The Management of Childhood Intracranial Tumours and the Role of the Ophthalmologist.

OBJECTIVE: This study looked at a single paediatric neuro-oncology centre's experience of childhood intracranial tumours seen in the ophthalmology clinic over an approximately five-year period. This was used to analyse the role of the ophthalmologist in their long term follow up. METHODS: A database was compiled of all children discussed at the neuro-oncology multi-disciplinary team (MDT) meeting between January 2012 and April 2017. All children who had an intracranial tumour determined by histology or suspected on neuro-imaging, who had also been seen in the ophthalmology clinic, were included. A retrospective case review was performed to create a record for each child. RESULTS: The database contained 129 children of which 82 (64%) were boys and 47 (36%) were girls. Of these 89 (69%) had a histological diagnosis and 40 (31%) had a tumour suspected on neuroimaging. The most common tumour locations were the posterior fossa (n = 54, 42%), diencephalon (n = 20, 16%) and the visual pathways (n = 17, 13%). Papilloedema at first presentation was only found in 39 (30%) children. The most common other neuro-ophthalmic manifestations were non-paralytic strabismus (n=33), sixth nerve palsy (n=19) and seventh nerve palsy (n=12). Non-paralytic strabismus was a presenting symptom in only one case. There were 13 ophthalmic surgical procedures required for these children, the most common being strabismus surgery. CONCLUSION: We report the types and locations of paediatric intracranial tumours seen in the ophthalmology clinic as well as their neuro-ophthalmic manifestations. Only 30% presented with papilloedema and approximately 10% required an ophthalmic surgical procedure.

The effect of phosphatidylinositol-3 kinase inhibition on matrix metalloproteinase-9 and reactive oxygen species release from chronic obstructive pulmonary disease neutrophils.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterised by increased neutrophilic inflammation. A potential novel anti-inflammatory target in COPD is phosphatidylinositol-3 kinase (PI3 kinase), which targets neutrophil function. This study evaluated the effects of selective PI3Kδ inhibition on COPD blood and sputum neutrophils both in the stable state and during exacerbations. METHODS: Blood and sputum neutrophils from stable and exacerbating COPD patients were cultured with the corticosteroid dexamethasone, a pan PI3 kinase inhibitor (ZSTK474), a δ selective PI3 kinase inhibitor (GSK045) and a p38 mitogen activated protein (MAP) kinase inhibitor (BIRB 796); matrix metalloproteinase (MMP)-9 and reactive oxygen species (ROS) release were analysed. RESULTS: PI3Kδ inhibition significantly reduced MMP-9, intracellular ROS and extracellular ROS release from blood neutrophils (45.6%, 30.1% and 47.4% respectively; p<0.05) and intracellular ROS release from sputum neutrophils (16.6%; p<0.05) in stable patients. PI3Kδ selective inhibition significantly reduced stimulated MMP-9 (36.4%; p<0.05) and unstimulated and stimulated ROS release (12.6 and 26.7%; p<0.05) from blood neutrophils from exacerbating patients. The effects of the p38 MAP kinase inhibitor and dexamethasone in these experiments were generally lower than PI3Kδ inhibition. CONCLUSION: PI3Kδ selective inhibition is a potential strategy for targeting glucocorticoid insensitive MMP-9 and ROS secretion from COPD neutrophils, both in the stable state and during exacerbations.

When employees can't afford health insurance: the self-funding approach.

As job opportunities for home care workers increase--particularly for aides--providers need to offer attractive benefits packages to reduce staff turnover. Through self-funded health benefits plans, home care organizations can offer more affordable coverage for their employees.

A randomized controlled trial comparing the accuracy of general diagnostic upper gastrointestinal endoscopy performed by nurse or medical endoscopists.

BACKGROUND AND STUDY AIMS: Rising demand for general diagnostic upper gastrointestinal endoscopy in the UK is outgrowing the capacity of doctors to provide this service within a reasonable time. One solution is to train nurses to carry out the procedure, but it is not known whether nurses can perform general diagnostic upper gastrointestinal endoscopy as competently as doctors. PATIENTS AND METHODS: A randomized controlled non-inferiority trial compared the adequacy and the accuracy of diagnostic upper gastrointestinal endoscopies performed by five medical and two nurse endoscopists. The videotaped procedures were assessed by a consultant gastroenterologist blinded to the identity of the endoscopist. RESULTS: 641 patients were randomly allocated (before attendance and consent procedure) to endoscopy carried out either by a doctor or a nurse. Of these, 412 were enrolled and 367 (89 %) were included in the analysis. An adequate view was obtained throughout in 53.4 % (93/177) of doctor endoscopies and 91.6 % (174/190) of nurse endoscopies (difference 38.2 %, 95 % CL 30.5 %, 47.2 %). In adequately viewed areas, the mean agreement between doctor and expert was 81.0 % and between nurse and expert it was 78.3 % (difference between the means 2.7 %, 95 % CL - 1.0 %, 6.4 %). There was no difference between doctors and nurses in the rate of biopsy performance (90.4 % and 91.1 %, respectively, P = 0.862). Nurses took longer (8.1 minutes vs. 4.6 minutes, P < 0.001) and used intravenous sedation more often (57.6 %, P = 0.027). Adequacy of view correlated positively with endoscopy duration ( P < 0.001), but diagnostic accuracy correlated inversely with duration ( P < 0.001). Neither adequacy or accuracy correlated significantly with use of intravenous sedation. CONCLUSIONS: In endoscopies performed by nurses, the proportion of adequate examinations was much higher than that found for doctors. In areas with an adequate view, there is no significant difference in accuracy between nurses and doctors. Nurses can provide an accurate general diagnostic upper gastrointestinal endoscopy service as competently as doctors.

Cyclosporin A has differential effects on the responses of murine B cells to TI antigens and B-cell mitogens.

The effect of cyclosporin A (CyA) on the response of murine splenocytes to B-cell mitogens, TI-1 and TI-2 antigens was investigated. The proliferative response to LPS was found to be four- to five-fold less sensitive to inhibition than that to dextran sulphate. Antibody responses to a TI-2 antigen in vivo were suppressed by CyA treatment, whereas responses to the TI-1 antigen DNP-LPS were markedly enhanced. Enhanced antibody responses to DNP-LPS were also demonstrable in vitro in the presence of CyA, and the enhancement was not removed by T-cell depletion. LPS-induced antibody production in vitro was enhanced at the same CyA concentrations that inhibited proliferation by 40-50%. The implications of these findings for the mechanism of action of CyA and for our understanding of B-cell differentiation are discussed.

Increased sensitivity of gastrin cells to gastric distension following antral denervation in the rat.

1. Secretion of the antral hormone gastrin is increased by protein in the gastric lumen and by nervous reflexes. We have examined the relative importance of luminal and neuronal mechanisms, by lesioning the antral innervation using benzalkonium chloride. 2. Benzalkonium chloride was applied to the serosa of the antrum in anaesthetized rats. In some animals, a stainless-steel cannula was also implanted in the corpus. Animals were allowed 10 days to recover. Plasma gastrin was measured by radioimmunoassay and mRNAs encoding gastrin, somatostatin and histidine decarboxylase were measured by Northern blot. 3. Antral denervation was associated with gastric retention after fasting, and elevated plasma gastrin (28.4 +/- 7 pM compared with 7.6 +/- 1.0 pM in controls). When fasted control or denervated rats were refed, plasma gastrin increased 3-fold in both cases. A gastrin-releasing peptide antagonist inhibited the post-prandial rise in plasma gastrin in control rats, but had no effect in antrally denervated rats. 4. In fasted, antrally denervated rats with a gastric fistula, basal gastric acid secretion was depressed 3-fold, and plasma gastrin concentrations were similar to controls. 5. Distension of the stomach with peptone via a barostat attached to the gastric cannula (5 cm H2O, 30 min), produced 3-fold increases in plasma gastrin in both control and denervated rats. However, distension with a non-nutrient solution at pH 6.0 had no effect in controls, but increased gastrin to a similar extent to peptone in denervated rats; distension with 50 mM HCl had no effect in either control or denervated rats. 6. Somatostatin and gastrin mRNA abundances in the antrum were depressed by about 35% by antral denervation, but somatostatin mRNA in the corpus was unchanged; GAPDH mRNA abundance was unaffected by antral denervation. 7. The data suggest that luminal nutrient releases gastrin in the rat, in vivo, via activation of antral neurons secreting gastrin-releasing peptide, and that the antral innervation normally inhibits G-cell responses to non-nutrient distension of the stomach. After antral denervation, gastric distension with a non-nutrient solution is an adequate stimulus for gastrin release.

Relation between cholecystokinin and antral innervation in the control of gastric emptying in the rat.

BACKGROUND: Antral motility and the hormone cholecystokinin (CCK) are major determinants of the rate of gastric emptying. The relation between CCK and antral neurons in regulating gastric emptying is uncertain. Benzalkonium chloride (BAC) causes selective lesions in gut myenteric neurons after serosal application. AIM: To develop a model of antral denervation using BAC to enable the study of the relation between CCK and antral neurons in regulating gastric emptying. METHODS: BAC, vehicle or the afferent neurotoxin capsaicin were applied to the serosal surface of the rat antrum or corpus; neurochemical markers of intrinsic and afferent neurons were detected by using immunohistochemistry and radioimmunoassay. Gastric retention of solids was determined after fasting, and emptying of liquids was measured in rats with gastric fistulae. RESULTS: In BAC treated rats radioimmunoassay of tissue extracts revealed a dose related specific loss of gastrin releasing peptide, substance P, and vasoactive intestinal polypeptide immunoreactivities from the treated region, and immunohistochemistry revealed loss of the neuronal marker PGP 9.5 and the afferent neuropeptide calcitonin gene related peptide (CGRP). Adjacent untreated regions were unaffected by BAC, with the exception that CGRP was depleted in both corpus and antrum after antral treatment. After antral BAC treatment fasted rats retained solids for over 48 hours. Moreover, in antrally denervated rats with gastric fistulae, the emptying of saline, acid and peptone was delayed substantially. The CCK dependent inhibition of gastric emptying of peptone was preserved after antral treatment with BAC. CONCLUSIONS: Serosal BAC causes lesions in the innervation of the treated region of the stomach. The innervation of the antrum is essential for normal emptying of both liquids and solids, but the inhibition of gastric emptying produced by CCK is not dependent on antral neurons.

Gastrin biosynthesis in the antrum of patients with pernicious anemia.

BACKGROUND & AIMS: The gastrin precursor progastrin produces multiple alternative active products, but the pathways of posttranslational processing in human antral mucosa have not yet been studied directly. The aim of this study was to investigate the biosynthetic relationships and release kinetics of newly synthesized progastrin-derived peptides in the antrum of patients with pernicious anemia. METHODS: Antral mucosal explants were incubated with [35S]sulfate and [3H]tyrosine to label progastrin and its derivatives, which were detected by online scintillation counting after immunoprecipitation and high-performance liquid chromatography. RESULTS: [35S]- and [3H]progastrin were detected within 2.5 hours, and labeled G34Gly and G34 were readily detected after 5-hour incubation. Pulse-chase studies indicated conversion of progastrin to G17 via G34Gly and G34. Secretion of newly synthesized G34, but not G34Gly, was routinely detected; G17Gly was present only in trace quantities in cell extracts and media. In control samples, progastrin synthesis was about 10 times lower than in pernicious anemia samples, although the proportions of different labeled amidated gastrins after 5-hour incubation were similar. CONCLUSIONS: In the antrum of patients with pernicious anemia, Gly-gastrins, particularly G34Gly, are biosynthetic intermediates and not major secretory products. Some G34 is secreted preferentially under basal conditions.

Octreotide suppression test predicts beneficial outcome from antrectomy in a patient with gastric carcinoid tumor.

Multiple gastric carcinoids are a well-recognized complication of hypergastrinemia associated with chronic atrophic gastritis. However, the management of large tumors (>2 cm in diameter) remains uncertain, with the decision between antrectomy or total gastrectomy being empirical. This report describes the investigation of a patient with chronic atrophic gastritis and multiple large gastric carcinoid tumors. Before surgery, octreotide was infused for 72 hours to suppress enterochromaffin-like (ECL) cell and gastrin cell function. The infusion decreased plasma gastrin and gastrin synthesis; moreover, there were marked reductions in markers of ECL cell function, e.g., histidine decarboxylase and chromogranin A messenger RNA abundance, in carcinoid tumor tissue and macroscopically normal corpus mucosa. An antrectomy was performed, after which the patient made an uneventful recovery. Six months after surgery, a single residual polyp, enriched with smooth muscle cells but not ECL cells, was removed. One year after antrectomy, the remaining stomach was normal. The response of ECL cell markers in carcinoid tissue to octreotide suggested that these cells were under neuroendocrine control and, therefore, predicted a beneficial outcome for antrectomy. It is suggested that an octreotide supression test coupled with assay of histidine decarboxylase or chromogranin A gene expression is useful in the assessment of gastric carcinoid tumors.

Effects of keratinocyte growth factor (KGF) on gut growth and repair.

Keratinocyte growth factor (KGF) is a mitogen found throughout the gastrointestinal tract, but its role in gastrointestinal pathophysiology is unclear. The effect of recombinant KGF on gut growth and repair has been examined using a variety of in vivo models. Rats receiving total parenteral nutrition had co-infusions of KGF or control for 6 days. Changes in gut growth (wet weight and vincristine-induced metaphase arrest) were then assessed. The effects of KGF on gastric repair and acid secretion in rats were determined using an indomethacin (20 mg/kg)/restraint model and animals fitted with chronic gastric fistulae. KGF at 0.1, 1, and 3 mg/kg increased gut growth as assessed by wet weight throughout the gastrointestinal tract and increased vincristine-induced accumulation of metaphases in the stomach and small intestine but not in the colon. Plasma gastrin, peptide YY, enteroglucagon, and glucagon-like peptide-1 were all increased, whereas insulin was lowered by KGF (all P < 0.01). KGF was ineffective in reducing indomethacin-induced gastric damage but caused a reduction in basal acid secretion of about 35 and 50 per cent when administered at 0.2 or 5 mg/kg (P < 0.05). These studies support the idea that KGF is involved in the control of proliferation of the gastrointestinal tract. They do not provide evidence, however, for a role in the early reparative process invoked during short-term models of gastrointestinal injury.

Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia.

BACKGROUND & AIMS: The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients. METHODS: Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells. RESULTS: Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway. CONCLUSIONS: Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.