The Effect of Isoleucine Supplementation on Body Weight Gain and Blood Glucose Response in Lean and Obese Mice.

Chronic isoleucine supplementation prevents diet-induced weight gain in rodents. Acute-isoleucine administration improves glucose tolerance in rodents and reduces postprandial glucose levels in humans. However, the effect of chronic-isoleucine supplementation on body weight and glucose tolerance in obesity is unknown. This study aimed to investigate the impact of chronic isoleucine on body weight gain and glucose tolerance in lean and high-fat-diet (HFD) induced-obese mice. Male C57BL/6-mice, fed a standard-laboratory-diet (SLD) or HFD for 12 weeks, were randomly allocated to: (1) Control: Drinking water; (2) Acute: Drinking water with a gavage of isoleucine (300 mg/kg) prior to the oral-glucose-tolerance-test (OGTT) or gastric-emptying-breath-test (GEBT); (3) Chronic: Drinking water with 1.5% isoleucine, for a further six weeks. At 16 weeks, an OGTT and GEBT was performed and at 17 weeks metabolic monitoring. In SLD- and HFD-mice, there was no difference in body weight, fat mass, and plasma lipid profiles between isoleucine treatment groups. Acute-isoleucine did not improve glucose tolerance in SLD- or HFD-mice. Chronic-isoleucine impaired glucose tolerance in SLD-mice. There was no difference in gastric emptying between any groups. Chronic-isoleucine did not alter energy intake, energy expenditure, or respiratory quotient in SLD- or HFD-mice. In conclusion, chronic isoleucine supplementation may not be an effective treatment for obesity or glucose intolerance.

Characterization of Upper Gastrointestinal Motility in Infants With Persistent Distress and Non-IgE-mediated Cow's Milk Protein Allergy.

BACKGROUND: Persistent crying in infancy is common and may be associated with gastroesophageal reflux disease (GERD) and/or non-IgE-mediated cow's milk protein allergy (CMPA). We aimed to document upper gastrointestinal motility events in infants with CMPA and compare these to findings in infants with functional GERD. METHODS: Infants aged 2 to 26 weeks with persistent crying, GERD symptoms and possible CMPA were included. Symptoms were recorded by 48-hour cry-fuss chart and validated reflux questionnaire (infant GERD questionnaire [IGERDQ]). Infants underwent a blinded milk elimination-challenge sequence to diagnose CMPA. GERD parameters and mucosal integrity were assessed by 24-hour pH-impedance monitoring before and after cow's milk protein (CMP) elimination. C-octanoate breath testing for gastric emptying dynamics, dual-sugar intestinal permeability, fecal calprotectin, and serum vitamin D were also measured. RESULTS: Fifty infants (mean age 13 ±â€Š7 weeks; 27 boys) were enrolled. On the basis of CMP elimination-challenge outcomes, 14 (28%) were categorized as non-IgE-mediated CMPA, and 17 (34%) were not allergic to milk; 12 infants with equivocal findings, and 7 with incomplete data were excluded. There were no baseline differences in GERD parameters between infants with and without CMPA. In the CMPA group, CMP elimination resulted in a significant reduction in reflux symptoms, esophageal acid exposure (reflux index), acid clearance time, and an increase in esophageal mucosal impedance. CONCLUSIONS: In infants with persistent crying, upper gastrointestinal motility parameters did not reliably differentiate between non-IgE-mediated CMPA and functional GERD. In the group with non-IgE-mediated CMPA, elimination of CMP significantly improved GERD symptoms, esophageal peristaltic function, and mucosal integrity.

Chronic stress induces hypersensitivity of murine gastric vagal afferents.

BACKGROUND: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. METHODS: Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. KEY RESULTS: The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. CONCLUSIONS AND INFERENCES: In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.

A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function.

KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach, respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. ABSTRACT: Tenascin-X (TNX) is a glycoprotein that regulates tissue structure via anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers-Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB-deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved using GABAB agonists.

Age-related impairment of esophagogastric junction relaxation and bolus flow time.

AIM: To investigate the functional effects of abnormal esophagogastric (EGJ) measurements in asymptomatic healthy volunteers over eighty years of age. METHODS: Data from 30 young controls (11 M, mean age 37 ± 11 years) and 15 aged subjects (9 M, 85 ± 4 years) were compared for novel metrics of EGJ-function: EGJ-contractile integral (EGJ-CI), "total" EGJ-CI and bolus flow time (BFT). Data were acquired using a 3.2 mm, 25 pressure (1 cm spacing) and 12 impedance segment (2 cm) solid-state catheter (Unisensor and MMS Solar GI system) across the EGJ. Five swallows each of 5 mL liquid (L) and viscous (V) bolus were analyzed. Mean values were compared using Student's t test for normally distributed data or Mann Whitney U-test when non-normally distributed. A P value < 0.05 was considered significant. RESULTS: EGJ-CI at rest was similar for older subjects compared to controls. "Total" EGJ-CI, measured during liquid swallowing, was increased in older individuals when compared to young controls (O 39 ± 7 mmHg.cm vs C 18 ± 3 mmHg.cm; P = 0.006). For both liquid and viscous bolus consistencies, IRP4 was increased (L: 11.9 ± 2.3 mmHg vs 5.9 ± 1.0 mmHg, P = 0.019 and V: 14.3 ± 2.4 mmHg vs 7.3 ± 0.8 mmHg; P = 0.02) and BFT was reduced (L: 1.7 ± 0.3 s vs 3.8 ± 0.2 s and V: 1.9 ± 0.3 s vs 3.8 ± 0.2 s; P < 0.001 for both) in older subjects, when compared to young. A matrix of bolus flow and presence above the EGJ indicated reductions in bolus flow at the EGJ occurred due to both impaired bolus transport through the esophageal body (i.e., the bolus never reached the EGJ) and increased flow resistance at the EGJ (i.e., the bolus retained just above the EGJ). CONCLUSION: Bolus flow through the EGJ is reduced in asymptomatic older individuals. Both ineffective esophageal bolus transport and increased EGJ resistance contribute to impaired bolus flow.

Laparoscopic Adjustable Gastric Banding in Australian Adolescents: Should It Be Done?

OBJECTIVE: There are very few studies on laparoscopic adjustable gastric banding (LAGB) in obese adolescents with follow up for more than 36 months, let alone good prospective data beyond 24 months in Australian adolescents. We aimed to evaluate medium term (>36 months) safety and efficacy of LAGB in adolescents with severe obesity. METHODS: This is a prospective cohort study (March 2009-December 2015) in one tertiary referral hospital including obese adolescents (14-18 years) with a body mass index (BMI) >40 (or ≥35 with comorbidities) who consented to have LAGB. Exclusion criteria were syndromal causes of obesity, depression and oesophageal motility disorders. Main outcome measures include change in weight and BMI at 6, 12, 24, 36 and 48 months post LAGB; postoperative complications; and admissions. RESULTS: Twenty-one adolescents (median [interquartile range (IQR)] 17.4 [16.5-17.7] years, 9 males, mean ± SD BMI 47.3 ± 8.4 kg/m2) had a median follow up of 45.5 [32-50] months post LAGB. Follow up data were available for 16 adolescents. Weight and BMI improved significantly at all follow up times (all p < 0.01). The median maximum BMI loss was 10 [7.1-14.7] kg/m2. There were four minor early complications. Seven bands were removed due to weight loss failure/regain (two had also obstructive symptoms). CONCLUSIONS: We have shown in the longest prospective LAGB postoperative follow up study of Australian adolescents that LAGB improves BMI in the majority of adolescents without significant comorbidities. LAGB is still a reasonable option to be considered as a temporary procedure to manage severe obesity during adolescence.

Pressure-Flow Analysis for the Assessment of Pediatric Oropharyngeal Dysphagia.

OBJECTIVES: To determine which objective pressure-impedance measures of pharyngeal swallowing function correlated with clinically assessed severity of oropharyngeal dysphagia (OPD) symptoms. STUDY DESIGN: Forty-five children with OPD and 34 control children without OPD were recruited and up to 5 liquid bolus swallows were recorded with a solid-state high-resolution manometry with impedance catheter. Individual measures of pharyngeal and upper esophageal sphincter (UES) function and a swallow risk index composite score were derived for each swallow, and averaged data for patients with OPD were compared with those of control children without OPD. Clinical severity of OPD symptoms and oral feeding competency was based on the validated Dysphagia Disorders Survey and Functional Oral Intake Scale. RESULTS: Those objective measures that were markers of UES relaxation, UES opening, and pharyngeal flow resistance differentiated patients with and without OPD symptoms. Patients demonstrating abnormally high pharyngeal intrabolus pressures and high UES resistance, markers of outflow obstruction, were most likely to have signs and symptoms of overt Dysphagia Disorders Survey (OR 9.24, P = .05, and 9.7, P = .016, respectively). CONCLUSION: Pharyngeal motor patterns can be recorded in children by the use of HRIM and pharyngeal function can be defined objectively with the use of pressure-impedance measures. Objective measurements suggest that pharyngeal dysfunction is common in children with clinical signs of OPD. A key finding of this study was evidence of markers of restricted UES opening.

Preliminary report of the (13)C-mixed triglyceride breath test to assess timing of pancreatic enzyme replacement therapy in children with cystic fibrosis.

BACKGROUND: Despite guidelines suggesting pancreatic enzyme replacement therapy (PERT) should be taken before or during a meal, it is currently unknown whether this has benefits over administration after a meal in individuals with cystic fibrosis (CF). METHODS: 18 children with pancreatic insufficient CF were randomised to two (13)C-mixed triglyceride ((13)C-MTG) breath tests to assess lipase activity with PERT administered 10min before and 10min after a meal. Results were expressed as percentage cumulative dose recovered (PCDR) of (13)CO2 and were compared with established values in healthy subjects. Gastric half emptying time (T½) was also assessed by a (13)C-octanoate breath test. RESULTS: There was no difference in mean PCDR of (13)CO2 between taking PERT before versus after the meal (p=0.68). Eleven subjects had a greater PCDR when PERT was taken before and 7 when PERT was taken after the meal. 6/8 subjects (75%) with a lower than normal PCDR at one time point normalised PCDR when PERT timing was changed. When PERT was taken after the meal, PCDR was higher in normal vs. fast T½ (p=0.04). CONCLUSIONS: Changing PERT timing can result in normalised lipase activity. Gastric emptying rate may influence optimal timing of PERT. Clinical Trial Registration Number - This study was undertaken prior to the registration process being a commonly required practice.

Systematic review of the impact of feed protein type and degree of hydrolysis on gastric emptying in children.

BACKGROUND: The choice of infant formula is thought to play an important role on gastric emptying (GE) in a variety of gastrointestinal disorders. It is known that many ingredients impact on GE, including the type of protein and level of hydrolysis. In clinical practice, feeds are often recommended due to putative improved GE related to the type of protein and level of hydrolysis, however whether this is scientifically justified still needs to be established. A systematic review comparing the impact of protein type and hydrolysis on GE in children was therefore performed. METHODS: The Patient, Intervention, Comparison and Outcome system was used. A structured literature search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, searching PubMed, Cochrane databases and Google Scholar from 1990 to 2014. We only included articles published in full text English language using specific search terms, including both scintigraphy and C13-octanoic acid breath test. RESULTS: We identified 126 publications of which 20 were eligible for inclusion but only 8 were included. Studies reviewed GE in both healthy children as well as those with neurodevelopmental delay and reflux. Two studies investigating GE of breast milk versus formula indicated a faster GE for breast milk. Four studies found that feeds containing whole whey in varying amounts emptied faster than predominant whole casein feeds and one study found no difference in GE. Five studies investigated a mix of whole versus hydrolysed protein and found conflicting results related to study population and hydrolysis. CONCLUSIONS: Breast milk has a faster GE than formula milk. Although there seems to be a trend towards whey feeds emptying faster, different methodologies, feed compositions and patient groups makes it difficult to draw firm conclusions. Future studies should be performed with comparable feeds in populations where increased GE may be of clinical benefit.

TRPV1 Channels and Gastric Vagal Afferent Signalling in Lean and High Fat Diet Induced Obese Mice.

AIM: Within the gastrointestinal tract vagal afferents play a role in control of food intake and satiety signalling. Activation of mechanosensitive gastric vagal afferents induces satiety. However, gastric vagal afferent responses to mechanical stretch are reduced in high fat diet mice. Transient receptor potential vanilloid 1 channels (TRPV1) are expressed in vagal afferents and knockout of TRPV1 reduces gastro-oesophageal vagal afferent responses to stretch. We aimed to determine the role of TRPV1 on gastric vagal afferent mechanosensitivity and food intake in lean and HFD-induced obese mice. METHODS: TRPV1+/+ and -/- mice were fed either a standard laboratory diet or high fat diet for 20wks. Gastric emptying of a solid meal and gastric vagal afferent mechanosensitivity was determined. RESULTS: Gastric emptying was delayed in high fat diet mice but there was no difference between TRPV1+/+ and -/- mice on either diet. TRPV1 mRNA expression in whole nodose ganglia of TRPV1+/+ mice was similar in both dietary groups. The TRPV1 agonist N-oleoyldopamine potentiated the response of tension receptors in standard laboratory diet but not high fat diet mice. Food intake was greater in the standard laboratory diet TRPV1-/- compared to TRPV1+/+ mice. This was associated with reduced response of tension receptors to stretch in standard laboratory diet TRPV1-/- mice. Tension receptor responses to stretch were decreased in high fat diet compared to standard laboratory diet TRPV1+/+ mice; an effect not observed in TRPV1-/- mice. Disruption of TRPV1 had no effect on the response of mucosal receptors to mucosal stroking in mice on either diet. CONCLUSION: TRPV1 channels selectively modulate gastric vagal afferent tension receptor mechanosensitivity and may mediate the reduction in gastric vagal afferent mechanosensitivity in high fat diet-induced obesity.

High-resolution manometry combined with impedance measurements discriminates the cause of dysphagia in children.

Pressure-flow analysis allows assessing esophageal bolus transport in relation to esophageal pressures. This study aimed to characterize pressure-flow metrics in relation to dysphagia in paediatric patients. We analysed esophageal pressure-impedance recordings of 5 ml liquid and viscous swallows from 35 children (17 M, mean 10.5 ± 0.8 years). Primary indication for referral was gastroesophageal reflux disease (GERD) (9), post-fundoplication dysphagia (5), idiopathic dysphagia (16), trachea-esophageal fistula (2) and other (3). Peristaltic function was assessed using the 20 mmHg iso-contour defect and the timing between bolus pressure and flow was assessed using the Pressure Flow Index, a metric elevated in relation to dysphagia. Patients were stratified in relation to dysphagia and to peristaltic defect size. Dysphagia was characterized by a weaker peristalsis for liquids and higher Pressure Flow Index for viscous. When patients were stratified based on weak or normal peristalsis, dysphagia with weak peristalsis related to a larger iso-contour defect size and dysphagia with normal peristalsis related to higher Pressure Flow Index. CONCLUSION: Pressure-flow analysis enables differentiation of patients with dysphagia due to weak peristalsis (poor bolus clearance) from abnormal bolus flow resistance (esophageal outflow obstruction). This new dichotomous categorization of esophageal function may help guide the selection of optimal treatment such as pharmacological or endoscopic therapy. WHAT IS KNOWN: • Pressure-flow analysis (PFA) can detect abnormalities in esophageal motility using integrated analysis of bolus propulsion and bolus flow during swallowing. • AIM analysis has recently been reported to be useful in identifying subtle pre-operative esophageal dysfunction in adult patients who developed post-fundoplication dysphagia as well as in patients with non-obstructive dysphagia. WHAT IS NEW: • Pressure-flow parameters can distinguish the cause of dysphagia in paediatric patients. • Combined high-resolution manometry and impedance measurements with pressure-flow analysis can differentiate paediatric patients with dysphagia symptoms in relation to either weak peristalsis (poor bolus clearance) or over-pressurization (abnormal bolus flow resistance). HOW MIGHT IT IMPACT ON CLINICAL PRACTICE IN THE FUTURE? • This study supports the use of a novel objective analysis method on recordings that are readily used in paediatric clinical practice. • The pressure-flow approach allows discriminating esophageal dysfunction in relation to dysphagia symptoms in children. This has not been achieved in children with current analysis methods. • The new findings of this study allow a dichotomous categorization of esophageal function, which may help to guide the selection of the most optimal treatment such as pharmacological or endoscopic therapy.

Gastric Emptying Is More Rapid in Adolescents With Type 1 Diabetes and Impacts on Postprandial Glycemia.

CONTEXT: Gastric emptying is a critical determinant of postprandial glycemic control in health and type 1 diabetes. There are few studies that assess the relationship between gastric emptying and postprandial glycaemia in adolescents with type 1 diabetes. OBJECTIVE: The objectives of the study were to quantify gastric emptying in adolescents with type 1 diabetes and examine its relationship to postprandial glycaemia and autonomic function. DESIGN: This was a case-control study. Gastric half-emptying time of a solid meal was measured by a (13)C-octanoate breath test. Cardio-autonomic function was measured by heart rate variability. Chronic and postprandial gastrointestinal symptoms were evaluated by questionnaire and visual analog scales. Blood glucose concentrations were monitored frequently during the study. SETTING: The study was conducted at a tertiary pediatric hospital in South Australia. PARTICIPANTS: Thirty adolescents (aged 15 ± 2.5 y) with type 1 diabetes and age- and sex-matched controls (gastric emptying, n = 20; heart rate variability, n = 135) participated in the study. MAIN OUTCOME: Gastric half-emptying time was the main outcome in the study. RESULTS: Gastric emptying was more rapid in subjects with type 1 diabetes than controls [median half emptying time 78 (interquartile range 61-99) vs 109 (interquartile range 71-124) min, P = .02]. The postprandial rise in blood glucose at 60 minutes was strongly related to gastric half-emptying time (R = -0.65, P = .0001). Gastric emptying was slower in subjects with fasting hyperglycemia but was not related to heart rate variability. Nausea, bloating, and anxiety were related to fasting glycemia (P = .03). CONCLUSION: Rapid gastric emptying is a major determinant of postprandial glycemia in adolescents with type 1 diabetes. This observation has significant implications for therapy.

Herbal substance, acteoside, alleviates intestinal mucositis in mice.

This study investigated the role of acteoside in the amelioration of mucositis. C57BL/6 mice were gavaged daily with acteoside 600 µg for 5 d prior to induction of mucositis and throughout the experimental period. Mucositis was induced by methotrexate (MTX; 12.5 mg/kg; s.c.). Mice were culled on d 5 and d 11 after MTX. The duodenum, jejunum, and ileum were collected for myeloperoxidase (MPO) activity, metallothionein (MT) levels, and histology. Acteoside reduced histological severity scores by 75, 78, and 88% in the duodenum, jejunum, and ileum, respectively, compared to MTX-controls on d 5. Acteoside reduced crypt depth by 49, 51, and 33% and increased villus height by 19, 38, and 10% in the duodenum, jejunum, and ileum, respectively, compared to MTX-controls on d 5. Acteoside decreased MT by 50% compared to MTX-control mice on d 5. Acteoside decreased MPO by 60% and 30% in the duodenum and jejunum, respectively, compared to MTX-controls on d 5. Acteoside alleviated MTX-induced small intestinal mucositis possibly by preventing inflammation.

Pressure-flow characteristics of normal and disordered esophageal motor patterns.

OBJECTIVE: To perform pressure-flow analysis (PFA) in a cohort of pediatric patients who were referred for diagnostic manometric investigation. STUDY DESIGN: PFA was performed using purpose designed Matlab-based software. The pressure-flow index (PFI), a composite measure of bolus pressurization relative to flow and the impedance ratio, a measure of the extent of bolus clearance failure were calculated. RESULTS: Tracings of 76 pediatric patients (32 males; 9.1 ± 0.7 years) and 25 healthy adult controls (7 males; 36.1 ± 2.2 years) were analyzed. Patients mostly had normal motility (50%) or a category 4 disorder and usually weak peristalsis (31.5%) according to the Chicago Classification. PFA of healthy controls defined reference ranges for PFI ≤142 and impedance ratio ≤0.49. Pediatric patients with pressure-flow (PF) characteristics within these limits had normal motility (62%), most patients with PF characteristics outside these limits also had an abnormal Chicago Classification (61%). Patients with high PFI and disordered motor patterns all had esophagogastric junction outflow obstruction. CONCLUSIONS: Disordered PF characteristics are associated with disordered esophageal motor patterns. By defining the degree of over-pressurization and/or extent of clearance failure, PFA may be a useful adjunct to esophageal pressure topography-based classification.

Body positioning and medical therapy for infantile gastroesophageal reflux symptoms.

OBJECTIVE: Proton-pump inhibitors (PPIs) reduce acid gastroesophageal reflux (GER) and esophageal acid exposure in infants; however, they do not reduce total GER or symptoms attributed to GER. Reflux is reduced in the left lateral position (LLP). We hypothesize that the effect of LLP in combination with acid suppression is most effective in reducing GER symptoms in infants. METHODS: In this prospective sham-controlled trial, infants (0-6 months) with symptoms suggestive of gastroesophageal reflux disease were studied using 8-hour pH-impedance, cardiorespiratory and video monitoring, direct nurse observation, and a validated questionnaire. Infants demonstrating a positive GER symptom association were randomized to 1 of 4 groups; PPI + LLP, PPI + head of cot elevation (HE), antacid (AA) + LLP, or AA + HE. HE and AA were considered "sham" therapies. After 2 weeks the 8-hour studies were repeated on-therapy. RESULTS: Fifty-one patients were included (aged 13.6 [2-26] weeks). PPI + LLP was most effective in reducing GER episodes (69 [13] to 46 [10], P < 0.001) and esophageal acid exposure (median [interquartile range] 8.9% [3.1%-18.1%] to 1.1% [0%-4.4%], P = 0.02). No treatment group showed improvement in crying/irritability, although vomiting was reduced in AA + LLP (from 7 [2] to 2 [0] episodes P = 0.042). LLP compared with HE produced greater reduction in total GER (-21 [4] vs -10 [4], P = 0.056), regardless of acid-suppressive therapy. Acid exposure was reduced on PPI compared with AA (-6.8 [2.1] vs -0.9 [1.4]%, pH < 4, P = 0.043) regardless of positional intervention. A post-hoc analysis using automated analysis software revealed a significant reduction in crying symptoms in the PPI + LLP group (99 [65-103] to 62 [32-96] episodes, P = 0.018). CONCLUSIONS: "Symptomatic gastroesophageal reflux disease" implies disease causation for distressing infant symptoms. In infants with symptoms attributed to GER, LLP produced a significant reduction in total GER, but did not result in a significant improvement in symptoms other than vomiting; however, automated analysis appeared to identify infants with GER-associated crying symptoms who responded to positioning therapy. This is an important new insight for future research.

Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: a randomized crossover trial.

CONTEXT: Cystic fibrosis-related diabetes is characterized by postprandial, rather than fasting, hyperglycemia. Gastric emptying and the release of the incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP)] are central to postprandial glycemic control. Lipolysis is required for fat to slow gastric emptying and stimulate incretin release. OBJECTIVE: We aimed to determine the effect of pancreatic enzyme replacement therapy (PERT) on postprandial glycemia in adolescents with cystic fibrosis (CF). DESIGN: This was a double-blinded randomized crossover trial. Subjects consumed a high-fat pancake, with either PERT (50 000 IU lipase) or placebo. Gastric emptying was measured by a breath test and blood sampled frequently for plasma blood glucose, insulin, glucagon, GLP-1, and GIP. Data were also compared with seven healthy subjects. PARTICIPANTS: Fourteen adolescents (13.1 ± 2.7 y) with pancreatic-insufficient CF and seven healthy age-matched controls participated in the study. MAIN OUTCOME MEASURE: Postprandial hyperglycemia was measured as peak glucose and area under the curve for blood glucose at 240 minutes. RESULTS: CF subjects had postprandial hyperglycemia compared with controls (area under the curve, P < .0001). PERT reduced postprandial hyperglycemia (P = .0002), slowed gastric emptying (P = .003), and normalized GLP-1 and GIP secretion (P < .001 for each) when compared with placebo, without affecting insulin. CONCLUSION: In young people with pancreatic insufficient CF, PERT markedly attenuates postprandial hyperglycemia by slowing gastric emptying and augmenting incretin hormone secretion.

Oesophageal pressure-flow metrics in relation to bolus volume, bolus consistency, and bolus perception.

BACKGROUND: The utility of combined oesophageal pressure-impedance recording has been enhanced by automation of data analysis. OBJECTIVE: To understand how oesophageal function as measured by automated impedance manometry (AIM) pressure-flow analysis varies with bolus characteristics and subjective perception of bolus passage. METHODS: Oesophageal pressure-impedance recordings of 5 and 10 ml liquid or viscous swallows and 2 and 4 cm solid swallows from 20 healthy control subjects (five male; 25-73 years) were analysed. Metrics indicative of bolus pressurization (intrabolus pressure and intrabolus pressure slope) were derived. Bolus flow resistance, the relationship between bolus pressurization and flow timing, was assessed using a pressure-flow index. Bolus retention was assessed using the ratio of nadir impedance to peak pressure impedance (impedance ratio). Subjective perception of bolus passage was assessed swallow by swallow. RESULTS: Viscosity increased the bolus flow resistance and reduced bolus clearance. Responses to boluses of larger volume and more viscous consistency revealed a positive correlation between bolus pressurization and oesophageal peak pressure. Flow resistance was higher in subjects who perceived bolus hold up of solids. CONCLUSIONS: Bolus volume and bolus type alter oesophageal function and impact AIM analysis metrics descriptive of oesophageal function. Perception of bolus transit was associated with heightened bolus pressurization relative to bolus flow.

Whey- vs casein-based enteral formula and gastrointestinal function in children with cerebral palsy.

OBJECTIVES: Children with severe cerebral palsy (CP) commonly have gastrointestinal (GI) dysfunction. Whey-based enteral formulas have been postulated to reduce gastroesophageal reflux (GOR) and accelerate gastric emptying (GE). The authors investigated whether whey-based (vs casein-based) enteral formulas reduce GOR and accelerate GE in children who have severe CP with a gastrostomy and fundoplication. METHODS: Thirteen children received a casein-based formula for 1 week and either a 50% whey whole protein (50% WWP) or a 100% whey partially hydrolyzed protein (100% WPHP) formula for 1 week. Reflux episodes, gastric half-emptying time (GE t(1/2)), and reported pain and GI symptoms were measured. RESULTS: Whey formulas emptied significantly faster than casein (median [interquartile range (IQR)] GE t(1/2), 33.9 [25.3-166.2] min vs 56.6 [46-191] min; P = .033). Reflux parameters were unchanged. GI symptoms were lower in children who received 50% WWP (visual analog symptom score, median [IQR], 0 [0-11.8]) vs 100% WPHP (13.0 [2.5-24.8]) (P = .035). CONCLUSION: This pilot study shows that in children who have severe CP with a gastrostomy and fundoplication, GE of the whey-based enteral formula is significantly faster than casein. The acceleration in GE does not alter GOR frequency, and there appears to be no effect of whey vs casein in reducing acid, nonacid, and total reflux episodes. The results indicate that enteral formula selection may be particularly important for children with severe CP and delayed GE.

Optimisation of the reflux-symptom association statistics for use in infants being investigated by 24-hour pH impedance.

BACKGROUND AND AIM: pH-impedance monitoring is used to diagnose symptomatic gastroesophageal reflux (GER) based on symptom association probability (SAP). Current criteria for calculation of SAP are optimised for heartburn in adults. Infants, however, demonstrate a different symptom profile. The aim of the present study was to optimise criteria for calculation of SAP in infants with GER disease. PATIENTS AND METHODS: Ten infants referred for investigation of symptomatic reflux were enrolled. GER episodes were recorded using a pH-impedance probe, which remained in place for 48 hours. During the test, cough, crying, and regurgitation were marked. Impedance recordings were analysed for the occurrence of bolus reflux episodes. SAP for behaviors following reflux episodes was separately calculated for day 1 and day 2 using automated reporting software, which enabled the time window used for SAP calculations to be modified from 15 to 600 seconds. Day-to-day agreement of SAP was assessed by calculating the 95% limits of agreement (mean difference ± 1.96 standard deviations of differences) and their confidence intervals. RESULTS: The number of bolus GER episodes and symptom episodes reported did not differ from day to day. The best agreement in SAP between the 2 days was found using time intervals of 2 minutes for cough, 5 minutes for crying, and 15 seconds and/or 2 to 5 minutes for regurgitation. CONCLUSIONS: We conclude that the standard 2-minute time interval is appropriate for the investigation of cough and regurgitation symptoms. The day-to-day agreement of SAP for crying was poor using standard criteria, and our results suggest increasing the reflux-symptom association time interval to 5 minutes.