Efficacy of needleless transcutaneous electroacupuncture in synchronization with breathing for symptomatic idiopathic gastroparesis: A blinded and controlled acute treatment trial.

BACKGROUND: Needleless transcutaneous electroacupuncture (TEA) improves nausea and myoelectrical activity in diabetic gastroparesis (GP). Synchronized TEA (STEA), which combines synchronized breathing with TEA, is more potent than TEA in enhancing vagal activity in healthy subjects. AIMS: To investigate whether STEA improves symptoms, electrogastrogram (EGG) and vagal activity in idiopathic gastroparesis (IGP). METHODS: Eighteen IGP subjects underwent 2 randomized visits (sham at non-acupoints or real STEA at acupoints) consisted of a 30-minute baseline, an Ensure challenge to provoke nausea, followed by 60-minute treatment with sham or real STEA, and 15-minute observation period. Severity of nausea, EGG, and vagal activity (based on electrocardiogram and serum Pancreatic Polypeptide, PP) were recorded. RESULTS: In sham or STEA, the nausea scores of 2.7 ± 0.5 and 1.9 ± 0.5 at fasting baseline, respectively, increased to 5.9 ± 0.4 and 5.8 ± 0.3 during Ensure test (P < .05, vs baseline), subsequently reduced to 3.4 ± 0.6 with sham or 3.6 ± 0.6 with STEA, respectively (P < .05, vs Ensure period). Experiments with sham and STEA started with similar % of normal waves on EGG (66.4 ± 3.9 and 61.8 ± 3.0, respectively); decreased to 63. 5 ± 4.1 and 58.2 ± 2.8 during the Ensure test. After STEA, there was ~24% increase in % of normal waves, significantly different from the sham (6.0%) (P < .01). In sham or STEA, vagal activity was identical at baseline and after the Ensure. STEA induced a 3-fold increase in vagal activity compared with sham (P < .01). Ensure increased serum PP levels, and both treatments decreased the PP CONCLUSIONS: In IGP, STEA is not superior to Sham in decreasing nausea, but is more effective in improving gastric dysrhythmia.

Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis.

BACKGROUND: Wireless motility capsule (WMC) findings are incompletely defined in suspected gastroparesis. We aimed to characterize regional WMC transit and contractility in relation to scintigraphy, etiology, and symptoms in patients undergoing gastric emptying testing. METHODS: A total of 209 patients with gastroparesis symptoms at NIDDK Gastroparesis Consortium centers underwent gastric scintigraphy and WMCs on separate days to measure regional transit and contractility. Validated questionnaires quantified symptoms. KEY RESULTS: Solid scintigraphy and liquid scintigraphy were delayed in 68.8% and 34.8% of patients; WMC gastric emptying times (GET) were delayed in 40.3% and showed 52.8% agreement with scintigraphy; 15.5% and 33.5% had delayed small bowel (SBTT) and colon transit (CTT) times. Transit was delayed in ≥2 regions in 23.3%. Rapid transit was rarely observed. Diabetics had slower GET but more rapid SBTT versus idiopathics (P ≤ .02). GET delays related to greater scintigraphic retention, slower SBTT, and fewer gastric contractions (P ≤ .04). Overall gastroparesis symptoms and nausea/vomiting, early satiety/fullness, bloating/distention, and upper abdominal pain subscores showed no relation to WMC transit. Upper and lower abdominal pain scores (P ≤ .03) were greater with increased colon contractions. Constipation correlated with slower CTT and higher colon contractions (P = .03). Diarrhea scores were higher with delayed SBTT and CTT (P ≤ .04). CONCLUSIONS & INFERENCES: Wireless motility capsules define gastric emptying delays similar but not identical to scintigraphy that are more severe in diabetics and relate to reduced gastric contractility. Extragastric transit delays occur in >40% with suspected gastroparesis. Gastroparesis symptoms show little association with WMC profiles, although lower symptoms relate to small bowel or colon abnormalities.

Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum.

BACKGROUND: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis. METHODS: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index. RESULTS: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04). CONCLUSION: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing.

BACKGROUND: Early satiety (ES) and postprandial fullness (PPF) are often present in gastroparesis, but the importance of these symptoms in gastroparesis has not been well-described. The aims were: (i) Characterize ES and PPF in patients with gastroparesis. (ii) Assess relationships of ES and PPF with etiology of gastroparesis, quality of life, body weight, gastric emptying, and water load testing. METHODS: Gastroparetic patients filled out questionnaires assessing symptoms (PAGI-SYM) and quality of life (PAGI-QOL, SF-36v2). Patients underwent gastric emptying scintigraphy and water load testing. KEY RESULTS: 198 patients with gastroparesis (134 IG, 64 DG) were evaluated. Early satiety was severe or very severe in 50% of patients. Postprandial fullness was severe or very severe in 60% of patients. Severity scores for ES and PPF were similar between idiopathic and diabetic gastroparesis. Increasing severity of ES and PPF were associated with other gastroparesis symptoms including nausea/vomiting, satiety/early fullness, bloating, and upper abdominal pain and GERD subscores. Increasing severity of ES and PPF were associated with increasing gastroparesis severity, decreased BMI, decreased quality of life from PAGI-QOL and SF-36 physical health. Increasing severity of ES and PPF were associated with increasing gastric retention of a solid meal and decreased volume during water load test. CONCLUSIONS & INFERENCES: Early satiety and PPF are commonly severe symptoms in both diabetic and idiopathic gastroparesis. Early satiety and PPF severity are associated with other gastroparesis symptom severities, body weight, quality of life, gastric emptying, and water load testing. Thus, ES and PPF are important symptoms characterizing gastroparesis. ClinicalTrials.gov number: NCT NCT01696747.

Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis.

BACKGROUND: Nausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG). METHODS: Gastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting. KEY RESULTS: Of 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI-SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating. CONCLUSIONS & INFERENCES: Nausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG.

Depleted interstitial cells of Cajal and fibrosis in the pylorus: Novel features of gastroparesis.

BACKGROUND: Depletion and ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric body and antrum have been observed in gastroparesis. This research was performed to investigate the ICC population in the muscularis propria and fibrosis of the muscular layer of the pylorus in gastroparesis. METHODS: Full thickness pyloric and antral biopsies were obtained from 17 gastroparetic and 6 non-gastroparetic controls. Biopsies were stained with C-Kit for ICC and Trichrome for collagen fibrosis. Interstitial cells of Cajal depletion in the antrum was defined as mean ICC count <10 per 20 high power fields (HPF) based on established data. KEY RESULTS: The average pyloric ICC count was ≥10/HPF in the control patients. Twelve (70.5%) gastroparetic patients had pyloric ICC loss. Only five patients (29.4%) had ICC loss in the antrum. Gastric emptying (GE) was not significantly different in patients with depleted vs normal pyloric ICC. However, GE at 2 h was slower in patients with antral ICC <10/HPF compared to those with normal antral ICC populations. Collagen fibrosis was observed in the pylorus of 14 (82.3%) patients. Inclusion bodies in the muscularis propria of the pylorus were identified in four patients, all with diabetic gastroparesis. CONCLUSIONS & INFERENCES: In gastroparetic patients, ICC loss in the pylorus is twice as common as in the antrum and fibrosis in the pyloric smooth muscle is nearly three times more common than the antrum. These findings can provide one explanation for pyloric dysfunction which is a contributing factor to the pathophysiology of gastroparesis.

Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes.

BACKGROUND: In studies of diabetic gastroparesis, patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM) are often combined for analyses. We compared gastroparesis severity, healthcare utilization, psychological function, and quality of life in T1DM vs T2DM gastroparesis patients. METHODS: Questionnaire, laboratory, and scintigraphy data from patients with gastroparesis and T1DM and T2DM from seven centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were compared at enrollment and after 48 weeks. Multiple regression models assessed baseline and follow-up differences between diabetes subtypes. KEY RESULTS: At baseline, T1DM patients (N = 78) had slower gastric emptying, more hospitalizations, more gastric stimulator implantations, higher hemoglobin A1c (HbA1c), and more anxiety vs T2DM patients (N = 59). Independent discriminators of patients with T1DM vs T2DM included worse gastroesophageal reflux disease, less bloating, more peripheral neuropathy, and fewer comorbidities (p ≤ 0.05). On follow-up, gastrointestinal (GI) symptom scores decreased only in T2DM (p < 0.05), but not in T1DM patients who reported greater prokinetic, proton pump inhibitor, anxiolytic, and gastric stimulator usage over 48 weeks (p ≤ 0.03). Gastrointestinal symptoms at baseline and 48 weeks with both subtypes were not associated with HbA1c, peripheral neuropathy, psychological factors, or quality of life. CONCLUSIONS & INFERENCES: Baseline symptoms were similar in T1DM and T2DM patients, even though T1DM patients had worse gastric emptying delays and higher HbA1c suggesting other factors mediate symptom severity. Symptom scores at 48 weeks decreased in T2DM, but not T1DM patients, despite increased medical and surgical treatment utilization by T1DM patients. Defining causes of different outcomes in diabetic gastroparesis warrants further investigation.

Anthropometric and physiologic assessment in sleep apnoea patients regarding body fat distribution.

BACKGROUND: Obstructive sleep apnoea (OSA) is characterised by repeated episodes of pauses in breathing during sleep due to obstruction of the upper airway that result in transient hypoxaemia, sleep fragmentation and long-term cardiovascular disease. The most common risk factors for OSA include: obesity, age over 50 and neck circumference of more than 41 cm for females and more than 43 cm in males. Sleep apnoea is more common in men than in women. The aim of the conducted research was to evaluate relations between the anthropometric features connected with adipose tissue distribution and the severity of OSA. MATERIALS AND METHODS: The study was carried out on 180 patients (144 males and 36 females) diagnosed with OSA syndrome. The standard sleep parameters obtained from night polysomnography as well as skin-fat fold thickness and neck circumference and waist-to-hip ratio were analysed. Statistical analysis was performed using STATISTICA 10. RESULTS: It was stated that anthropometric parameters connected with the accu-mulation of adipose tissue in upper body were significantly related to severity of OSA in males (p ≤ 0.05). Body mass index (BMI) was significantly correlated with severity of OSA in females (p ≤ 0.05). CONCLUSIONS: In males, there is a connection between the severity of OSA, BMI and a higher accumulation of adipose tissue in upper part of the body measured by neck circumference and shoulder thickness of skin-fat folds, whereas in females only by BMI.

Estimation of age at death: examination of variation in cortical bone histology within the human clavicle.

BACKGROUND: Continuously, numerous human remains of unknown identity are revealed all over the world. One of the elements of the identification process may be a proper assessment of a histological section of bone fragments in order to answer questions related to the age of the subject. The aim of the study was to define an optimum bone fragment to obtain samples for histological examination. MATERIALS AND METHODS: The study material consisted of fragments of shafts of left clavicles taken from 39 males and 25 females (aged 22-86). The clavicles came from autopsies conducted between 2005 and 2011 at the Department of Forensic Medicine of Poznan and the Bialystok Medical University. The following were taken into account while estimating the age of the bone remains: clavicle length (CL), clavicle width (CW), clavicle thickness (CT), number of osteons in the field of vision (ON), number of osteons with the Haversian canal of more than 70 µm (HC > 70 µm), average diameter of the Haversian canals (avg. ØHC), area occupied by interstitial lamellae (ILA %), area occupied by osteons (OA %), area occupied by fragments-remnants of osteons remain as irregular arcs of lamellar fragments (OFA %), average thickness of outer circumferential lamellae (avg. OCL, µm), the relation of osteons with the Haversian canal of more than 70 µm in diameter to the total number of osteons (HC > 70 µm, %), at p < 0.00001. The age of the bone remains was estimated using univariate linear regression function. RESULTS: It was determined that the best place for sampling the osseous tissue for the analysis was the shaft of the clavicle. It was stated than the number of osteons with a large diameter increased with age. The relation of osteons with the Haversian canal of more than 70 µm in diameter to the total number of osteons (HC > 70 µm, %). The level of statistical significant was p < 0.00001. All analysed microscopic features of the osseous tissue showed significant statistical changes occurring with age. CONCLUSIONS: The exact method for preparing osseous tissue for a microscopic analysis to determine the age of the remains is the preparation of histological sections, as the structure of the osseous tissue does not change while processing the material and the time of preparations is relatively short (7-8 days). The best predictors of age with the use of the function of univariate linear regression were: the diameter of Haversian canal, the number of osteons with Haversian canal of more than 70 µm in diameter, the relation of osteons with Haversian canal bigger than 70 µm in diameter to the total number of osteons as well as fragments of secondary osteons.

Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis.

BACKGROUND: There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC. METHODS: Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer. KEY RESULTS: Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types. CONCLUSIONS & INFERENCES: Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages.

Gastric electrical stimulation with Enterra therapy improves symptoms of idiopathic gastroparesis.

BACKGROUND: Gastric electrical stimulation (GES) is a therapeutic option for intractable symptoms of gastroparesis (GP). Idiopathic GP (ID-GP) represents a subset of GP. AIMS: A prospective, multicenter, double-blinded, randomized, crossover study to evaluate the safety and efficacy of Enterra GES in the treatment of chronic vomiting in ID-GP. METHODS: Thirty-two ID-GP subjects (mean age 39; 81% F, mean 7.7 years of GP) were implanted with GES. The stimulator was turned ON for 1½ months followed by double-blind randomization to consecutive 3-month crossover periods with the device either ON or OFF. ON stimulation was followed in unblinded fashion for another 4.5 months. Twenty-five subjects completed the crossover phase and 21 finished 1 year of follow-up. KEY RESULTS: During the unblinded ON period, there was a reduction in weekly vomiting frequency (WVF) from baseline (61.2%, P < 0.001). There was a non-significant reduction in WVF between ON vs OFF periods (the primary outcome) with median reduction of 17% (P > 0.10). Seventy-five percent of patients preferred the ON vs OFF period (P = 0.021). At 1 year, WVF remained decreased (median reduction = 87%, P < 0.001), accompanied by improvements in GP symptoms, gastric emptying and days of hospitalization (P < 0.05). CONCLUSIONS & INFERENCES: (i) In this prospective study of Enterra GES for ID-GP, there was a reduction in vomiting during the initial ON period; (ii) The double-blind 3-month periods showed a non-significant reduction in vomiting in the ON vs OFF period, the primary outcome variable; (iii) At 12 months with ON stimulation, there was a sustained decrease in vomiting and days of hospitalizations.

Factors related to abdominal pain in gastroparesis: contrast to patients with predominant nausea and vomiting.

BACKGROUND: Factors associated with abdominal pain in gastroparesis are incompletely evaluated and comparisons of pain vs other symptoms are limited. This study related pain to clinical factors in gastroparesis and contrasted pain/discomfort- with nausea/vomiting-predominant disease. METHODS: Clinical and scintigraphy data were compared in 393 patients from seven centers of the NIDDK Gastroparesis Clinical Research Consortium with moderate-severe (Patient Assessment of Upper Gastrointestinal Disorders Symptoms [PAGI-SYM] score ≥ 3) vs none-mild (PAGI-SYM < 3) upper abdominal pain and predominant pain/discomfort vs nausea/vomiting. KEY RESULTS: Upper abdominal pain was moderate-severe in 261 (66%). Pain/discomfort was predominant in 81 (21%); nausea/vomiting was predominant in 172 (44%). Moderate-severe pain was more prevalent with idiopathic gastroparesis and with lack of infectious prodrome (P ≤ 0.05) and correlated with scores for nausea/vomiting, bloating, lower abdominal pain/discomfort, bowel disturbances, and opiate and antiemetic use (P < 0.05), but not gastric emptying or diabetic neuropathy or control. Gastroparesis severity, quality of life, and depression and anxiety were worse with moderate-severe pain (P ≤ 0.008). Factors associated with moderate-severe pain were similar in diabetic and idiopathic gastroparesis. Compared to predominant nausea/vomiting, predominant pain/discomfort was associated with impaired quality of life, greater opiate, and less antiemetic use (P < 0.01), but similar severity and gastric retention. CONCLUSIONS & INFERENCES: Moderate-severe abdominal pain is prevalent in gastroparesis, impairs quality of life, and is associated with idiopathic etiology, lack of infectious prodrome, and opiate use. Pain is predominant in one fifth of gastroparetics. Predominant pain has at least as great an impact on disease severity and quality of life as predominant nausea/vomiting.

The addition of pyloroplasty as a new surgical approach to enhance effectiveness of gastric electrical stimulation therapy in patients with gastroparesis.

BACKGROUND: Improvement of gastroparesis (GP) symptoms has been documented in patients treated with gastric electrical stimulation (GES), but acceleration of gastric emptying (GET) is unpredictable. The aim of our study was to evaluate the advantage of adding surgical pyloroplasty (PP) to GES for improvement of GET and control of symptoms in diabetes mellitus (DM), idiopathic (ID), and postvagotomy (P-V) GP. METHODS: A total of 49 (17 - DM, 9 - ID, 23 - P-V) consecutive GP patients: 38 female; mean age 42 (21-73 years); mean weight 158 lbs (102-245), underwent GES implantation, and 26 (53%) additionally received PP. Total Symptoms Score, 4-h GET, adverse events (AEs), and days of hospitalizations were captured at baseline and at the last visit. KEY RESULTS: The mean follow-up was 7 months. Total Symptoms Score in patients who received Enterra and PP or GES alone significantly improved compared to their baseline scores (P < 0.001). GET improved by 64% at 4 h (P < 0.001) in patients with Enterra and PP, compared to 7% observed after GES therapy alone (ns). The most impressive acceleration of GET was seen in the P-V group, who received both therapies (P = 0.004) and 8 (60%) of them normalized GET. No AEs accompanied the addition of PP to the Enterra surgery. CONCLUSIONS & INFERENCES: (i) In drug-refractory GP the addition of PP to GES substantially accelerated GET; (ii) The GET response in P-V group was the most impressive; (iii) Significant symptom reductions were achieved by both procedures; and (iv) PP added to GES may sustain better long-term symptoms control particularly in the P-V setting.

Is symptom relief associated with reduction in gastric retention after gastric electrical stimulation treatment in patients with gastroparesis? A sensitivity analysis with logistic regression models.

BACKGROUND: Enterra gastric electrical stimulation (GES) is an alternative treatment for gastroparesis (GP) when standard medical therapy fails. The aims of this study were to evaluate the association between total symptom score (TSS) and reduction in gastric retention (GR) after GES by GP etiology and to examine the sensitivity of the association to varying cutpoints used to define GR and TSS improvement. METHODS: Gastric retention assessed with a standardized (99m) Tc radio-labeled egg meal and TSS measured by a five-point Likert scale in 221 GP patients treated with Enterra GES therapy for at least 1 year were analyzed. Bivariate chi-square test and multivariable logistic regression with all possible cutpoints were used to assess the consistency of association and quantitate the relationship across three GP etiologies. KEY RESULTS: Symptom relief in diabetic GP was more likely attributable to GR reduction as indicated by the consistently significant odds ratios (P < 0.01) across all cutpoints. The association in idiopathic GP was inconclusive because odds ratios were sensitive to cutpoints with P-values ranging from 0.01 to 0.47. No association was found for patients with post surgical gastroparesis (P > 0.1 for all cutpoints). Patient age, gender, baseline TSS and baseline GR had no significant effect at 5% level on clinical improvement regardless of cutpoints for GR. CONCLUSIONS & INFERENCES: Association between clinical improvements and GR reduction following GES treatment depends on patient etiology and was able to be demonstrated in diabetic GP. The association for idiopathic GP was inconclusive and no such association was found for post surgical GP across all possible cutpoint combinations.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology.

BACKGROUND: Wireless pH and pressure motility capsule (wireless motility capsule) technology provides a method to assess regional gastrointestinal transit times. AIMS: To analyse data from a multi-centre study of gastroparetic patients and healthy controls and to compare regional transit times measured by wireless motility capsule in healthy controls and gastroparetics (GP). METHODS: A total of 66 healthy controls and 34 patients with GP (15 diabetic and 19 idiopathic) swallowed wireless motility capsule together with standardized meal (255 kcal). Gastric emptying time (GET), small bowel transit time (SBTT), colon transit time (CTT) and whole gut transit time (WGTT) were calculated using the wireless motility capsule. RESULTS: Gastric emptying time, CTT and WGTT but not SBTT were significantly longer in GP than in controls. Eighteen percent of gastroparetic patients had delayed WGTT. Both diabetic and idiopathic aetiologies of gastroparetics had significantly slower WGTT (P < 0.0001) in addition to significantly slower GET than healthy controls. Diabetic gastroparetics additionally had significantly slower CTT than healthy controls (P = 0.0054). CONCLUSIONS: In addition to assessing gastric emptying, regional transit times can be measured using wireless motility capsule. The prolongation of CTT in gastroparetic patients indicates that dysmotility beyond the stomach in GP is present, and it could be contributing to symptom presentation.

Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis.

Our goal was to investigate associations between the status of interstitial cells of Cajal (ICC) and electrogastrogram (EGG) parameters, gastric emptying and symptoms in a large cohort of patients with gastroparesis. Forty-one patients with refractory gastroparesis who were referred for gastric electrical stimulation (GES) underwent full thickness gastric (antrum) biopsy during the surgery to place the GES device. The biopsy samples were stained with c-kit and scored for the presence of ICC based on criteria obtained from 10 controls. All patients underwent EGG recordings, a 4-h standardized scintigraphic gastric emptying study and symptom assessment prior to the surgery. Based on antral biopsy, 15 patients (36%) had almost no ICC (ICC- group) and 26 patients had adequate cell numbers (ICC+ group). EGG recordings in the ICC- group displayed significantly less normal slow waves than in the ICC+ group both in the fasting and fed states. Tachygastria in the ICC- group was significantly more than in the ICC+ group both in the fasting (32 +/- 8%vs 11 +/- 2%) and fed states (27 +/- 9%vs 12 +/- 2%). There was no statistical difference in gastric emptying, symptom severity of gastroparesis, aetiology, age and gender between the two groups. Severely depleted ICC occurs in up to 36% of gastroparetic patients and significantly correlates with an abnormal EGG. Severely depleted ICC does not correlate with the severity of gastroparesis as assessed by gastric emptying or symptom status but did result in a poorer symptomatic response to GES. These data suggest that the EGG may have a role for predicting ICC status during clinical evaluation of gastroparetic patients.

Mechanisms of symptomatic improvement after gastric electrical stimulation in gastroparetic patients.

The aims were to investigate the effects of gastric electrical stimulation (GES) on autonomic function, gastric distention and tone, and central control mechanisms in gastroparetic patients. Ten gastroparetic patients refractory to standard medical therapy participated in this study and data were collected at baseline, within two weeks before surgery for implantation of GES system, and at follow-up sessions between 6 and 12 weeks after GES therapy was initiated. In each session, electrocardiogram, electrogastrogram (EGG) and gastric barostat measurements were conducted before and after a caloric liquid meal. Positron Emission Tomography (PET) brain scans were performed on a separate day. During GES therapy there was a significant increase in the discomfort threshold for mean pressure from 21 mmHg at baseline to 25 mmHg at follow-up, and for mean volume from 561 mL to 713 mL. A significant increase in the postprandial EGG power (amplitude) was observed between baseline and follow up. The sympathovagal balance was significantly decreased after GES therapy, indicating a significant increase in vagal activity. The cumulative PET data showed an increase in quantitative radioactive counts relative to the standardized data base in both the thalamic and caudate nuclei after chronic GES therapy. We conclude that our data suggest that the symptomatic improvement achieved by GES in gastroparesis is best explained by activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting accompanied by enhanced vagal efferent autonomic function and decreased gastric sensitivity to volume distention which enhances postprandial gastric accommodation.

Association between changes in symptoms and gastric emptying in gastroparetic patients treated with gastric electrical stimulation.

To investigate whether there is an association between gastric emptying rate and symptom improvement in gastroparetic patients treated with gastric electrical stimulation (GES), we retrospectively reviewed 63 gastroparetic patients who received GES therapy for at least 1 year. Patient characteristics, seven upper gastrointestinal (GI) symptoms and 4-h standardized gastric emptying test (GET) were evaluated at baseline and at 1 year of GES. All symptoms were significantly reduced (P < 0.001). Mean gastric retention was reduced by 7% (P = 0.102) for measurement at 4 h. Of the 63 patients, 14 had their GET normalized and 49 remained delayed after 1 year. Normalized GET patients had a similar symptom improvement as those whose GET remained delayed. Of all upper GI symptoms, the improvements in vomiting (P = 0.04), nausea (P = 0.002) and epigastric pain (P = 0.001) were significantly correlated with reduction in 4-h gastric retention between baseline and 12 months of GES therapy for patients with normalized gastric emptying but there were no correlations with any symptoms and change in gastric emptying for those patients who remained delayed. In summary, overall gastric emptying is not significantly accelerated at 4 h after successful symptomatic improvement with GES but nausea, vomiting and epigastric pain can be correlated with normalization of GET in a subset of patients.

Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy.

Our goal was to investigate 31 adult patients (mean age 29 years, range 18-62 years) meeting Rome II criteria for cyclic vomiting syndrome (CVS). All subjects completed a clinical questionnaire, a Hamilton Rating Scale for Anxiety (HAM-A) and Zung Depression Inventory. Gastric emptying time was assessed in 30 subjects and electrogastrogram (EGG) in 11 between acute attacks. Twenty-seven patients treated with amitriptyline completed a follow-up questionnaire. The mean age of onset of the patients was 30 years (range 14-53 years) and cycles of nausea and vomiting were accompanied by often-severe epigastric and diffuse abdominal pain. A typical attack ranged from 1 to 14 days, with the majority being 4-6 days. The HAM-A revealed that 84% had an anxiety disorder, and based on Zung Depression Inventory 78% suffered from mild-to-severe depression. Only 4 (13%) patients reported migraine, but 14 had a family history of migraine. Gastric emptying time was rapid in 23 (77%), normal in 4 and delayed in 3. The EGG was abnormal in 7 of 11 patients, with 4 having tachygastria. Of 13 patients using marijuana, 7 had symptom relief, while 2 had resolution of CVS after stopping use. The overall treatment experience in the 24 patients receiving amitriptyline up to 1 mg kg(-1) day(-1) for at least 3 months indicated that 93% had decreased symptoms and 26% achieved full remission. Cyclic vomiting syndrome in adults has the following hallmarks: prominence of accompanying abdominal pain and increased prevalence of anxiety and depression, rapid gastric emptying and tachygastric EGG, and successful suppression of attacks by chronic amitriptyline therapy.