The association of histologic gastritis with gastroesophageal reflux and delayed gastric emptying

The aims of this study were to: 1) investigate the incidence of histologic gastritis in patients with gastroesophageal reflux (GER); 2) ascertain if gastritis in GER patients could be correlated with impaired gastric emptying; and 3) determine if the presence of histologic antral gastritis correlated with other parameters of esophageal and gastric function. Twenty-three GER patients, mean age 53.3 years (range 28-68 years) with subjective and objective evidence for GER; and 20 normal subjects (13 males and seven females), mean age 28.7 years (range 19-46 years), underwent upper gastrointestinal endoscopy. Antral biopsies obtained from the greater curvature were graded as: 0 = normal; 1 = chronic gastritis; 2 = chronic active gastritis; and 3 = chronic atrophic gastritis. All patients underwent a gastric emptying study using an isotope-labeled semisolid meal. Eighteen of the 23 GER patients (78%) had histologic gastritis compared to two (10%) of the normals. No subject had endoscopic evidence of gastritis. Gradings of histologic gastritis were significantly (p less than 0.05) correlated with delayed gastric emptying. Twelve GER patients had severe gastritis (grades 2 or 3) and their gastric emptying, 79.7% +/- 5.8 (mean +/- S.E.M.) retention of isotope at 90 minutes after the meal, was significantly slower (p less than 0.01) than the 11 GER patients with either grade 0 or 1 gastritis, 56.1% +/- 5.9 retention, or the normal subjects, 51.8% +/- 1.7. We conclude that: 1) histologic gastritis is associated with GER disease; and 2) slowing of gastric emptying can be significantly correlated with increased severity of histologic gastritis in GER patients.     

The Mr 95,000 gelatin-binding protein in differentiated human macrophages and granulocytes

Cultured adherent human macrophages and a promonocytic cell line, U 937, were previously shown to produce a Mr 95,000 gelatin-binding protein. The protein has no immunologic cross-reactivity with the well- characterized gelatin-binding protein fibronectin and the Mr 70,000 gelatin-binding protein produced by a variety of mesenchymal or epithelial cell types (T. Vartio et al, J Biol Chem 257:8862, 1982). In the present study the Mr 95,000 protein was found in Triton X-100 extracts of granulocytes purified from human blood buffy coat. The protein, as isolated by gelatin-agarose, was immunologically cross- reactive with the corresponding macrophage protein in immunoblotting assay. When peripheral blood and bone marrow cells were examined for the presence of the Mr 95,000 protein by indirect immunofluorescence, positive staining was detected only in differentiated granulocytes but not to any significant extent in metamyelocytes, myelocytes, promyelocytes, or in normal or leukemic blasts. In granulocytes the protein had a granular cytoplasmic distribution. In freshly prepared monocyte cultures, the Mr 95,000 protein was detected in low amounts in the cytoplasm, while along with differentiation of the cells into macrophages, the immunofluorescence increased in a reticular and vesicular cytoplasmic pattern and in a juxtanuclear cap, probably representing the Golgi complex. In conclusion, the Mr 95,000 gelatin- binding protein was specifically detected in macrophages and granulocytes and may thus serve as a differentiation marker for these phagocytic cells.     

The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR‐ABL down‐regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non‐canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR‐ABL silencing reduced full‐length NOTCH1 (NOTCH1‐FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1‐ICD), resulting in decreased expression of the NOTCH1 targets c‐MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3 (rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1‐ICD, p < 0.05). Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR‐ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial

INTRODUCTION: Erythromycin, a motilin agonist, is a potent prokinetic. ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. METHODS: Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C(13) octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit. RESULTS: The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline -169, -101, -155, -143, and -138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms. CONCLUSIONS: The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying.     

Risk Assessment: A Reflection on the Principles of Tools to Help Manage Risk of Violence in Mental Health

The proposition that the vast majority of persons experiencing mental illness will never be violent is complicated by the large body of literature demonstrating a heightened risk of violent behaviour in persons suffering from mental disorder. In an era in which resources and individual judgement appear to dictate treatment, the question arises as to why structured clinical judgement is not utilized more in front-line assessment of risk for violence in those with mental and personality disorders? Our review of the literature on mental disorder and violence, risk assessment and risk management led to the contention that front-line mental health professionals can employ structured clinical judgement underpinned by the principles of risk assessment tools, such as the HCR-20. Ongoing resource development, education and availability of expertise should aid the development of more uniform approaches to violence risk management and therapeutic amelioration of the likelihood for violence in persons affected by mental illness.     

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

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