Search

Rationale and Objectives: We describe our experience in measuring parenchyma stiffness across the liver Couinaud segments in lieu of the conventional practice of using a single slice-wise "global" region-of-interest. We hypothesize that the heterogeneous nature of fibrosis can lead to regional stiffness within the organ, and that it can be reflected by Couinaud segment-based magnetic resonance elastography measurements.Materials and Methods: This retrospective study involved from 173 patients (116 males, 57 females, 1.0-22.5 years, 14.7 ± 3.5 years) who underwent exams between June 2017 and September 2018. Liver stiffness across the eight Couinaud segments was measured in addition to a single-slice global measurement by two analysts. Inter- and intrarater analysis was performed in a subset of 20 cases. Individual segment stiffness values, the average across the segments, and the coefficients of variation (CoV) were compared to global single-slice-derived values using linear and Lin's concordance correlation coefficients. Linear correlations between stiffness values versus age, gender, and body-mass-index (BMI) were also evaluated.Results: We observed CoVs ranging from 3.1%-79.2%, 17.2 ± 7.2%. The CoV was not correlated with age or BMI (r2 < 0.01, p = 0.99 for both). The CoV did not differ between males (17.1 ± 5.6%) and females (17.3 ± 9.8%) (p = 0.88). There were no correlations between global stiffness versus age (r2 = 0.02, p = 0.84) or BMI (r2 = 0.03, p = 0.68). A range of 0.58-0.86 was observed for Lin's concordance correlation coefficient between segmental stiffness, the average stiffness across segments, and global stiffness. Segments II and VII had the highest frequency of being the stiffest Couinaud segment. The average stiffness across the segments correlated strongly with the single-slice global measurement (r2 = 0.88, p< 0.01).Conclusion: There exists potential variations in parenchyma stiffness across the liver Couinaud segments, which may reflect the heterogeneous nature of fibrosis. This variation can potentially provide additional diagnostic and clinical information. [ABSTRACT FROM AUTHOR]

Objective: To determine whether early patient-directed oral nutrition in children with mild acute pancreatitis decreases the length of hospitalization without increasing complications.Study Design: Hospitalized patients aged 2-21 years of age who met the criteria for acute pancreatitis based on the Revised Atlanta Classification were enrolled prospectively and allowed to eat by mouth at their discretion (patient-directed nutrition [PDN]). These patients were compared with a retrospective cohort of children who were allowed to eat based on traditional practices (treatment team-directed nutrition [TTDN]). Outcomes included length of hospitalization, time nil per os (NPO), and complications within 30 days of discharge.Results: The study included 30 patients in the PDN group and 92 patients in the TTDN group. Patients in the PDN group had a median length of stay of 48.5 hours (IQR 37-70 hours) compared with 93 hours (IQR 52-145 hours) in the TTDN group (P < .0001). Patients were NPO for a median of 14 hours (IQR 7-19.5 hours) in the PDN group compared with 34 hours (IQR 19.3-55 hours) in the TTDN group (P < .0001). No patients in the PDN group developed complications within 30 days of discharge.Conclusion: Early patient-directed oral nutrition in mild acute pancreatitis was well tolerated and resulted in decreased length of NPO status and hospitalization with no obvious complications.Clinical Trial Registration: ClinicalTrials.gov: NCT01423786. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether the age of onset was associated with unique features or disease course in pediatric acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP).Study Design: Demographic and clinical information on children with ARP or CP was collected at INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) centers. The Cochran-Armitage trend test and Jonckheere-Terpstra test were used to examine for differences between pediatric age groups (<6, 6-11, and ≥12 years).Results: Between September 2012 and March 2016, 342 children with ARP or CP were enrolled; 129 (38%) were <6 years of age at the time of first diagnosis of acute pancreatitis, 111 (32%) were 6-11 years of age, and 102 (30%) were ≥12 years of age. Early-onset disease was associated with mutations in cationic trypsinogen (PRSS1) (P < .01), chymotrypsin C (CTRC) (P = .01), family history of acute pancreatitis (P = .02), family history of CP (P < .01), biliary cysts (P = .04), or chronic renal failure (P = .02). Later-onset disease was more commonly present with hypertriglyceridemia (P = .04), ulcerative colitis (P = .02), autoimmune diseases (P < .0001), or medication use (P < .01). Children with later-onset disease also were more likely to visit the emergency department (P < .05) or have diabetes (P < .01).Conclusions: Early-onset pancreatitis is associated strongly with PRSS1 or CTRC mutations and family history of pancreatitis. Children with later-onset disease are more likely to have nongenetic risk factors. Future studies are needed to investigate whether the disease course, response to therapy, or clinical outcomes differ relative to the timing of disease onset. [ABSTRACT FROM AUTHOR]

Objective To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. Study design We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Results Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). Conclusions Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial. [ABSTRACT FROM AUTHOR]

We review the current clinical evaluation and management of the most common esophageal and gastrointestinal motility disorders in children based on the literature and our experience in a pediatric motility center in the United States. The disorders discussed include esophageal achalasia, pre- and post-fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, chronic intestinal pseudo-obstruction, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprung''s disease, chronic functional constipation, and motility disorders associated with imperforate anus. [Copyright &y& Elsevier]

Background: The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury with thrombus formation and subsequent ischemic tubulointerstitial damage. The endothelin ET(B) receptor has been shown to mediate both endothelial cell proliferation and vasodilation, and we therefore hypothesized that blockade of this receptor might promote more severe injury in this model.Methods: TMA was induced in recently established transgenic rats that lack expression of ET(B) receptor in the kidney; these animals were compared to control rats with TMA both in the short-term (days 1 and 3) when acute glomerular injury was most manifest, and the long-term (day 17) when glomeruli have recovered but tubulointerstitial injury is still present. Renal damage was assessed by histological analysis and blood urea nitrogen (BUN) measurements.Results: No difference in the TMA model was observed between rats with and without ET(B) receptor on days 1 or 3. At day 17, however, rats without the ET(B) receptor showed more severe tubulointerstitial injury compared with those with ET(B) receptor, which was associated with higher BUN levels. The tubulointerstitial damage was associated with a more severe loss of peritubular capillaries.Conclusions: These findings suggest that the ET(B) receptor may protect peritubular capillaries under the ischemic insult, and serve a defensive role in the tubulointerstitium induced by renal microvascular injury. [ABSTRACT FROM AUTHOR]

Abstract: Heterodimerization of G-protein coupled receptors can alter receptor pharmacology. ETA and ETB receptors heterodimerize when co-expressed in heterologous expression lines. We hypothesized that ETA and ETB receptors heterodimerize and pharmacologically interact in vena cava from wild-type (WT) but not ETB receptor deficient (sl/sl) rats. Pharmacological endothelin receptor interaction was assessed by comparing ET-1-induced contraction in rings of rat thoracic aorta and thoracic vena cava from male Sprague Dawley rats under control conditions, ETA receptor blockade (atrasentan, 10 nM), ETB receptor blockade (BQ-788, 100 nM) or ETB receptor desensitization (Sarafotoxin 6c, 100 nM) and ETA plus ETB receptor blockade or ETA receptor blockade plus ETB receptor desensitization. In addition, similar pharmacological ET receptor antagonism experiments were performed in rat thoracic aorta and vena cava from WT and sl/sl rats. ETA but not ETB receptor blockade or ETB receptor desensitization inhibited aortic and venous ET-1-induced contraction. In vena cava but not aorta, when ETB receptors were blocked (BQ-788, 100 nM) or desensitized (S6c, 100 nM), atrasentan caused a greater inhibition of ET-1-induced contraction. Vena cava from WT but not sl/sl rats exhibited similar pharmacological ET receptor interaction. Immunocytochemistry was performed on freshly dissociated aortic and venous vascular smooth muscle cells to determine localization of ETA and ETB receptors. ETA and ETB receptors qualitatively co-localized more strongly to the plasma membrane of aortic compared to venous vascular smooth muscle cells. Our data suggest that pharmacological ETA and ETB receptor interaction may be dependent on the presence of functional ETB receptors and independent of receptor location. [Copyright &y& Elsevier]

We investigated the role of endothelin ETB receptor in the development of monocrotaline-induced pulmonary hypertension, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. Three weeks after injection of saline or monocrotaline (60 mg/kg, s.c.), hemodynamics, cardiac hypertrophy and endothelin-1 levels in right ventricle were determined. Monocrotaline produced a marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, pulmonary arterial medial thickening and the endothelin-1 levels. These monocrotaline-induced alterations tended to be enhanced in ETB-deficient homozygous rats, compared with cases in wild-type rats. The treatment with the selective ETA receptor antagonist ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid] for 3 weeks (10 mg/kg/day, twice daily) almost completely suppressed the monocrotaline-induced pulmonary hypertension and related organ damage both in ETB-deficient and wild-type animals to the same levels. Thus, we suggest that the antagonism of the ETA receptor is essential for the protection from monocrotaline-induced pulmonary hypertension, irrespective of the presence of the ETB receptors, although a protective role of ETB receptor-mediated action in the pathogenesis of this disease model cannot be ruled out. [Copyright &y& Elsevier]

We investigated the role of endothelin ETB receptor in the remnant kidney model of chronic renal failure, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. After 5/6 nephrectomy, systolic blood pressure and renal functional parameters were measured for 12 weeks. At the end of the experimental period, arterial blood sample, remnant kidney, heart and aorta were collected and used for biochemical measurements and histopathological studies. The ETB-deficient sl/sl rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in sl/sl than in wild-type rats. While aortic endothelin-1 contents were increased similarly in both groups, the level of renal endothelin-1 content was significantly elevated in sl/sl rats, but not in the wild-type rats. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablation-induced chronic renal failure in ETB receptor-deficient rats and that ETB receptor-mediated actions are protective against vascular and renal injuries in this disease. [Copyright &y& Elsevier]

We determined the role of endothelin ETB receptor in the renal hemodynamic and excretory responses to big endothelin-1, using A-192621, a selective endothelin ETB receptor antagonist and the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. An intravenous injection of big endothelin-1 produced a hypertensive effect, which is greater in wild-type (+/+) rats pretreated with A-192621 and in homozygous (sl/sl) rats. Big endothelin-1 markedly increased urine flow, urinary excretion of sodium and fractional excretion of sodium in wild-type rats treated with the vehicle. These excretory responses to big endothelin-1 were markedly reduced by pharmacological endothelin ETB receptor blockade. On the other hand, big endothelin-1 injection to the endothelin ETB receptor-deficient homozygous animals resulted in a small diuretic effect. When renal perfusion pressure was protected from big endothelin-1-induced hypertension by an aortic clamp, the excretory responses in vehicle-treated wild-type rats were markedly attenuated. In homozygous or A-192621-treated wild-type rats, there was a small but significant decreasing effect in urine flow. In addition, big endothelin-1 significantly elevated nitric oxide (NO) metabolite production in the kidney of wild-type rats but not in the homozygous rats. We suggest that the diuretic and natriuretic responses to big endothelin-1 consist of pressure-dependent and pressure-independent effects and that the increased NO production via the activation of endothelin ETB receptors in the kidney is closely related to the big endothelin-1-induced excretory responses. [Copyright &y& Elsevier]

Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response. This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10–18) with ARP/CP and their parents from twenty-one INSPPIRE ( IN ternational S tudy Group of P ediatric P ancreatitis: I n search for a cu RE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization. This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration # : NCT03707431. [ABSTRACT FROM AUTHOR]