Jeffrey L. Conklin

Lactose Intolerance and the Role of the Lactose Breath Test

Lactose intolerance is a common cause of gastrointestinal symptoms in all populations worldwide. Generally, lactose intolerance is suspected in patients who develop symptoms of bloating, gas, and even diarrhea after the ingestion of lactose-containing food products. The prevalence varies by community and ethnic group. In South America, Africa, and Asia, rates of lactose intolerance exceed 50%, with some countries in Asia having a prevalence approaching 100% (1). In the United States the prevalence is reported to be 15% among Caucasians, 53% among Hispanic Americans, and 80% among Americans of African ancestry (2). Its wide epidemiologic spectrum of prevalence makes lactose intolerance a challenge to study. In addition, symptoms of lactose intolerance can be confused with functional bowel disease or even organic diseases such as inflammatory bowel disease or celiac disease. Thus, accurate diagnostic testing to identify true lactose-related symptoms and malabsorption is needed.

Gastric Electrical Stimulation with the TANTALUS® System in Obese Type 2 Diabetes Patients: Effect on Weight and Glycemic Control

Background: The TANTALUS® System is an investigational device that consists of an implantable pulse generator connected to gastric electrodes. The system is designed to automatically detect when eating starts and only then deliver sessions of gastric electrical stimulation (GES) with electrical pulses that are synchronized to the intrinsic antral slow waves. We report the effect of this type of GES on weight loss and glucose control in overweight/obese subjects with type 2 diabetes mellitus (T2DM). This study was conducted under a Food and Drug Administration/Institutional Review Board-approved investigational device exemption. Method: Fourteen obese T2DM subjects on oral antidiabetes medication were enrolled and implanted laparoscopically with the TANTALUS System (body mass index 39 ± 1 kg/m2, hemoglobin A1c [HbA1c] 8.5 ± 0.2%). Gastric electrical stimulation was initiated four weeks after implantation. Weight, HbA1c, fasting blood glucose, blood pressure, and lipid levels were assessed during the study period. Results: Eleven subjects reached the 6-month treatment period endpoint. Gastric electrical stimulation was well tolerated by all subjects. In those patients completing 6 months of therapy, HbA1c was reduced significantly from 8.5 ± 0.7% to 7.6 ± 1%, p < .01. Weight was also significantly reduced from 107.7 ± 21.1 to 102.4 ± 20.5 kg, p < .01. The improvement in glucose control did not correlate with weight loss (R 2 = 0.05, p = .44). A significant improvement was noted in blood pressure, triglycerides, and cholesterol (low-density lipoprotein only). Conclusions: Short-term therapy with the TANTALUS System improves glucose control, induces weight loss, and improves blood pressure and lipids in obese T2DM subjects on oral antidiabetes therapy.

New Clinical Method for Distinguishing D-IBS from Other Gastrointestinal Conditions Causing Diarrhea: The LA/IBS Diagnostic Strategy

Modern methods of diagnosing diarrhea-predominant irritable bowel syndrome (D-IBS) require a “diagnosis of exclusion” approach. In this study we aim to test the diagnostic ability of using the fluctuation of frequency and consistency of bowel patterns in IBS to discriminate it from other causes of diarrhea. Eligible subjects were asked to complete a questionnaire on the changes in form and frequency of bowel habits by time. The primary endpoint was to evaluate the diagnostic effectiveness of having irregularly irregular bowel function and form as more characteristic of IBS versus non-IBS causes. Patients were prospectively recruited from a tertiary care GI clinic. Subjects had to have diarrhea as their primary complaint. In the case of IBS, D-IBS subjects were recruited. Subjects with celiac disease, Crohn’s and ulcerative colitis were recruited for comparison and were categorically called “non-IBS.” Non-IBS subjects could not have a recent history of blood in stool or a history of bowel surgery, fistulae or narcotic use. Sixty-two IBS and 37 non-IBS subjects were recruited. Among the 62 IBS subjects, 49 (79%) stated that their bowel habits varied in form and frequency on a daily basis compared to 35% in non-IBS subjects (ORxa0=xa08.9,CIxa0=xa03.5–22.5, Pxa0<xa00.00001). When subjects were compared by the number of different stool forms they had witnessed in the prior week, IBS subjects noted 3.58xa0±xa00.19 types and non-IBS reported 2.35xa0±xa00.16 (Pxa0<xa00.00001). Using ≥3 stool forms per week as a method of discriminating IBS from non-IBS, 50 out of 62 subjects with IBS (81%) reported this greater number of forms compared to 15 out of 37 (41%) non-IBS subjects (sensitivityxa0=xa00.81; specificityxa0=xa00.60). The use of this simple tool that identifies an irregularly irregular bowel form and function is successful in separating D-IBS from non-IBS subjects.

Apple Sauce Improves Detection of Esophageal Motor Dysfunction During High-Resolution Manometry Evaluation of Dysphagia

BackgroundEsophageal manometry utilizes water swallows to evaluate esophageal motor abnormalities in patients with dysphagia, chest pain, or reflux symptoms. Although manometry is the gold standard for evaluation of these symptoms, patients with dysphagia often have normal results in manometry studies.AimThe objective of this work was to test the hypothesis that challenging the esophagus with viscous apple sauce boluses uncovers motor abnormalities in patients with dysphagia not seen when using water swallows.MethodsHigh-resolution esophageal manometry was performed using ten water swallows followed by ten apple sauce swallows in consecutive subjects presenting with dysphagia. Subjects with grossly abnormal water swallow evaluations were excluded. Each swallow was categorized as normal, hypotensive (distal isobaric contour plots of <30xa0mmHg over >5xa0cm), or simultaneous (distal esophageal velocity ≥8.0xa0cm/s). Ineffective esophageal motility (IEM) was defined as ≥30% hypotensive swallows, and pressurization was defined as ≥20% simultaneous pressure waves.ResultsData from 41 subjects was evaluated. Overall, 96.3% of water swallows were normal, 2.9% hypotensive, and 0.7% simultaneous. Only 70.3% of viscous swallows were normal; 16.7% were hypotensive and 13.0% were simultaneous (Pxa0<xa00.001 all groups). Seven (17.1%) met criteria for IEM, and pressurization with viscous swallows was observed for nine (22.0%). Fourteen subjects (34.1%) had abnormal results from viscous studies. The presence of any abnormal water swallows was predictive of abnormal viscous swallows (ORxa0=xa09.00, CIxa0=xa02.15–80.0), although the presence of hypotensive or simultaneous water swallows was not associated with IEM (ORxa0=xa00.63, CIxa0=xa00.16–2.17) or pressurization (ORxa0=xa07.00, CIxa0=xa00.90–315.4) with viscous apple sauce.ConclusionsApple sauce challenge increased identification of classifiable motor disorders in patients with dysphagia and may be preferred to alternative bolus materials.

Esophageal Motor Dysfunction and Gastroesophageal Reflux Are Prevalent in Lung Transplant Candidates

BACKGROUNDnGastroesophageal reflux and aspiration contribute to the development of bronchiolitis obliterans and accelerate graft deterioration after lung transplantation (LTx). We evaluated LTx candidates for esophageal motor abnormalities and gastroesophageal reflux.nnnMETHODSnConsecutive patients evaluated for LTx underwent 24-hour pH monitoring using a dual-channel pH probe and high-resolution esophageal manometry. High-resolution manometry was also performed in healthy control subjects. The prevalence of abnormal acid exposure was noted in the LTx candidates.nnnRESULTSnThirty LTx candidates and 10 control subjects were evaluated. Lung transplantation candidates had higher residual upper and lower esophageal sphincter pressures. The mean proportion of peristaltic swallows was 21% lower in LTx candidates. Both hypotensive and aperistaltic swallows were sixfold more prevalent in LTx candidates than in control subjects. All control subjects had normal high-resolution manometry whereas 23 LTx candidates (76.7%) had esophageal peristaltic dysfunction. Abnormal acid exposure time was seen in the proximal and distal esophagus in 25% and 36% of LTx candidates, respectively. Lung transplantation candidates with idiopathic pulmonary fibrosis had more aperistaltic contractions, more negative minimum intrathoracic pressure, and a higher frequency of abnormal distal esophagus acid exposure. The majority of patients with complications after LTx demonstrated motor, anatomic, or pH abnormalities.nnnCONCLUSIONSnDisordered esophageal motor function and gastroesophageal reflux are common in LTx candidates. We believe high-resolution esophageal manometry is a valid tool to use and the abnormalities we identified may be representative of this unique patient population. The role of this study in predicting a worse outcome should be further studied in patients after LTx.

Heterotopic gastric mucosa (inlet patch) in a patient with laryngopharyngeal reflux (LPR) and laryngeal carcinoma: a case report and review of literature

The inlet patch is an area of heterotopic gastric mucosa most commonly located in the postcricoid portion of the esophagus at, or just below, the level of the upper esophageal sphincter. Esophageal and supraesophageal symptoms are commonly associated with inlet patch, while esophageal adenocarcinoma rarely complicates it. Laryngeal adenocarcinoma associated with inlet patch is not described in the literature. Herein, we present the first reported case of inlet patch associated with laryngeal carcinoma. A 33-year-old female with long-standing asthma and presumed gastroesophageal reflux developed laryngeal cancer at age 22 years that was treated with concomitant radiation and induction chemotherapy. Subsequently, she had refractory heartburn, dysphagia, and cough. These symptoms continued despite two Nissen fundoplications, glottic web division, and optimal medical management. Upper endoscopy at our institution revealed an upper esophageal stricture and a 1 cm inlet patch. Biopsies showed columnar mucosa (predominantly gastric cardiac/fundic type) consistent with inlet patch, with focal intestinal metaplasia. Subsequent endoscopic mucosal resection of the inlet patch resulted in an amelioration of throat and chest pain, cough, and hoarseness. Dysphagia and regurgitation were improved by serial dilatations of the upper esophageal stricture. This case reveals a number of clinical findings associated with inlet patch--chest pain, dysphagia, cough, and hoarseness--as well as a clinical finding that has not been previously associated with inlet patch: laryngeal cancer. Symptoms refractory to optimal medical management and/or surgical intervention should make the clinician and endoscopist more cognizant of the inlet patch.

Effect of sildenafil on gastric emptying in healthy adults

Background and Aim:u2002 Phosphodiesterase type 5 hydrolyzes and inactivates cyclic guanosine monophosphate produced by the nitric oxide‐stimulated guanylate cyclase. Sildenafil is a potent, reversible, and highly selective inhibitor of this phosphodiesterase. It causes smooth muscle relaxation by increasing intracellular concentrations of cyclic guanosine monophosphate. The aim of this study was to test the hypothesis that sildenafil alters gastric emptying and the intragastric distribution of food in healthy adults.

Acute and chronic histological changes of the small bowel secondary to C. jejuni infection in a rat model for post-infectious IBS.

BackgroundCampylobacter jejuni has been implicated in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS) in humans, effects which may be because of cytolethal distending toxin (CDT). In this study, we characterized both acute and chronic-phase histological changes of the small bowel in rats exposed to wild-type C. jejuni 81-176, or a strain that does not produce CDT, by using a validated rat model of PI-IBS.MethodsSprague–Dawley rats were given 1.0xa0×xa0108xa0CFU of either wild-type C. jejuni 81-176 (C+, PI/C+) or the CDT-negative strain (CDT−), or vehicle alone (Control). Acute-phase rats (C+, CDT−) were euthanized on days 2, 4, 8, 16, and 32. Chronic-phase rats (PI/C+, Control) were euthanized 3xa0months after clearing the initial infection. Segments of duodenum, jejunum, and ileum were resected and the contents plated for C. jejuni culture, and tissue sections were stained for histology.Results We observed preferential infection of the ileum and jejunum by Campylobacter jejuni. Compared with controls, epithelial cell basal membrane ballooning, villous tip disruption, and reduced villous-to-crypt ratios were observed for both C+ and CDT− rats. Villous widening, the only result significantly different in C+ vs. CDT− rats, was greatest at day 4 (134.1xa0±xa021.12xa0μm vs. 109.9xa0±xa010.6xa0μm for CDT−, Pxa0<xa00.01). Little or no cellular inflammatory changes were seen during acute C. jejuni infection. Three months after clearing the initial infection, no histological changes remained.ConclusionSignificant histological changes, with the absence of inflammatory cells, are seen in the duodenum, jejunum, and ileum of rats during acute infection with C. jejuni. These changes occurred irrespective of the presence or absence of the CDT toxin.

Antibiotic Prophylaxis Prevents the Development of a Post-Infectious Phenotype in a New Rat Model of Post-Infectious IBS

BackgroundA recent post-infectious rat model with Campylobacter jejuni 81-176 has replicated the events noted in humans with post-infectious irritable bowel syndrome (IBS). In this study, we test whether prophylactic treatment with the antibiotic rifaximin will prevent the development of long-term altered bowel function in this model.MethodsSprague–Dawley rats were divided into two groups. Both groups were gavaged with a 1xa0mL solution of 108 cfu/mL of C. jejuni. However, one group was also prophylactically gavaged with a solution of rifaximin 200xa0mg per day for 3xa0days (the day before gavage, the day of gavage, and the day after gavage with C. jejuni). Fresh stool was collected from rats daily until two consecutive stool cultures were negative for C. jejuni. The rats were then housed for 3xa0months. At the end of 3xa0months, fresh stool was collected on three consecutive days to determine stool % wet weight and stool consistency on a stool score.ResultsRats that received rifaximin antibiotic prophylaxis had a greater rate of stool shedding of C. jejuni. However, the mean duration of colonization was shorter in the rifaximin-treated group (10.3xa0±xa07.1xa0days) compared to rats receiving no prophylaxis (12.6xa0±xa05.9xa0days) (Pxa0<xa00.01). After 3xa0months, rats that did not receive rifaximin had a greater variability in stool % wet weight (Pxa0<xa00.01). Furthermore, the average stool consistency over 3xa0days of measurement was closer to normal in the rifaximin-treated rats, with a consistency of 1.1xa0±xa00.3, compared to 1.5xa0±xa00.4 in rats receiving no prophylaxis (Pxa0<xa00.00001).ConclusionsProphylactic treatment of rats with the antibiotic rifaximin in a new animal model of post-infectious IBS with C. jejuni mitigated the development of long-term altered stool form and function.

Peroxynitrite inhibits epidermal growth factor receptor signaling in Caco-2 cells

Intestinal mucosa serves as an important barrier that may be disrupted by inflammation. A complex system of cellular and humoral factors, including epidermal growth factor (EGF), maintains the integrity of this barrier. We hypothesized that peroxynitrite, generated in inflamed intestinal epithelium, can alter the EGF receptor function by nitrating tyrosine residues and blocking ligand-activated tyrosine autophosphorylation. Caco-2 cells or A431 cell membranes were treated with peroxynitrite or its decomposed form. Cell proliferation was measured by [3H]thymidine uptake. Immunoblot and immunoprecipitation were used to assess the tyrosine phosphorylation and nitration. Binding of epidermal growth factor to its receptor was detected by affinity labeling with 125I-EGF. Peroxynitrite inhibited EGF-induced Caco-2 cell proliferation and binding of EGF to its receptor in a concentration-dependent manner. Peroxynitrite abolished EGF-stimulated receptor autophosphorylation and nitrated EGF receptor tyrosine residues. Peroxynitrite generated during inflammation may disrupt the EGF-induced signaling in intestinal epithelial cells.