Hypomorphic SI genetic variants are associated with childhood chronic loose stools.

OBJECTIVE: The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. METHODS: A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. RESULTS: Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). CONCLUSION: Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

Efficacy and Safety of Carbon Dioxide Versus Air Insufflation for Colonoscopy in Deeply Sedated Pediatric Patients.

OBJECTIVES: Studies have shown the advantages of carbon dioxide (CO2) over air insufflation in the adult population during colonoscopies. This study was designed to investigate the efficacy and safety of CO2 insufflation in deeply sedated children undergoing colonoscopy. METHODS: This was a prospective, randomized, double-blind clinical trial. We recruited 100 consecutive pediatric patients who had colonoscopy under deep sedation for various indications. Patients were first randomized by history of abdominal pain and then randomly assigned to either CO2 or air insufflation. Postprocedural abdominal pain scores were registered on a 10-point visual analog rating scale and significant pain was defined as a score of 3 or higher. Abdominal circumferences and end tidal CO2 (ETCO2) levels were measured. Complications during and after the procedure were recorded. RESULTS: We did not find statistically significant difference between CO2 and air insufflation on univariate analysis because of low number of children experiencing significant pain after colonoscopy. After adjusting for baseline pain, we found that pain was significantly lower in patients after CO2 versus air insufflation on multivariable analysis (P = 0.03). The significant factors related to pain were duration of the procedure (P = 0.006), history of abdominal pain (P = 0.002) and previous abdominal surgery (P = 0.02). CO2 insufflation was associated with decreased abdominal circumference after colonoscopy (P = 0.002). Girls were more likely to have pain regardless of intervention (P = .04). CONCLUSIONS: Most children tolerate endoscopic procedures without significant pain. Our study was underpowered to show significant difference between air and CO2 on univariate analysis. CO2 insufflation during colonoscopy, however, may reduce postprocedural abdominal pain. Significant factors for increased pain on multivariate analysis included colonoscopy length over 30 minutes, history of abdominal pain, and previous abdominal surgery.

Nausea exacerbates symptom burden, quality of life, and functioning in adolescents with functional abdominal pain disorders.

BACKGROUND: Nausea frequently co-exists with functional abdominal pain disorders (FAPDs) and may be linked to a higher disease burden. This study aimed to prospectively compare multisystem symptoms, quality of life, and functioning in FAPDs with and without nausea. METHODS: Adolescents ages 11-18 years fulfilling Rome III criteria for a FAPD were grouped by the presence or absence of chronic nausea. Subjects completed validated instruments assessing nausea (Nausea Profile Questionnaire = NPQ), quality of life (Patient-Reported Outcome Measurement Information System), functioning (Functional Disability Inventory), and anxiety (State-Trait Anxiety Inventory for Children). Group comparisons were performed for instruments, multisystem symptoms, school absences, and clinical diagnoses. KEY RESULTS: A total of 112 subjects were included; 71% reported chronic nausea. Patients with Nausea compared to No Nausea had higher NPQ scores (P ≤ 0.001), worse quality of life (P = 0.004), and greater disability (P = 0.02). State and trait anxiety scores were similar (P = 0.57, P = 0.25). A higher NPQ score correlated with poorer quality of life, more disability, and higher anxiety. Specific comorbidities were more common in Nausea vs No Nausea group: dizziness (81% vs 41%; P ≤ 0.001), concentrating difficulties (68% vs 27%; P ≤ 0.001), chronic fatigue (58% vs 20%; P = 0.01), and sleep disturbances (73% vs 48%; P = 0.02). The Nausea group reported more school absences (P = 0.001) and more commonly met criteria for functional dyspepsia (P = 0.034). CONCLUSION AND INFERENCES: Nausea co-existing with FAPDs is associated with a higher extra-intestinal symptom burden, worse quality of life, and impaired functioning in children. Assessing and targeting nausea therapeutically is essential to improve outcomes in FAPDs.

Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment.

BACKGROUND: Finding an effective, non-pharmacological approach to treat opioid withdrawal could remove some of the barriers associated with pharmacotherapy. The BRIDGE® is a noninvasive, percutaneous electrical nerve field stimulator developed to target pain. OBJECTIVES: This pilot study aimed to determine (1) the effects of the BRIDGE on withdrawal scores during the induction phase of opioid withdrawal therapy, (2) the percentage of subjects who successfully transitioned to medication assisted therapy (MAT). METHODS: Adult patients treated with the BRIDGE during medically supervised withdrawal were included in this open label, uncontrolled, and retrospective study. The clinical opioid withdrawal scale (COWS) scores were prospectively recorded at different intervals (20, 30, and 60 min) and analyzed retrospectively. A subset of patients had scores recorded 5-days post-BRIDGE. Those who returned to the clinic and received their first dose of maintenance medication were considered to be successfully transitioned. RESULTS: In this cohort (n=73), 65% were male. The mean COWS score prior to BRIDGE placement was 20.1 (±6.1). Twenty minutes after BRIDGE placement, the mean score was reduced to 7.5 (±5.9) (62.7% reduction, p<0.001). The scores further decreased after 30 minutes 4.0 (±4.4) and 60 minutes 3.1 (±3.4) (84.6% reduction, p<0.001). No rescue medications were administered during this period. The mean withdrawal score on day 5 was 0.6 (97.1% reduction, p<0.001) (n=33). Overall, 64/73 patients (88.8%) successfully transitioned to MAT. CONCLUSIONS: Neurostimulation with the BRIDGE is associated with a reduction in opioid withdrawal scores. This effect persisted during the induction period and allowed for effective transition to MAT.

Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial.

BACKGROUND: Development of safe and effective therapies for paediatric abdominal pain-related functional gastrointestinal disorders is needed. A non-invasive, US Food and Drug Administration-cleared device (Neuro-Stim, Innovative Health Solutions, IN, USA) delivers percutaneous electrical nerve field stimulation (PENFS) in the external ear to modulate central pain pathways. In this study, we evaluated the efficacy of PENFS in adolescents with abdominal pain-related functional gastrointestinal disorders. METHODS: In this randomised, sham-controlled trial, we enrolled adolescents (aged 11-18 years) who met Rome III criteria for abdominal pain-related functional gastrointestinal disorders from a single US outpatient gastroenterology clinic. Patients were randomly assigned (1:1) with a computer-generated randomisation scheme to active treatment or sham (no electrical charge) for 4 weeks. Patients were stratified by sex and presence or absence of nausea. Allocation was concealed from participants, caregivers, and the research team. The primary efficacy endpoint was change in abdominal pain scores. We measured improvement in worst abdominal pain and composite pain score using the Pain Frequency-Severity-Duration (PFSD) scale. Participants with less than 1 week of data and those with organic disease identified after enrolment were excluded from the modified intention-to-treat population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT02367729. FINDINGS: Between June 18, 2015, and Nov 17, 2016, 115 children with abdominal pain-related functional gastrointestinal disorders were enrolled and assigned to either PENFS (n=60) with an active device or sham (n=55). After exclusion of patients who discontinued treatment (n=1 in the PENFS group; n=7 in the sham group) and those who were excluded after randomisation because they had organic disease (n=2 in the PENFS group; n=1 in the sham group), 57 patients in the PENFS group and 47 patients in the sham group were included in the primary analysis. Patients in the PENFS group had greater reduction in worst pain compared with sham after 3 weeks of treatment (PENFS: median score 5·0 [IQR 4·0-7·0]; sham: 7·0 [5·0-9·0]; least square means estimate of change in worse pain 2·15 [95% CI 1·37-2·93], p<0·0001). Effects were sustained for an extended period (median follow-up 9·2 weeks [IQR 6·4-13·4]) in the PENFS group: median 8·0 (IQR 7·0-9·0) at baseline to 6·0 (5·0-8·0) at follow-up versus sham: 7·5 (6·0-9·0) at baseline to 7·0 (5·0-8·0) at follow-up (p<0·0001). Median PFSD composite scores also decreased significantly in the PENFS group (from 24·5 [IQR 16·8-33.3] to 8·4 [3·2-16·2]) compared with sham (from 22·8 [IQR 8·4-38·2] to 15·2 [4·4-36·8]) with a mean decrease of 11·48 (95% CI 6·63-16·32; p<0·0001) after 3 weeks. These effects were sustained at extended follow-up in the PENFS group: median 24·5 (IQR 16·8-33·3) at baseline to 12 (3·6-22·5) at follow-up, compared with sham: 22·8 (8·4-38·2) at baseline to 16·8 (4·8-33·6) at follow-up (p=0·018). Ten patients reported side-effects (three of whom discontinued the study): ear discomfort (n=6; three in the PENFS group, three in the sham group), adhesive allergy (n=3; one in the PENFS group, two in the sham group), and syncope due to needle phobia (n=1; in the sham group). There were no serious adverse events. INTERPRETATION: Our results show that PENFS with Neuro-Stim has sustained efficacy for abdominal pain-related functional gastrointestinal disorders in adolescents. This safe and effective approach expands treatment options and should be considered as a non-pharmacological alternative for these disorders. FUNDING: American Neurogastroenterology and Motility Society.

Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats.

A non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) has been suggested to modulate central pain pathways. We investigated the effects of BRIDGE® device on the responses of amygdala and lumbar spinal neurons and the development of post-colitis hyperalgesia. Male Sprague-Dawley rats received intracolonic trinitrobenzene sulfonic acid (TNBS) and PENFS on the same day. Control rats had sham devices. The visceromotor response (VMR) to colon distension and paw withdrawal threshold (PWT) was recorded after 7days. A different group of rats had VMR and PWT at baseline, after TNBS and following PENFS. Extracellular recordings were made from neurons in central nucleus of the amygdala (CeA) or lumbar spinal cord. Baseline firing and responses to compression of the paw were recorded before and after PENFS. Sham-treated rats exhibited a much higher VMR (>30mmHg) and lower PWT compared to PENFS-treated rats (p<0.05). PENFS decreased the VMR to colon distension and increased the PWT compared to pre-stimulation (p<0.05). PENFS resulted in a 57% decrease in spontaneous firing of the CeA neurons (0.59±0.16 vs control: 1.71±0.32imp/s). Similarly, the response to somatic stimulation was decreased by 56% (3.6±0.52 vs control: 1.71±0.32 imps/s, p<0.05). Spinal neurons showed a 47% decrease in mean spontaneous firing (4.05±0.65 vs control: 7.7±0.87imp/s) and response to somatic stimulation (7.62±1.7 vs control: 14.8±2.28imp/s, p<0.05). PENFS attenuated baseline firing of CeA and spinal neurons which may account for the modulation of pain responses in this model of post-inflammatory visceral and somatic hyperalgesia.

Gastrointestinal Pharmacology.

There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial. A small study found that cyproheptadine was beneficial in the treatment of FAPDs in children. There are conflicting data regarding amitriptyline. While one small study found a significant benefit in quality of life compared with placebo, a large multicenter study found no benefit compared with placebo. The antidepressant, citalopram, failed to meet the primary outcomes in intention-to-treat and per-protocol analysis. Rifaximin has been shown to be efficacious in the treatment of adults with IBS. Those findings differ from studies in children where no benefit was found compared to placebo. To date, there are no placebo-controlled trials published on the use of linaclotide or lubiprostone in children. Alpha 2 delta ligands such as gabapentin and pregabalin are sometimes used in the care of this group of children, but no clinical trials are available in children with FAPDs. Similarly, novel drugs that have been approved for the care of irritable bowel with diarrhea in adults such as eluxadoline have yet to be studied in children. CONCLUSIONS: Little data support the use of most medications commonly used to treat FAPDs in children. More randomized, placebo-controlled studies are needed to assess the efficacy of pharmacological interventions in the treatment of FAPDs in children.

Disaccharidase Deficiencies in Children With Chronic Abdominal Pain.

OBJECTIVES: Carbohydrate intolerance or malabsorption has been suggested as a cause of chronic abdominal pain (CAP) in a subset of patients. We aimed to evaluate disaccharidase deficiencies in children with functional CAP and to correlate deficiencies with clinical features. METHOD: Patients presenting to the gastroenterology clinic at Children's Hospital of Wisconsin with abdominal pain prospectively completed a detailed demographic, history, and symptom questionnaire. The CAP cohort included those with at least 1 month of symptoms. Data on disaccharidase activity and histology of endoscopic biopsies were collected retrospectively. Only patients with normal histology were included in the study. The association between groups with low disaccharidases and clinical features was examined. RESULTS: A total of 203 pediatric patients with CAP were included. The mean (SD) age was 11.5 (3.1) years, and 32.5% were male. The percentages of abnormally low disaccharidase levels using the standard laboratory cutoffs were lactase, 37%; sucrase, 21%; glucoamylase, 25%; and palatinase, 8%. Thirty-nine percent of the patients with low lactase also had low sucrase, and 67% of the patients with low sucrase had low lactase. There was no significant difference in the activities of any of the disaccharidases or sucrase/lactase ratio in relation to age. Also, no association was found between stool consistency, stool frequency, or location of pain and low disaccharidase activity. CONCLUSIONS: A large proportion of patients with CAP have deficiencies in disaccharidases. Bowel frequency, vomiting, or location of pain was no different between groups, suggesting that these clinical features cannot be used to predict disaccharidase deficiencies.

Pascual Bailón Hergueta Megino, farmacéutico del partido de Molina de Aragón (1814-1896) / Pascual Bailón Hergueta Megino, pharmaceutical Party Molina de Aragón (1814-1896)

En este trabajo se presentan datos biográficos de D. Pascual Bailón Hergueta Megino. Este farmacéutico nacido en Molina de de Aragón (Guadalajara) ejerció en el siglo XIX en su pueblo natal. Defendió como imprescindible la formación acedémica para su profesión y argumentó en sus abundantes escritos en los periódicos profesionales contra el intrusismo y la charlatanería. También fue un activo defensor de sus planteamientos sociales apoyando cuando tuvo oportunidad los intereses de su pueblo y provincia. Asimismo tubo gran interés en aprender y colaborar en la nueva ciencia botánica necesaria para elaborar los crecientes medicamentos que ofrecía su conocimiento, pero en ningún momento la valoró sobre su dedicación a la farmacia. En esta investigación se recoge toda la información biográfica encontrada acerca de Pascual Bailón, sus obras referidas a la profesión de farmacéutico y también sus contribuciones a la cultura y a la sociedad Molinesa. Se ha realizado un inventario lo más completo posible de su obra impresa y manuscrita, así como la de autores que lo citan a él o a sus trabajos. Se entiende que el trabajo aquí presentado puede ayudar a valorar objetivamente el trabajo realizado por este farmacéutico, su interés científico e histórico, teniendo en cuenta el momento y los recursos disponibles por su autor

In this work, biographical data about D. Pascual Bailon Hergueta Megino are presented. This pharmaceutical was born in Molina de Aragon (Guadalajara). He worked in the nineteenth century in his hometown. He defended as essential the academic training for their profession and argued in his prolific writings in professional journals against the intrusiveness and quackery. He was also an active supporter of social approaches to defend the interests of his people and province. He also showed great interest in collaborating with advances in botanical science necessary to develop new medicines. But never considered it above his dedication to pharmacy. This research summarizes all the biographical information found about Pascual Bailon, his works related to the profession of pharmacist and his contributions to culture and society of Molina. The work includes a complete inventory of its printed and handwritten work, as well as the authors who mentioned him or his works in their publications. It is understood that the work presented here can help to objectively evaluate the work of this pharmaceutical, which is of scientific and historical interest, having in regard the historical moment as well as the resources available by the autor

Can You Teach a Teen New Tricks? Problem Solving Skills Training Improves Oral Medication Adherence in Pediatric Patients with Inflammatory Bowel Disease Participating in a Randomized Trial.

BACKGROUND: Medication nonadherence is associated with higher disease activity, greater health care utilization, and lower health-related quality of life in pediatric inflammatory bowel diseases (IBD). Problem solving skills training (PSST) is a useful tool to improve adherence in patients with chronic diseases but has not been fully investigated in IBD. This study assessed feasibility, acceptability, and preliminary efficacy of PSST in pediatric IBD. METHODS: Recruitment occurred during outpatient clinic appointments. After completion of baseline questionnaires, families were randomized to a treatment group or wait-list comparison group. The treatment group received either 2 or 4 PSST sessions. Youth health-related quality of life was assessed at 3 time points, and electronic monitoring of oral medication adherence occurred for the study duration. RESULTS: Seventy-six youth (ages 11-18 years) on an oral IBD maintenance medication participated. High retention (86%) and treatment fidelity rates (95%) supported feasibility. High satisfaction ratings (mean values ≥4.2 on 1-5 scale) supported intervention acceptability. Modest increases in adherence occurred after 2 PSST sessions among those with imperfect baseline adherence (d = 0.41, P < 0.10). Significant increases in adherence after 2 PSST sessions were documented for participants aged 16 to 18 years (d = 0.95, P < 0.05). Improvements in health-related quality of life occurred after 2 PSST sessions. No added benefit of 4 sessions on adherence was documented (d = 0.05, P > 0.05). CONCLUSIONS: Phone-delivered PSST was feasible and acceptable. Efficacy estimates were similar to those of lengthier interventions conducted in other chronic illness populations. Older adolescents benefited more from the intervention than their younger counterparts.

Velocidad de la onda de pulso: relevancia de la edad en normotensión, hipertensión esencial e hipertensión limítrofe / Pulse Wave Velocity: Relevance of Age in Normotensive, Essential Hypertensive and Borderline Hypertensive Patients

Introducción: Se han descripto varios parámetros de medición del estado de la función arterial y, de ellos, la velocidad de la onda de pulso (VOP) es el único que permite una medición directa de la rigidez arterial. A medida que aumenta la edad del individuo se va produciendo una pérdida de la capacidad elástica, conocida como envejecimiento vascular, proceso este que estaría acelerado en los pacientes con hipertensión arterial. Objetivos: Normalizar por décadas los valores de la VOP en pacientes normotensos (NT), hipertensos esenciales (HT) e hipertensos limítrofes (LT) y diferenciar los efectos del envejecimiento sobre la VOP de los vinculados a la hipertensión arterial. Material y métodos: Se estudiaron 221 pacientes consecutivos, de ambos sexos, que fueron clasificados, por sus valores de presión arterial (PA), en tres grupos: NT (n = 120, 46 ± 13 años): PA < 135/85 mm Hg; HT (n = 60, 50 ± 13 años): PA > 140/90 mm Hg; y LT (n = 41, 47 ± 12 años): PA = 135-139/85-89 mm Hg. Posteriormente fueron divididos en cuatro grupos por edades: GI ≤ 39 años, GII = 40-49 años, GIII = 50-59 años y GIV > 60 años. La VOP se midió con transductores mecanográficos y cálculo computarizado. Se utilizaron las pruebas de ANOVA, de Newman-Keuls y de regresión lineal multivariada. Resultados: La VOP aumentó significativamente (p < 0,05) con la edad en todos los grupos etarios (m/seg): GI: NT (n = 42): 8,6 ± 1,1, HT (n = 16): 9,5 ± 1,3, LT (n = 10): 9,0 ± 0,5; GII: NT (n = 24): 9,5 ± 1,2, HT (n = 16): 10,7 ± 1,2, LT (n = 14): 9,8 ± 0,8; GIII: NT (n = 30): 10,3 ± 1,5, HT (n = 12): 12,1 ± 1,5, LT (n = 11): 11,0 ± 1,3; y GIV: NT (n = 24): 11,4 ± 1,8, HT (n = 16): 14,1 ± 2,4, LT (n = 6): 13,3 ± 1,1. Las ecuaciones de regresión halladas fueron: en NT, VOP = 0,08 × edad + 0,04 × presión arterial sistólica (PAS) + 1,07 (r = 0,71); en HT, VOP = 0,12 × edad + 0,06 × PAS - 2,51 (r = 0,81); y en LT, VOP = 0,10 × edad + 0,02 × PAS + 0,02 (r = 0,73) (p < 0,05). Conclusiones: La VOP aumentó con la edad, siendo el incremento mayor en HT para cada grupo etario. Los sujetos LT tuvieron valores intermedios entre los otros dos grupos. Ello sugiere un deterioro de la función arterial adicional inducido por la hipertensión arterial sobre el envejecimiento. Este efecto adicional puede estimarse con la ecuación de regresión obtenida para cada grupo.

Background: Among the various parameters used to describe arterial function, pulse wave velocity (PWV) is the only one allowing direct measurement of arterial stiffness. Loss of arterial elastic capacity with increasing age, a process known as vascular aging, is enhanced in hypertensive patients. Objectives: The aim of this study was to normalize PWV in normotensive (NT), essential hypertensive (HT) and borderline hypertensive (BL) patients and differentiate the effects of aging on PWV from those associated to hypertension. Methods: A total of 221 consecutive male and female patients were included in the study. They were classified into three groups according to their blood pressure (BP) values: NT (n=120, 46±13 years): BP<135/85 mmHg; HT (n=60, 50±13 years): BP>140/90 mmHg; and BL (n=41, 47±12 years): BP=135-139/85-89 mmHg. They were then stratified into four groups according to age: GI≤39 years, GII=40-49 years, GIII=50-60 years and GIV>60 years. Mechanographic transducers and computerized calculation were used to measure PWV. Data analysis was performed using ANOVA, Newman-Keuls, and multivariate linear regression tests. Results: Pulse wave velocity increased with age in all age groups (p<0.05). Mean PWV (m/s) in G1 was: NT (n=42): 8.6±1.1, HT (n=16): 9.5±1.3, BL (n=10): 9.0±0.5; in GII: NT (n=24): 9.5±1.2, HT (n=16): 10.7±1.2, BL (n=14): 9.8±0.8; in GIII: NT (n=30): 10.3±1.5, HT (n=12): 12.1±1.5, BL (n=11): 11.0±1.3; and in GIV: NT (n=24): 11.4±1.8, HT (n=16): 14.1±2.4, BL (n=6): 13.3±1.1. Regression equations were: for NT, PWV=0.08 × age+0.04 × systolic blood pressure (SBP)+1.07 (r=0.71); for HT, PWV=0.12 × age+0.06 × SBP-2.51 (r=0.81); and for BL, PWV=0.10 × age+0.02 × SBP+0.02 (r=0.73) (p<0.05). Conclusions: Pulse wave velocity increased with age, and was higher in HT patients for each age group. Borderline hypertensive patients presented intermediate values between the other two groups. These results suggest additional vascular impairment induced by hypertension over that of aging. This surplus effect could be estimated from the regression equation obtained for each group.

NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation.

NMDA receptors (NMDAR) are important in the development and maintenance of central sensitization. Our objective was to investigate the role of spinal neurons and NMDAR in the maintenance of chronic visceral pain. Neonatal rats were injected with acidic saline adjusted to pH 4.0 in the gastrocnemius muscle every other day for 12 days. In adult rats, NR1 and NR2B subunits were examined in the lumbo-sacral (LS) spinal cord. A baseline, visceromotor response (VMR) to graded colorectal distension (CRD) was recorded before and after administration of the NMDA antagonist, CGS-19755. Extracellular recordings were performed from CRD-sensitive LS spinal neurons and pelvic nerve afferents (PNA) before and after CGS-19755. Rats that received pH 4.0 saline injections demonstrated a significant increase in the expression NR2B subunits and VMR response to CRD>20 mmHg. CGS-19755 (i.v. or i.t.) had no effect in naïve rats, but significantly decreased the response to CRD in pH 4.0 saline injected rats. CGS-19755 had no effect on the spontaneous firing of SL-A, but decreased that of SL-S. Similarly, CGS-19755 attenuates the responses of SL-S neurons to CRD, but had no effect on SL-A neurons or on the response characteristics of PNA fibers. Neonatal noxious somatic stimulation results in chronic visceral hyperalgesia and sensitizes a specific subpopulation of CRD-sensitive spinal neurons. The sensitization of these SL-S spinal neurons is attenuated by the NMDAR antagonist. The results of this study suggest that spinal NMDARs play an important role in the development of hyperalgesia early in life.

The use of non-narcotic pain medication in pediatric gastroenterology.

The perception of pain in children is easily influenced by environmental factors and psychological comorbidities that are known to play an important role in its origin and response to therapy. Chronic abdominal pain is one of the most commonly treated conditions in modern pediatric gastroenterology and is the hallmark of 'functional' disorders that include irritable bowel syndrome, functional dyspepsia, and functional abdominal pain. The development of pharmacological therapies for these disorders in adults and children has been limited by the lack of understanding of the putative, pathophysiological mechanisms that underlie them. Peripheral and central pain-signaling mechanisms are known to be involved in chronic pain originating from the gastrointestinal tract, but few therapies have been developed to target specific pathways or enhance correction of the underlying pathophysiology. The responses to therapy have been variable, potentially reflecting the heterogeneity of the disorders for which they are used. Only a few small, randomized clinical trials have evaluated the benefit of pain medications for chronic abdominal pain in children and thus, the decision on the most appropriate treatment is often based on adult studies and empirical data. This review discusses the most common, non-narcotic pharmacological treatments for chronic abdominal pain in children and includes a thorough review of the literature to support or refute their use. Because of the dearth of pediatric studies, the focus is on pharmacological and alternative therapies where there is sufficient evidence of benefit in either adults or children with chronic abdominal pain.

Comparison of light and electron microscopy in measurement of esophageal intercellular space in children.

OBJECTIVES: A good objective marker of esophageal mucosal damage from gastroesophageal reflux disease (GERD) is lacking in children. Increased esophageal epithelial intercellular (EEIC) space measured using electron microscopy (EM) has been proposed as a surrogate of esophageal mucosal damage in adults with GERD. The aim of the present study was to compare EEIC space measured using EM and light microscopy (LM) in children with nonerosive reflux disease (NERD) with asymptomatic controls. METHODS: Distal esophageal mucosal biopsy was used to measure EEIC space using EM in 35 NERD subjects and 8 controls. In a subset of these patients we used phase contrast LM to measure EEIC space area (26 NERD subjects and 8 controls). RESULTS: The median (range) EEIC space measured using EM in the NERD group was 1.15 (0.74-1.64) µm compared with 0.93 (0.67-1.11) µm in the control group (P = 0.002). The median (range) EEIC space measured using LM was 14.4% (9.6%-26.3%) in the NERD group and 9.6% (8.5%-17.2%) in controls (P = 0.003). Using a cutoff value of 1.02 µm for normal EEIC space measured by EM, we obtained 73% sensitivity and 75% specificity to distinguish the NERD group from the control group, and using a cutoff value of 11.1% for EEIC space measured by LM, we obtained 96% sensitivity and 75% specificity. CONCLUSIONS: EEIC space is increased in children with NERD compared with that in controls, suggesting that changes in EEIC space can be a useful marker of esophageal mucosal injury in children with NERD. Our results suggest that the accuracy of EM and LM to evaluate EEIC space changes in NERD is comparable, and LM may be a more cost-effective option.

Chronic idiopathic nausea of childhood.

OBJECTIVES: To compare children with primary, chronic idiopathic nausea to those with secondary nausea associated with functional abdominal pain. STUDY DESIGN: Retrospective chart review of 45 children with a primary complaint of chronic nausea several times per week. Comparisons were made to prospectively collected data on 49 children with functional abdominal pain and comorbid nausea. RESULTS: The majority of those affected were adolescent Caucasian females. Subjects with chronic nausea had a more severe presentation with daily 88% (vs 26%) and constant 60% (vs 10%) nausea (P < .001), one-half with peak morning intensity. In the chronic nausea group, 62% had migraines, and 71% (vs 22%) had familial migraines (P < .001), 36% had postural tachycardia syndrome and 27% cyclic vomiting syndrome. Both groups suffered comorbid symptoms (anxiety, dizziness, fatigue, and sleep problems). The chronic nausea cohort underwent extensive, negative medical evaluations. CONCLUSIONS: Chronic idiopathic nausea of childhood is a poorly described symptom. Patients with primary (vs secondary) chronic nausea were more likely Caucasian, older adolescent females with severe, daily nausea and comorbid conditions such as anxiety, dizziness, and fatigue as well as significantly more migraine features. Chronic nausea is a major, disabling symptom that requires increased recognition as a separate functional entity. Future studies may need to focus on comorbid conditions including migraine and dysautonomia.

Visceral analgesic effect of 5-HT(4) receptor agonist in rats involves the rostroventral medulla (RVM).

The 5-HT(4) receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. In male rats, visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD). Inflammation was induced by intracolonic injection of tri-nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not spinal, injection of TEG attenuated the VMR. While GR113808, (selective 5-HT(4) antagonist) blocked the effect, naloxone (NLX) an opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and ß-funaltrexamine (ß-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT(4) receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.

Assessment of abdominal pain through global outcomes and recent FDA recommendations in children: are we ready for change?

OBJECTIVES: Irritable bowel syndrome is a multisymptom construct, with abdominal pain (AP) acting as the driving symptom of patient-reported severity. The Food and Drug Administration considers a >30% decrease in AP as satisfactory improvement, but this has not been validated in children. We investigated the correspondence of 2 measures for AP assessment, ≥30% improvement in AP and global assessment of improvement. METHODS: Secondary analysis of data from 72 children who completed a randomized clinical trial for abdominal pain-associated functional gastrointestinal disorders. Children completed daily assessment of AP intensity, functional disability inventory (FDI), question regarding pain's interference with activities, and 2 global assessment questions. We measured the extent to which ≥30% improvement of AP and global assessment questions correlated with each other and with disability. RESULTS: The global questions correlated with each other (r=0.74; P<0.0001) and with a ≥30% improvement in AP (P<0.01). Global outcomes were satisfaction with treatment was inversely related to the child's report of interference with activities (P<0.01) and symptom relief was positively associated with ≥30% improvement in FDI scores (P<0.009). A 30% change in FDI scores was associated with global questions of symptom relief (P=0.009) but not with satisfaction with treatment (P=0.07). The association of AP improvement with interference with activities (P=0.14) or change in FDI scores (P=0.27) did not reach significance. CONCLUSIONS: Currently used global assessments are significantly associated with decreased pain intensity, decreased interference with daily activities, and a ≥30% change in FDI scores, whereas recommended 30% improvement in pain intensity is not as comprehensive.

High prevalence of nausea in children with pain-associated functional gastrointestinal disorders: are Rome criteria applicable?

OBJECTIVES: The aim of the study was to determine the prevalence of nausea in pediatric patients with pain-associated functional gastrointestinal disorders (FGIDs), examine the effect on social and school functioning, and examine the applicability of pediatric Rome III criteria. METHODS: A total of 221 pediatric patients (6-18 years of age) with chronic abdominal pain prospectively completed a demographic, history, and gastrointestinal symptom questionnaire adapted from the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS). The 6-item, revised Pediatric Migraine Disability Assessment Score tool was used to assess the effect of symptoms on school, home, and social disability. Rome III criteria were applied to all subjects. RESULTS: A total of 183 patients with pain and nausea for a minimum of 2 months were identified. Ninety-six patients were studied after excluding those with vomiting and/or organic disease. Among these, 53% had nausea at least 2 times per week and 28% experienced daily nausea. Frequency of nausea was significantly correlated with poor school and social functioning, and uniquely predicted social disability beyond pain. Although 87% met adult Rome criteria for functional dyspepsia, only 29% met corresponding pediatric Rome criteria. Additionally, 22% met the criteria for irritable bowel syndrome (IBS)-diarrhea, 13% for IBS-constipation, 13% for abdominal migraine, and 31% were classified as having functional abdominal pain. Pediatric IBS-diarrhea and IBS-constipation overlapped in 5% of patients. CONCLUSIONS: Nausea is a prevalent symptom in patients with pain-associated FGIDs and correlates with poor school and social functioning. There is substantial overlap among FGIDs in children with nausea.

MicroRNA-mediated GABA Aα-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats.

The nociceptive transmission under pathological chronic pain conditions involves transcriptional and/or translational alteration in spinal neurotransmitters, receptor expressions, and modification of neuronal functions. Studies indicate the involvement of microRNA (miRNA) - mediated transcriptional deregulation in the pathophysiology of acute and chronic pain. In the present study, we tested the hypothesis that long-term cross-organ colonic hypersensitivity in neonatal zymosan-induced cystitis is due to miRNA-mediated posttranscriptional suppression of the developing spinal GABAergic system. Cystitis was produced by intravesicular injection of zymosan (1% in saline) into the bladder during postnatal (P) days P14 through P16 and spinal dorsal horns (L6-S1) were collected either on P60 (unchallenged groups) or on P30 after a zymosan re-challenge on P29 (re-challenged groups). miRNA arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significant, but differential, up-regulation of mature miR-181a in the L6-S1 spinal dorsal horns from zymosan-treated rats compared with saline-treated controls in both the unchallenged and re-challenged groups. The target gene analysis demonstrated multiple complementary binding sites in miR-181a for GABA(A) receptor subunit GABA(Aα-1) gene with a miRSVR score of -1.83. An increase in miR-181a concomitantly resulted in significant down-regulation of GABA(Aα-1) receptor subunit gene and protein expression in adult spinal cords from rats with neonatal cystitis. Intrathecal administration of the GABA(A) receptor agonist muscimol failed to attenuate the viscero-motor response (VMR) to colon distension in rats with neonatal cystitis, whereas in adult zymosan-treated rats the drug produced significant decrease in VMR. These results support an integral role for miRNA-mediated transcriptional deregulation of the GABAergic system in neonatal cystitis-induced chronic pelvic pain.