Prevalence of Histological Gastritis in a Community Population and Association with Epigastric Pain.

BACKGROUND AND AIMS: Gastritis is a common histological diagnosis, although the prevalence is decreasing in developed populations, alongside decreasing prevalence of H. pylori infection. We sought to determine the prevalence of the etiology of gastritis in a Swedish population sample and to analyze any associations with symptoms, an area of clinical uncertainty. METHODS: Longitudinal population-based study based in Östhammar, Sweden. A randomly sampled adult population completed a validated gastrointestinal symptom questionnaire (Abdominal Symptom Questionnaire, ASQ) in 2011 (N = 1175). Participants < 80 years of age and who were eligible were invited to undergo esophagogastroduodenoscopy (EGD) (N = 947); 402 accepted and 368 underwent EGD with antral and body biopsies (average 54.1 years, range 20-79 years; 47.8% male) with H. pylori serology. RESULTS: Gastritis was found in 40.2% (148/368; 95% CI 35.2-45.2%). By rank, the most common histological subtype was reactive (68/148; 45.9%), then H. pylori (44/148; 29.7%), chronic non-H. pylori (29/148; 19.6%), and autoimmune (4/148; 2.7%). Gastritis was significantly associated with older age and H. pylori status (p < 0.01). Gastritis subjects were divided into three histological categories: chronic inactive inflammation, autoimmune gastritis, and active inflammation; there was no difference in the presence of upper gastrointestinal symptoms when categories were compared to cases with no pathological changes. Functional dyspepsia or gastroesophageal reflux were reported in 25.7% (38/148) of those with gastritis (any type or location) versus 34.1% (75/220) with no pathological changes (p = 0.32). Epigastric pain was more common in chronic H. pylori negative gastritis in the gastric body (OR = 3.22, 95% CI 1.08-9.62). CONCLUSION: Gastritis is common in the population with a prevalence of 40% and is usually asymptomatic. Chronic body gastritis may be associated with epigastric pain, but independent validation is required to confirm these findings. Clinicians should not generally ascribe symptoms to histological gastritis.

Food and functional dyspepsia: a systematic review.

BACKGROUND: Functional dyspepsia (FD) is a debilitating functional gastrointestinal disorder characterised by early satiety, post-prandial fullness or epigastric pain related to meals, which affects up to 20% of western populations. A high dietary fat intake has been linked to FD and duodenal eosinophilia has been noted in FD. We hypothesised that an allergen such as wheat is a risk factor for FD and that withdrawal will improve symptoms of FD. We aimed to investigate the relationship between food and functional dyspepsia. METHODS: Sixteen out of 6451 studies identified in a database search of six databases met the inclusion criteria of studies examining the effect of nutrients, foods and food components in adults with FD or FD symptoms. RESULTS: Wheat-containing foods were implicated in FD symptom induction in six studies, four of which were not specifically investigating gluten and two that were gluten-specific, with the implementation of a gluten-free diet demonstrating a reduction in symptoms. Dietary fat was associated with FD in all three studies that specifically measured this association. Specific foods reported as inducing symptoms were high in either natural food chemicals, high in fermentable carbohydrates or high in wheat/gluten. Caffeine was associated with FD in four studies, although any association with alcohol was uncertain. CONCLUSIONS: Wheat and dietary fats may play key roles in the generation of FD symptoms and reduction or withdrawal eased symptoms. Randomised trials investigating the roles of gluten, FODMAPs (fermentable oligosaccharide, disaccharide, monosaccharide and polyols) and high fat ingestion and naturally occurring food chemicals in the generation of functional dyspepsia symptoms are warranted and further investigation of the mechanisms is now required.

Comparing virtual with conventional microscopy for the consensus diagnosis of Barrett's neoplasia in the AspECT Barrett's chemoprevention trial pathology audit.

AIMS: To compare the diagnostic accuracy of conventional versus virtual microscopy for the diagnosis of Barrett's neoplasia. METHODS AND RESULTS: Sixty-one biopsies from 35 ASPirin Esomeprazole ChemopreventionTrial (AspECT) trial patients were given a Barrett's neoplasia score (1-5) by a panel of five pathologists using conventional microscopy. Thirty-three biopsies positive for neoplasia were digitized and rescored blindly by virtual microscopy. Diagnostic reliability was compared between conventional and virtual microscopy using Fleiss' kappa. There was substantial reliability of diagnostic agreement (κ = 0.712) scoring the 61 biopsies and moderate agreement scoring the subgroup of 33 'positive' biopsies with both conventional microscopy (κ = 0.598) and virtual microscopy (κ = 0.436). Inter-observer diagnostic agreement between two pathologists by virtual microscopy was substantial (κ = 0.76). Comparison of panel consensus neoplasia scores between conventional and virtual microscopy was almost perfect (κ = 0.8769). However, with virtual microscopy there was lowering of the consensus neoplasia score in nine biopsies. CONCLUSIONS: Diagnostic agreement with virtual microscopy compares favourably with conventional microscopy in what is recognized to be a challenging area of diagnostic practice. However, this study highlights possible limitations for this method in the primary diagnostic setting.

A Candidate Magnetic Sense Organ in the Yellowfin Tuna, Thunnus albacares.

Single-domain magnetite crystals have been isolated and characterized from tissue located in a sinus within the dermethmoid bone of the skull of the yellowfin tuna, Thunnus albacares. Their chemical composition, narrow size distribution, and distinctive crystal morphology indicate that these crystals are biochemical precipitates. Experiments on the interaction between particles reveal the organization of the particles in situ and suggest a possible form for candidate magnetoreceptor organelles. The consistent localization of such particles with similar arrangement within the dermethmoids of this and other pelagic fishes suggests that the ethmoid region is a possible location for a vertebrate magnetic sense organ.

Regulation of prostate cell growth and morphogenesis by Dickkopf-3.

Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dickkopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNA-mediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression.

Functional dyspepsia is associated with duodenal eosinophilia in an Australian paediatric cohort.

BACKGROUND: The pathophysiology of functional dyspepsia (FD) remains unknown. Duodenal eosinophil infiltration has been reported. AIM: To assess the association between dyspeptic symptoms and duodenal eosinophilia in children undergoing upper gastrointestinal endoscopy. METHODS: In this retrospective cohort study, children with normal upper endoscopy and routine histology at a single tertiary paediatric centre between 2010 and 2014 were included. FD was defined as epigastric pain or discomfort >2 months without response to acid suppression. Controls presented with nonerosive reflux disease, dysphagia or rumination syndrome. Intramucosal eosinophil counts were compared between the groups using uni- and multivariate regression analyses. RESULTS: Thirty-six cases and 36 nonmatched controls were identified. Atopic history (39% vs. 25%) and psychological comorbidity (53% vs. 39%; both P = 0.2) were frequent in cases and controls. Self-reported nausea (64% vs. 17%; P < 0.0001), lethargy (19% vs. 0%; P = 0.005) and family functional gastrointestinal disorder(FGID) (28% vs. 3%; P = 0.003) were more common in cases than controls. Duodenal eosinophil counts [median (IQR): 151 (118-207) vs. 76 (60-106) per mm2 ; P < 0.001] were significantly higher in cases than controls with >112 eosinophils per mm2 predictive for FD (OR: 33.6, 95% CI: 7.1-159.0; P < 0.001). Duodenal eosinophilia was associated with weight loss (OR: 7.1, 95% CI: 1.1-45.5; P = 0.04). CONCLUSIONS: Functional dyspepsia in children is strongly associated with duodenal eosinophilia, in the absence of endoscopic or routine histological findings. Frequent atopic and psychological comorbidity illustrate likely multifactorial mechanisms.

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

Magnetite-based magnetoreception.

Orientation, navigation, and homing are critical traits expressed by organisms ranging from bacteria through higher vertebrates. Sensory systems that aid such behavior have provided key selective advantages to these groups over the past 4 billion years, and are highly evolved; magnetoreception is no exception. Across many species and groups of organisms, compelling evidence exists that the physical basis of this response is tiny crystals of single-domain magnetite (Fe3O4). It is the opinion of the authors that all magnetic field sensitivity in living organisms, including elasmobranch fishes, is the result of a highly evolved, finely-tuned sensory system based on single-domain, ferromagnetic crystals.

Brn-3a neuronal transcription factor functional expression in human prostate cancer.

Neuroendocrine differentiation has been associated with prostate cancer (CaP). Brn-3a (short isoform) and Brn-3c, transcriptional controllers of neuronal differentiation, were readily detectable in human CaP both in vitro and in vivo. Brn-3a expression, but not Brn-3c, was significantly upregulated in >50% of tumours. Furthermore, overexpression of this transcription factor in vitro (i) potentiated CaP cell growth and (ii) regulated the expression of a neuronal gene, the Nav1.7 sodium channel, concomitantly upregulated in human CaP, in an isoform-specific manner. It is concluded that targeting Brn-3a could be a useful strategy for controlling the expression of multiple genes that promote CaP.

Inhibition of cytotoxic T-cell clonal expansion by cyclophosphamide and the recovery of cytotoxic T-lymphocyte precursors by supernatants from mixed-lymphocyte cultures.

Spleen cells from mice treated with cyclophosphamide (150 mg/kg) and cultured at suboptimal concentrations do not generate a cytotoxic T-lymphocyte (CTL) response to allogeneic tumor cells. The reduced response of spleen cells from cyclophosphamide-treated mice is not due to the elimination of CTL precursors because normal responses are obtained by the addition of a helper factor(s) derived from mixed lymphocyte culture supernatants. The results indicate that helper cells, required for development of CTL responses to tumor alloantigens, are eliminated by cyclophosphamide in the absence of evident toxicity to CTL precursors.

A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo.

Functional expression of voltage-gated sodium channel alpha-subunits (VGSCalphas), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro. Furthermore, VGSC activity in vitro directly potentiates processes integral to metastasis. To investigate VGSCalpha expression in CaP in vivo, immunohistochemistry and real-time PCR were performed on human prostate biopsies (n>20). VGSCalpha immunostaining was evident in prostatic tissues and markedly stronger in CaP vs non-CaP patients. Importantly, RT-PCRs identified Nav1.7 as the VGSCalpha most strikingly upregulated (approximately 20-fold) in CaP, and the resultant receiver-operating characteristics curve demonstrated high diagnostic efficacy for the disease. It is concluded that VGSCalpha expression increases significantly in CaP in vivo and that Nav1.7 is a potential functional diagnostic marker.

Identification of early environmental risk factors for irritable bowel syndrome and dyspepsia.

BACKGROUND: The role of childhood environment including exposure to infection via siblings and pets in irritable bowel syndrome (IBS) and dyspepsia is relatively unknown. We assessed proxy measures of microbial exposure in early childhood to assess if these are associated with IBS and functional dyspepsia in later life. METHODS: Participants (n = 767, response rate = 53%) were a random population sample from Sydney, Australia who previously responded to a validated survey. IBS and functional dyspepsia were defined using Rome III criteria. Early environmental risk factors assessed included type of birth delivery, premature birth, breastfeeding, bedroom sharing, and pet exposure (the latter two then combined as early hygiene factors) up to 5 years of age. Post infectious IBS (PI-IBS) was assessed by development of IBS following gastroenteritis. KEY RESULTS: In this sample, in adult life 17% developed IBS (of which 20% had PI-IBS) and 12% functional dyspepsia. Development of IBS was associated with childhood factors-a shorter duration of breastfeeding (odds ratios [OR] = 0.87, 95% CI: 0.78-0.97, p = 0.01), sharing a bedroom (OR = 1.89, 95% CI: 1.73-3.08, p = 0.01), exposure to a herbivore pet (OR = 1.65 (1.10, 2.48), p = 0.02), and hygiene factors (OR = 4.39; 95% CI: 1.89-10.21, p = 0.001). The sole factor associated with functional dyspepsia was exposure to a herbivore pet (1.79; 95% CI: 1.19-2.87, p = 0.02). CONCLUSIONS & INFERENCES: Childhood environment factors, particularly bedroom sharing and pet exposure, combined with subsequent risk of microbial exposure are a risk factor for IBS in later life. These associations however need confirmation to rule out any risk of a type I error.

Aromatase activity and interleukin-6 production by normal and malignant breast tissues.

The aromatase enzyme complex, which regulates the conversion of androstenedione to estrone, may have an important role in regulating estrogen synthesis in breast tissues. In this study the effect of tumor location on aromatase activity in adjacent tissue was examined and related to interleukin-6 (IL-6) production, which has been shown to stimulate aromatase activity in breast cancer cells. Samples of normal and malignant breast tissues were obtained from 11 women undergoing mastectomy. In 7 patients, aromatase activity was highest in the quadrant in which the tumor was located or on which the tumor impinged. Aromatase activity in tumor-bearing quadrants was significantly higher than that in adjacent and opposite quadrants. Aromatase activity and IL-6 production, expressed in terms of tissue weight, were significantly higher for tumor tissue compared with normal breast adipose tissue. A significant correlation was found between aromatase activity and IL-6 production for breast tumor tissue (rs = 0.56; P < 0.05), but not for adipose tissue from the breast quadrants. Aromatase activity and IL-6 production were also measured in tissue obtained from a normal woman undergoing reduction mammoplasty who had previously had breast augmentation by silicone injection, not contained within a capsule. In tissue from this patient there was evidence of chronic inflammation and a marked macrophage response. Aromatase activity in this tissue was considerably higher than that detected in mastectomy adipose tissue samples, and a significant correlation was found between aromatase activity and IL-6 production (rs = 0.77; P < 0.05). A preliminary study to examine the potential role of cells of the immune system in regulating breast tissue aromatase activity revealed that conditioned medium collected from macrophages and lymphocytes could markedly stimulate aromatase activity in tumor-derived fibroblasts. The results of this study confirmed that breast tumor location can influence aromatase activity in adjacent tissues and showed that aromatase activity is increased in tumor-bearing quadrants. The increased production of IL-6 by tumor tissue and its correlation with aromatase activity suggest that tumors may be the major source of IL-6, which is able to influence aromatase activity in adjacent tissues.

Immunochemical detection of cell cycle synchronization in a human erythroleukemia cell line, K562.

Cells of the human erythroleukemic line K562 can be induced by manipulation of culture conditions to arrest within the G1 phase of the cell cycle, and subsequently to enter S phase synchronously after release from G1. Cell cultures subjected to serum deprivation and hydroxyurea (HU) treatment demonstrated less than 5% of the cells to be in S phase. Four hours after release from HU, 63% of the cells were in S phase, as detected by immunofluorescent staining. This protocol offers a method for synchronization of K562 cells at the G1/S border and a technique for detection of S-phase cells without the use of radioisotopes or flow cytometry instrumentation.

Magnetic orientation and the magnetic sense in arthropods.

The physical properties of the earth's magnetic field are summarized with the aim of emphasizing their significance as cues that can be exploited in orientational tasks. Past work has revealed magnetic orientation in vertebrates as well as invertebrates, including arthropods. The key finding to date has been that, as opposed to many vertebrates, the magnetic compass of arthropods responds to the polarity, rather than to the inclination of the earth's magnetic field. As in the case of vertebrates, the debate over how arthropods detect magnetic fields has yet to be resolved. Currently, evidence has been reported in support of a detection system based on magnetite crystals together with a variety of detection systems based on events occurring at the molecular level. Interactions between the magnetic and other compasses in orientation experiments suggest the existence of an area in the brain where spatial orientation information from magnetic and other stimuli converges. The slow advance of our knowledge on magnetic orientation in arthropods, as opposed to the much better understanding of magnetic orientation in vertebrates, arises from difficulties in identifying the appropriate behavioural contexts in which arthropods respond to magnetic fields in both laboratory and field situations. Arthropods thus present challenges not only in demonstrating magnetic orientation, but also in elucidating the sensory mechanisms involved in the perception of magnetic fields.

Hemoglobin induction by Ara-C in human erythroleukemic cells (K562) is cell-cycle dependent.

This study was undertaken to answer the question of whether chemical induction of hemoglobin in the human erythroleukemic line K562 is cell-cycle dependent. Cells were synchronized with respect to the cell cycle by manipulation of culture conditions. S phase was detected microscopically by immunofluorescent staining. Hemin and arabinofuranosylcytosine (Ara-C) were used to induce hemoglobin synthesis in K562 cells. The action of hemin causes induction without specificity in regard to cell cycle phase, while Ara-C is dependent upon cell cycle phase, with cells within late G1 and early S phases being sensitive to the effect of the agent. These studies also confirm the results that the action of hemin is reversible but the induction caused by Ara-C is irreversible. The synergistic effects of these two inducing agents resulted in a sharper rise in the percentage of induced cells.

Gastric metaplasia: its role in duodenal ulceration.

There is good evidence to suggest that gastric metaplasia in the proximal duodenum and Helicobacter pylori gastritis are essential requirements for the development of duodenal ulceration in most cases. Gastric metaplasia is most likely to be a defence response or adaptation to excess acid reaching the duodenum. The appearance of gastric-type epithelium over the duodenal villi probably results from substitution by cells migrating from Brunner's gland ducts. These metaplastic foci provide sites for colonization by H. pylori passing through the duodenum; the organisms do not attach to native duodenal epithelial cells. Having colonized the metaplastic areas, H. pylori provokes an active chronic inflammatory response akin to that seen in the gastric mucosa. Active chronic duodenitis leads to a weakening of mucosal defence against acid-peptic attack, and erosion and ulceration may ensue. Healing of ulcers by conventional acid-reducing treatments does not influence the extent of gastric metaplasia, (although there may be some reduction with long-term proton pump inhibitors); nor do such regimens affect the background duodenitis. Only with eradication of H. pylori is there resolution of inflammation, but studies to date indicate that eradication alone has no substantial effect on the prevalence or extent of gastric metaplasia. Nevertheless the elimination of H. pylori appears to remove one of the essential co-factors for duodenal ulceration and the patient can be considered cured, despite the persistence of gastric metaplasia.

Two-week eradication regimen for metronidazole-resistant Helicobacter pylori.

At present there is no generally accepted treatment regimen for eradicating metronidazole-resistant Helicobacter pylori. This study determines the eradication rate after treatment with 40 mg omeprazole o.m. and 500 mg amoxycillin q.d.s. for 14 days, with 120 mg tripotassium dicitrato bismuthate q.d.s. for the first week (Days 1-7) and 750 mg ciprofloxacin b.d. for the second week (Days 8-14). Thirty patients (16 male, mean age 45 years, range 16-80 years) with duodenal ulcers (n = 18) or non-ulcer dyspepsia (n = 2) and metronidazole-resistant H. pylori detected by histology, culture, in vitro sensitivity tests and a positive 13C-urea breath test entered the study. Follow-up was by 13C-urea breath test at the end of treatment and at 1, 3, 6, and 12 months. Eradication was defined as a negative 13C-urea breath test at least 1 month after finishing treatment. H. pylori was successfully eradicated in 21/30 (71%) patients (median follow-up 10.2 months, range 4-12 months). A pre-treatment ciprofloxacin-resistant strain was isolated in 1/9 patients in whom eradication failed. Of 30 patients 29 completed the 2-week regimen; one patient experienced dizziness after 3 days of treatment. The most common side-effect was increased stool frequency (n = 6). This 2-week treatment regimen for metronidazole-resistant H. pylori is well tolerated and achieves an eradication rate of 70%.

Lansoprazole, clarithromycin and metronidazole for seven days in Helicobacter pylori infection.

BACKGROUND: This study determines the efficacy and safety of a 1-week triple therapy regimen of lansoprazole, clarithromycin and metronidazole in an area with a high prevalence of pre-treatment metronidazole-resistant strains of Helicobacter pylori. METHODS: Seventy-five H. pylori positive patients with gastritis or duodenal ulcer were entered into an open study of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. H. pylori status was determined by CLOtest, histology, culture and by 13C-urea breath test (repeated > or = 28 days after treatment). RESULTS: Seventy-one patients completed the treatment and returned for follow-up. H. pylori was eradicated in 61 of 71 (86%) patients by per-protocol analysis, and in 61 of 75 (81%) patients by intention-to-treat analysis. H. pylori was eradicated in 12 of 16 (75%) patients with metronidazole-resistant strains compared with 22 of 24 (92%) in patients with metronidazole-sensitive strains of H. pylori (P = 0.14). Fourty-five patients reported at least one adverse event, and three patients stopped treatment due to them (two with headaches and one with diarrhoea). CONCLUSIONS: A 1-week course of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. eradicates H. pylori in up to 86% of patients. It is of proven benefit in patients with pre-treatment metronidazole-resistant strains of H. pylori.