10 functional dyspepsia patients and 10 controls. Analysis of the impedance-pH signals included incidence of air swallows, belching, acid and non-acid reflux. RESULTS: The incidence of air swallows in functional dyspepsia patients were significantly higher compared with controls (153 +/- 15 vs. 79 +/- 10, P < 0.001), while the incidence of liquid-only swallows were not significantly increased. The proportions of gas-containing reflux episodes (belches) and non-acid reflux episodes in functional dyspepsia patients were significantly higher when compared with controls (66.4 vs. 44.4%, P = 0.04 and 70.1 vs. 45.9%, P = 0.009, respectively). CONCLUSION: Patients with functional dyspepsia swallow air more frequently than controls and this is associated with an increased incidence of non-acid gaseous gastro-oesophageal reflux.

Role of intra-oesophageal impedance monitoring in the evaluation of endoscopic gastroplication for gastro-oesophageal reflux disease.

BACKGROUND: In the evaluation of several endoscopic antireflux procedures, a discrepancy in the degree of improvement between symptoms and objective reflux parameters as measured by pH-metry has been reported. AIM: To assess the additional value of impedance monitoring in the evaluation of endoscopic gastroplication for gastro-oesophageal reflux disease. METHODS: Eighteen patients with gastro-oesophageal reflux disease were treated with three endoscopic gastroplications, and underwent 24 h pH-impedance monitoring before and 3 months after treatment. RESULTS: Total reflux exposure time as assessed by pH-metry and impedance monitoring was significantly decreased after treatment (P = 0.047 and <0.001, respectively). When assessed with impedance monitoring, the mean number of reflux episodes was significantly decreased after the procedure (82 vs. 56, pre vs. post, P < 0.001). Furthermore, the mean numbers of liquid and acid reflux episodes in patients with symptomatic improvement were significantly reduced after treatment (P = 0.04 and 0.02, respectively). After treatment, mean volume clearance time (s) and mean number of proximal reflux episodes were significantly decreased (P < 0.001 and 0.002, respectively). CONCLUSIONS: Impedance monitoring can identify the specific effect of endoscopic gastroplication on the different types of reflux episodes with regard to gas-liquid composition and pH, as well as on volume clearance and the proximal extent of the refluxate.

Persisting symptoms and decreased health-related quality-of-life in a cross-sectional study of treated achalasia patients.

BACKGROUND: Little is known about symptom characteristics of treated achalasia patients and their effect on health-related quality-of-life (HRQoL). AIMS: To examine clinical remission, achalasia-associated symptoms and HRQoL in treated achalasia patients. METHODS: The Eckardt clinical symptom score, RAND-36 and a disease-specific HRQoL questionnaire were sent to 171 treated achalasia patients. RESULTS: 76.6% of the patients returned their questionnaire. 44.9% of them were not in symptomatic remission. Prevalence of frequent dysphagia (at least daily) and chest pain (at least weekly) was 46% and 38%, respectively. Achalasia patients had lower general HRQoL scores than control subjects (all RAND-36 subscales, except health change; P < or = 0.002). Patients with frequent symptoms of chest pain and dysphagia showed lower HRQoL than patients with less frequent symptoms on three RAND-36 subscales (pain, social functioning and general health perceptions; P < 0.003). Patients in clinical remission showed higher HRQoL than patients who were not, however HRQoL in the 'remission group' remained significantly impaired as compared to controls (all RAND-36 subscales except emotional role limitations and mental health; P < 0.001). CONCLUSIONS: Many achalasia patients remain severely symptomatic after treatment and have decreased HRQoL. Frequent symptoms are associated with lower HRQoL. Patients in clinical remission show substantially improved, but not restored HRQoL.

Regional differences in expression of TPH-1, SERT, 5-HT(3) and 5-HT(4) receptors in the human stomach and duodenum.

The aim of this study was to increase the understanding of the role of serotonergic signalling in normal gastroduodenal function at a molecular level. Mucosal biopsy specimens were collected from the fundus, antrum and duodenum of 11 healthy subjects. Serotonin (5-HT)-positive cells were counted and the mRNA levels of tryptophan hydroxylase (TPH), serotonin transporter (SERT), 5-HT(4) receptor and 5-HT(3) receptor subunits were quantified by real-time reverse transcription polymerase chain reaction. The number of 5-HT-positive cells was larger in the duodenum compared with the stomach (P < 0.001). Serotonin transport protein expression was 19-fold higher in the duodenum compared with the antrum and 457-fold higher compared with the fundus (P < 0.001). Tryptophan hydroxylase-1 expression was lower in the duodenum compared with the antrum and fundus (regional differences -2.3 and -3.6, respectively). The 5-HT(4) receptor and the 5-HT(3C) and 5-HT(3E) receptor subunits were more abundantly expressed in duodenum compared with the stomach (P < 0.001). The larger number of 5-HT-positive cells, the higher expression of 5-HT(3) and 5-HT(4) receptors, and in particularly the higher uptake capacity of 5-HT in the duodenum, point out to a more prominent role of serotonergic signalling at the mucosal level in the duodenum compared with the stomach.

[British and American screening guidelines inadequate for prevention of colorectal carcinoma in patients with inflammatory bowel disease]. / Preventie van colorectaal carcinoom bij inflammatoir darmlijden onvoldoende met de Britse en Amerikaanse opsporingsrichtlijnen.

OBJECTIVE: To determine how many cases of inflammatory bowel disease (IBD)-related colorectal cancer (CRC) occur before recommended colonoscopy screening commences. DESIGN: Descriptive. METHOD: A nationwide automated histological and cytopathological archive (PALGA) was used to identify patients with IBD and CRC in the period January 1990-June 2006 at the University Medical Center Utrecht, The Netherlands. The interval between the diagnosis of IBD or IBD-related symptoms and the diagnosis of CRC was calculated. The observed interval was compared with the recommended starting point for surveillance according to the British Society of Gastroenterology (BSG) and the American Gastroenterological Association (AGA), i.e. after 8-10 years for pancolitis or after 15-20 years for left-sided colitis. RESULTS: 33 colorectal cancers were found in 29 patients with IBD. The median age at the time of diagnosis was 29 years (range: 11-82) for IBD and 47 years (range: 23-82) for CRC. 7 of the 29 patients (24%) developed CRC before the minimum recommended time to initiate screening (8 years for pancolitis, 15 years for left-sided colitis), and 9 patients (31%) developed CRC within the maximum recommended time to initiate screening (10 years for pancolitis, 20 years for left-sided colitis). If the onset of IBD-related symptoms was considered the starting point of the disease (rather than the diagnosis of IBD), 17-24% of patients developed a CRC before surveillance would have commenced. CONCLUSION: These results suggest that, by following the British and American guidelines for screening for IBD-related CRC, a substantial portion of cases (17-31%) would not be diagnosed in a timely manner.

The 5-HT4 antagonist R216073 does not affect gastric motor and sensory function in patients with functional dyspepsia.

BACKGROUND: Serotonin and the 5-HT4 receptor play an important role in gastrointestinal motor and sensory functions. While 5-HT4 agonists are known for their prokinetics properties, the effect of 5-HT4 antagonists on upper gastrointestinal functions is largely unknown. AIM: To assess the effect of a 5-HT4 receptor antagonist (R216073) on gastric relaxation and visceral sensitivity in patients with functional dyspepsia. Secondly, the influence of a functional polymorphism in the gene encoding the serotonin transport protein on drug response was determined. METHODS: A double-blind, randomized, placebo-controlled, two-period crossover study was performed in 20 functional dyspepsia patients. The effect of a single dose of 2,000 mg R216073 on gastric relaxation and sensitivity was tested using three-dimensional ultrasonography and a nutrient drinktest. RESULTS: R216073 did not affect partial gastric volumes or upper abdominal sensations scored during three-dimensional ultrasonography (P > 0.05). The maximum tolerated volume or upper abdominal sensations induced by the drinktest were not affected by R216073 (P > 0.05). The serotonin transport protein promoter polymorphism was not associated with any of the end-points of the study. CONCLUSIONS: A single dose of R216073 had no effect on fundic relaxation, drinking capacity, or upper abdominal symptoms in patients with functional dyspepsia.

The gastro-oesophageal common cavity revisited.

The manometric common cavity phenomenon has been used as indicator of gastro-oesophageal reflux of liquid or gaseous substances. Using combined pH and impedance recording as reference standard the value of a common cavity as indicator of gastro-oesophageal reflux was tested. Ten healthy male subjects underwent combined stationary pressure, pH and impedance recording for 4.5 h. After 1.15 h of recording, a reflux-eliciting meal was consumed. The chi-squared and Kolmogorov-Smirnov tests were used for the statistical analysis. A common cavity was found in 95 (43%) of the 223 reflux events detected by impedance, while seven common cavities were unrelated to a reflux episode. In 54% of the reflux events detected by impedance without a common cavity, a possible common cavity was obscured by either contractile activity or artefacts of various origin. The types of reflux associated with a common cavity (liquid 60%, mixed 31%, gas 9%) and without a common cavity (liquid 59%, mixed 29%, gas 12%) did not differ, or did the acidity of the reflux episodes (with common cavity: acid 67%; without common cavity: acid 58%). The common cavity is a specific but not a sensitive marker of gastro-oesophageal reflux. Furthermore, common cavities are not specific for a particular type of reflux.

Assessment of oesophageal emptying in achalasia patients by intraluminal impedance monitoring.

Oesophageal emptying can be assessed by radiographic and scintigraphic tests with radiation exposure or by multichannel intraluminal impedance monitoring (MII). The aim of this study was to evaluate the applicability of MII for the assessment of oesophageal emptying in achalasia patients. In 10 achalasia patients, impedance tracings were scored independently by three observers after ingestion of a 100-mL barium bolus. Bolus clearance time (BCT) and height of barium column were scored using fluoroscopic images acquired at 20-s intervals. All patients showed a low baseline impedance level in the distal oesophagus. Air trapping in the proximal oesophagus was detected in nine patients. BCT on MII was similar to that on fluoroscopy in 40-70% of the patients. Correlations between height of barium on fluoroscopy and fluid level on MII were poor to moderate at different time intervals. Concordance (Kendall's coefficient) between the three observers for assessment of fluid level on MII was 0.31 (P = 0.04) at 1 and 5 min, 0.26 (P = 0.08) at 10 and 0.44 (P = 0.01) at 15 min. We conclude that in achalasia patients, low baseline impedance levels and air entrapment in the proximal oesophagus limit the value of intraluminal impedance monitoring as a test of oesophageal emptying.

Relationship between the mechanism of gastro-oesophageal reflux and oesophageal acid exposure in patients with reflux disease.

This study investigated the relationship between the oesophageal acid exposure time and the underlying manometric motor events in patients with gastro-oesophageal reflux disease (GORD). In 31 patients, 3-hour oesophageal motility and pH were measured after a test meal. Ten patients underwent 24-hour ambulatory manometry and pH recording. In the 3-hour postprandial study, of 367 reflux episodes 79% was associated with a transient lower oesophageal sphincter relaxation (TLOSR), 14% with absent basal lower oesophageal sphincter (LOS) pressure and the remaining 7% with other mechanisms, representing 62, 28 and 10% of the acid exposure time, respectively. Acid reflux duration per motor mechanism was longer for absent basal LOS pressure than for TLOSR (189 +/- 23 s and 41 +/- 5 s, respectively, P < 0.001). In the 24-hour ambulatory study, the contribution of TLOSRs to reflux frequency vs acid exposure time were 65 vs 54% interprandially and 74 vs 53% after the meal. During the night, absence of basal LOS pressure accounted for 36% of reflux events representing 71% of acid exposure time. In conclusion, the duration of oesophageal acid exposure following a TLOSR is shorter than reflux during absent basal LOS pressure. TLOSRs are, the major contributor to oesophageal acid exposure during the day. At night, however, reflux during absent basal LOS pressure is the major contributor to acid exposure.

Relationships of upper gastrointestinal motor and sensory function with glycemic control.

Acute changes in the blood glucose concentration have a major reversible effect on esophageal, gastric, intestinal, gallbladder, and anorectal motility in both healthy subjects and diabetic patients. For example, gastric emptying is slower during hyperglycemia than euglycemia and accelerated during hypoglycemia. Acute hyperglycemia also affects perceptions arising from the gastrointestinal tract and may accordingly, be important in the etiology of gastrointestinal symptoms in diabetes. Elevations in blood glucose that are within the normal postprandial range also affect gastrointestinal motor and sensory function. Upper gastrointestinal motor function is a critical determinant of postprandial blood glucose concentrations by influencing the absorption of ingested nutrients. Interventions that reduce postprandial hyperglycemia, by modulating the rate of gastric emptying, have the potential to become mainstream therapies in the treatment of diabetes.

Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the perception of postprandial hunger in normal subjects.

OBJECTIVE: The major aims of this study were to determine in normal subjects whether the effects of erythromycin on gastric emptying, postprandial hunger, and fullness are modified by the blood glucose concentration. RESEARCH DESIGN AND METHODS: A total of 10 normal subjects (aged 20-39 years) underwent concurrent measurements of gastric emptying, blood glucose, hunger, and fullness on four separate occasions: twice during euglycemia (approximately 4 mmol/l) and twice during hyperglycemia (approximately 15 mmol/l). Either erythromycin (3 mg/kg) or saline (0.9%) was administered intravenously immediately before ingestion of a radioisotopically labeled solid meal. RESULTS: Gastric emptying was slower (P < 0.0001) during hyperglycemia when compared with euglycemia after both erythromycin and saline administration. During hyperglycemia, erythromycin reduced the lag phase (77.8 +/- 12.6 vs. 20.3 +/- 7.3 min; P < 0.05) but had no effect on the postlag emptying rate (0.32 +/- 0.077% per min vs. 0.24% per min). Hunger decreased (P < 0.001) and fullness increased (P < 0.001) after the meal. Postprandial hunger was less during hyperglycemia after saline infusion (P < 0.05) but not after erythromycin. Hunger was greater after erythromycin during both hyperglycemia and euglycemia (P < 0.05). CONCLUSIONS: At a blood glucose concentration of approximately 15 mmol/l, 1) gastric emptying of a solid meal is slower, when compared with euglycemia, even after administration of erythromycin; 2) the effect of erythromycin on gastric emptying of a solid meal is attenuated; and 3) the perception of postprandial hunger is reduced.

Abnormalities of antroduodenal motility in type I diabetes.

OBJECTIVE: In the present study, a recently developed manometric technique was used to study antroduodenal motility in ambulant type I diabetic subjects. RESEARCH DESIGN AND METHODS: In 12 patients with type I diabetes, antroduodenal manometry was performed for 20 h during the fasting period and the postprandial period after a standardized dinner and breakfast. All patients had evidence of cardiac autonomic neuropathy and complained of dyspeptic symptoms. During the manometric study, the blood glucose levels were frequently monitored and kept close to euglycemia in the diabetic patients. The results were compared with 12 healthy control subjects. RESULTS: The migrating motor complex cycles observed in the diabetic subjects were longer than in the control subjects, 118.9 +/- 46.0 vs. 87.0 +/- 21.6 min (P < 0.05). This increase was attributable to a prolonged phase II, 78.0 +/- 35.5 vs. 37.7 +/- 18.5 min (P < 0.05). In the diabetic subjects, antral phase III was seen significantly less than in the control subjects, 16.7 vs. 43.3% (P < 0.005). In 50% of the diabetic patients, total absence of antral phase III was observed-this phenomenon was not seen in the healthy control subjects. After dinner, the antral motility index was less in diabetic subjects compared with the healthy volunteers, indicating antral hypomotility (P < 0.01). Six diabetic patients showed abnormal duodenal activity such as early recurrence of phase III and bursts after dinner. No significant differences in antral motility index or in duodenal motility patterns were observed after breakfast. Six diabetic patients complained of dyspeptic symptoms after dinner, whereas none had dyspeptic symptoms after breakfast. In 67% of the patients, nausea was reported after an early phase III or a burst. CONCLUSIONS: This study shows that prolonged ambulatory antroduodenal manometry is a feasible technique in patients. Recording multiple migrating motor complexes showed that interdigestive motor abnormalities of the stomach and duodenum are common in diabetic patients. Furthermore, it shows the occurrence of antral hypomotility and abnormal duodenal motility patterns after a high-calorie meal, with dyspeptic symptoms in diabetic patients being related to the composition of the meal.

Effects of oral erythromycin on fasting and postprandial antroduodenal motility in patients with type I diabetes, measured with an ambulatory manometric technique.

OBJECTIVE: The aim of this double-blind crossover study was to evaluate the effects of oral erythromycin (250 mg t.i.d.) on fasting and postprandial gastrointestinal motility and gastrointestinal symptoms in patients with type I diabetes. RESEARCH DESIGN AND METHODS: Antroduodenal motility was recorded with an ambulatory manometric technique for a 20-h period, including a high-caloric high-fat dinner and a low-caloric low-fat breakfast and a long fasting period, after 2 weeks erythromycin and placebo treatment in 12 patients with type I diabetes. During the manometric study, plasma glucose concentrations were assessed by frequent self-testing. Gastrointestinal symptoms were scored daily to assess the severity of the symptoms (range 0-3). RESULTS: Oral erythromycin decreased the migrating motor complex cycle length from 118.9 +/- 46.0 to 86.2 +/- 25.3 min (P = 0.03) by shortening phase II from 68.7 +/- 23.5 to 48.5 +/- 19.4 min (P < 0.05). The total number of duodenal phase III increased from 48 to 62 (P = 0.075). However, the degree of antral participation to duodenal phase III did not increase. Erythromycin significantly decreased the duration of the postprandial period after dinner (from 417.0 +/- 137.9 to 348.8 +/- 93.8 min, P = 0.04). During this shorter postprandial period, the number of antral contractions (P < 0.01) and the antral motility index increased (P < 0.03), and early phase III activity at the level of the duodenum was abolished. In diabetic patients with antral hypomotility, after dinner, the mean symptom score improved significantly, from 2.07 +/- 0.86 to 1.52 +/- 0.63 (P = 0.018). CONCLUSIONS: This ambulatory antroduodenal manometric study showed that oral erythromycin (250 mg t.i.d.) improves both fasting and postprandial antroduodenal motor activity after a high-caloric meal in patients with type I diabetes. Furthermore, in diabetic subjects with postprandial antral hypomotility, erythromycin reduces dyspeptic symptoms.

Prevalence of delayed gastric emptying in diabetic patients and relationship to dyspeptic symptoms: a prospective study in unselected diabetic patients.

OBJECTIVE: Data on the prevalence of abnormal gastric emptying in diabetic patients are still lacking. The relation between gastric emptying and dyspeptic symptoms assessed during gastric emptying measurement has not yet been investigated. The aim was to investigate the prevalence of delayed gastric emptying in a large cohort of unselected diabetic patients and to investigate the relation between gastric emptying and gastrointestinal sensations experienced in the 2 weeks before and during the test meal, prospectively. RESEARCH DESIGN AND METHODS: Gastric emptying was evaluated in 186 patients (106 with type 1 diabetes, mean duration of diabetes 11.6 +/- 11.3 years) using 100 mg (13)C-enriched octanoic acid added to a solid meal. RESULTS: Gastric emptying was significantly slower in the diabetic subjects than in the healthy volunteers (T(50): 99.5 +/- 35.4 vs. 76.8 +/- 21.4 min, P < 0.003; Ret(120 min): 30.6 +/- 17.2 vs. 20.4 +/- 9.7%, P < 0.006). Delayed gastric emptying was observed in 51 (28%) diabetic subjects. The sensations experienced in the 2 weeks before the test were weakly correlated with the sensation scored during the gastric emptying test. Sensations assessed during the gastric emptying test did predict gastric emptying to some extent (r = 0.46, P < 0.0001), whereas sensations experienced in the previous 2 weeks did not. CONCLUSIONS: This prospective study shows that delayed gastric emptying can be observed in 28% of unselected patients with diabetes. Upper gastrointestinal sensations scored during the gastric emptying tests do predict the rate of gastric emptying to some extent and sensation experienced during daily life does not.

Genomic organization and promoter characterization of human CXCR4 gene.

CXCR4 is the receptor for the CXC chemokine SDF1 that has essential functions on embryo organogenesis, immunological functions and T lymphocyte trafficking. Recently, CXCR4 has drawn unexpected attention as it was recently identified as a co-factor required for entry of lymphotropic HIV isolates in CD4+ T lymphocytes. CXCR4 is the only SDF1 receptor identified so far. This suggests that CXCR4 expression is critical for the biological effects of SDF1. To investigate the mechanisms controlling both the constitutive and induced expression of CXCR4 receptors we have isolated and characterized the promoter region and determined the genomic structure of the human gene. The CXCR4 gene contains two exons separated by an intronic sequence. A 2.6 kb 5'-flanking region located upstream the CXCR4 open reading frame contains a TATA box and the transcription start site characteristic of a functional promoter. This region also contains putative consensus binding sequences for different transcription factors, some of them associated with the hemopoiesis and lymphocyte development.