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A 74-year-old man with metastatic gastro-oesophageal adenocarcinoma involving coeliac lymph nodes and liver was treated with fluorouracil and oxaliplatin (FOLFOX) chemotherapy. Despite initial good response, Oxaliplatin was omitted after development of significant peripheral neuropathy. His subsequent imaging showed progression of disease, predominantly in the liver. Selective internal radionuclide therapy (SIRT–Yttrium-90 (90Y) resin microsphere radioembolisation) was chosen by the multidisciplinary team as the modality to target his dominant left hepatic lobar disease. 90Y is a β-particle emitter suitable for radionuclide therapy, which, until recently, was not thought to be able to provide images directly from the decay of the radionuclide.1 Pretreatment (18F) …

The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy.We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology.The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P0.0001) were significantly higher with the addition of AATKI.The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.

Superannuation fund fees have come under public scrutiny in recent years, with some observers arguing that fees are set too high. This report focuses on a sample of Australian superannuation funds to gain a better understanding of the factors that influence the fees that they charge. We examine how fund size, asset allocation, risk category and fund type influence investment fees. Previous research has not precisely linked the investment fee to the asset allocation of each superannuation fund in Australia. The results reveal that exposure to certain asset classes helps to explain investment fees. Our results show that this difference provides an intuitive reason as to why investment fees differ between funds. The simple economic reasoning is that the superannuation funds with higher investment fees usually have higher allocations to riskier asset classes, which are more expensive to manage. After taking into account the asset allocation for each fund, we find convincing evidence that there are differences in the fees charged by corporate funds, industry funds, retail funds and public sector funds. These fee differences exist across investment, administration and total fees. We find that industry funds charge an investment fee that is over 12 basis points cheaper than a retail fund after taking into account the differences in asset allocation. This is a significant amount given that the average investment fee is around 60 basis points in our sample.

This paper draws on exploratory research examining the sexual and ageing identities of gay men in England and the way in which these affect welfare needs and service use experiences. In this case, the focus is not upon the research findings per se, but on the research methods used to elucidate them. The author theorises about the ways in which the qualitative interviewing that took place was influenced by his age, homosexuality, and gender during the interaction with older gay men. The conclusions are that the shared gender and sexual orientation (although not without their differences) were crucial to the successful completion of the research and in trying to ensure participants felt valued and empowered. Therefore, it is asserted from this that increasingly reflexive research is paramount to the development of qualitative methodologies and gerontology, to ensure the academe is inclusive of diverse identities and that its research stands up to rigorous scrutiny.

Several studies have explored the production and immunogenicity of HpaA as a potential protective antigen against Helicobacter pylori but little is known regarding its protective capabilities. We therefore evaluated the protective efficacy of recombinant HpaA (rHpaA) as a candidate vaccine antigen against H. pylori. To explore the impact of genetic diversity, inbred and outbred mice were prophylactically and therapeutically immunized with rHpaA adjuvanted with cholera toxin (CT). Prophylactic immunization induced a reduction in bacterial colonization in BALB/c and QS mice, but was ineffective in C57BL/6 mice, despite induction of antigen-specific antibodies. By contrast, therapeutic immunization was effective in all three strains of mice. Prophylactic immunization with CT-adjuvanted rHpaA was more effective when delivered via the nasal route than following intragastric delivery in BALB/c mice. However, HpaA-mediated protection was inferior to that induced by bacterial lysate. Hence, protective efficacy is inducible with vaccines containing HpaA, most relevantly shown in an outbred population of mice. The effectiveness of protection induced by HpaA antigen was influenced by host genetics and was less effective than lysate. HpaA therefore has potential for the development of effective immunization against H. pylori but this would probably entail the antigen to be one component of a multiantigenic vaccine.

Having a good mentor early in your career can mean the difference between success and failure in any field. Adrian Lee, Carina Dennis and Philip Campbell look at what makes a good mentor. Now in their third year, the Nature awards for mentoring in science recognize outstanding achievement in scientific mentoring and the fostering of scientific creativity. Nominations for 2007 — for high-achieving mentors in South Africa — are now closed. But in this issue we publish “Nature's guide for mentors”. Drawing from the rich resource provided by the applications for the 2006 awards, the guide is intended for young scientists embarking on a career as a mentor either of their graduate students or of staff in their research team.

© 2015 Elsevier Inc. This paper aims to estimate the global information distribution in the OTC gold market. Using the two-scale realized variance as a proxy for information flow, we estimate the information shares of Asia, Europe, London/New York and the United States, with London/New York covering the two-hour overlapping trading in London afternoon and New York morning. We find that over the sample period of 1996 to 2012, the average daily information shares are 17%, 31%, 22%, and 30% for Asia, Europe, London/New York and the U.S., respectively. On a per-hour basis, the information share of London/New York is over two and half times of those of the rest of Europe and the U.S., and over five times of the information share of Asia. Despite doubling its share of OTC trading, Asia's information share actually declined from about 20% in the late 1990s to around 15% in 2009-2012, with the opposite trend for the London/New York market. Private information flow, measured by the volatility impact of unexpected order flows, has a flatter distribution across Asia, Europe, and the U.S., possibly due to the presence of the same large gold dealers in different markets. The declining information share of Asia and the concentration of information to the two-hour London/New York trading raise concerns for regional market development and global market stability.

We compared seedling emergence and soil seed bank composition under an Acacia mangium plantation and an adjacent tropical heath forest in the Andulau Forest Reserve, Brunei Darussalam. Soil samples were collected from ten 20 x 20 m plots set up in three contrasting habitats: the Acacia plantation, the adjacent heath forest, and the transition zone in-between. Soil samples were subjected to smoke and heat treatments, following which seedling emergence was observed daily over a 12-week period. In a parallel investigation, variations in species richness, seed density and seed viability of the soil seed banks of the ten plots were investigated. Seedling emergence was significantly highest in the plantation and lowest in the heath forest plots respectively. However, no significant differences among treatments, and no significant treatment-habitat interactions were detected. Species richness, seed density and seed viability in the plantation plots were significantly lower than the transition zone and intact heath forest plots. A. mangium seeds were not recorded in the heath forest soil seed banks but were detected in the plantation and transition zone plots. Lower native plant species richness, seed density and viability in the A. mangium plantation could imply higher regeneration potential for the heath forest habitat if severe habitat destruction was to occur in this forest reserve. We suggest that proper plantation management practices and close monitoring of soil seed banks are the best mechanisms that could be adopted to minimize the gradual spread of invasive Acacias into natural tropical heath forests of Borneo.

We investigate whether the cultural distance between a homebuyer’s ethnicity and that of the neighborhood affects a homebuyer’s location choice of the home and the home’s transaction price. Utilizing individual home sales data of culturally diverse Sydney, Australia, we find homebuyers are more likely to choose neighborhoods with a shorter cultural distance, and are willing to pay a premium for homes in those locations, consistent with homebuyers’ preference for similar cultures. Home culture preference is stronger for ethnicities from recent migration waves, particularly Asia. Our results are robust to endogeneity and self-selection concerns. The findings have implications on the role of cultural and demographic shifts on housing prices.

Background: Helicobacter pylori is a causative agent of gastric and duodenal ulcers and gastric cancer. Its urease enzyme allows survival in acid conditions and drives bacterial intracellular metabolism. We aimed to investigate the role of urease in determining the intragastric distribution of Helicobacter species in vivo. Materials and Methods: The C57BL/6 mouse model of gastritis was used for infection with Helicobacter felis (CS1) or H. pylori (SS1). Urease-modulating compounds urea and/or fluorofamide (urease inhibitor) were administered to mice over 7 days. Concurrent gastric acid inhibition by omeprazole was also examined. Bacterial distribution in the antrum, body, antrum/body, and body/cardia transitional zones was graded “blindly” by histologic evaluation. Bacterial colony counts on corresponding tissue were also conducted. Results: Urease inhibition by fluorofamide decreased H. pylori survival in most gastric regions (p

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (≤10 μM) micromolar range. The antiparkinsonian drugs l -DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1–D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine’s actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson’s disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations.

Background. The interleukin-10-deficient (IL-10−/–) mice maintained in specific-pathogen-free (SPF) conditions develop typhlocolitis when experimentally infected with Helicobacter species. However, there is limited information regarding the role of Helicobacter species that naturally colonize IL-10−/– mice in typhlocolitis development. The aim of this study was to examine in SPF IL-10−/– mice the association between natural colonization specific Helicobacter species and typhlocolitis development. Material and methods. Cecum and proximal colon from 72 C57BL/6 × 129/Ola IL-10−/– mice (8–20 weeks old) were removed for DNA extraction and histologic evaluation. Genus-specific polymerase chain reaction– denaturing gradient gel electrophoresis (PCR–DGGE) and species-specific PCR were used to detect Helicobacter species. Mice were grouped by age, sex, and Helicobacter colonization status, and their histologic scores were compared. The development of clinical typhlocolitis was observed in a further 12 mice. Results. Species-specific PCR showed that mice were colonized with Helicobacter ganmani and/or Helicobacter hepaticus. The PCR–DGGE detected H. ganmani, H. hepaticus and an H. ganmani-like organism. The histologic scores in mice colonized with H. hepaticus were significantly higher than that in mice colonized with H. ganmani. Male mice showed significantly higher histologic scores than female mice. Four of the 12 mice developed clinical typhlocolitis in 38 weeks. Conclusions. Natural colonization with different Helicobacter species was found in IL-10−/– mice within the same breeding colony. The severity of typhlocolitis differed according to the colonizing Helicobacter species. Furthermore, the rate of typhlocolitis development in IL-10−/– mice naturally colonized with Helicobacter species was significantly slower than that reported in experimentally infected mice.

Little is currently known about the aging and later life experiences of older gay men in Britain. This paper seeks to broaden the gerontological understanding of aging for this hitherto invisible group. Using data generated from interviews with 15 homosexual men aged 57-84, the paper argues that traditionally recognized perceptions of aging and transitions from middle to old age are not necessarily reliable indicators of gay men’s experiences. The signposts to aging discussed so far do not account for varied personal characteristics and backgrounds. The framework of aging reminders developed by Karp (2000)1 is shown to be relevant to the perceptions of aging included in the data. However it is argued that these reminders are not necessarily evident just to people in their fifties, and that they may also be experienced in different ways. The paper develops Karp’s model, deconstructing the reminders he introduced to show the variety of ages at which they become evident, the heteronormativity of the existing framework and how this can be reduced, the way reminders inter-connect, and how those relating to the body can usefully be subdivided to elucidate the number of different ways the body can be experienced, highlighting the transition to later life.

While Helicobacter pylori is accepted as the major bacterial agent of gastric disease in humans, some patients and many animals are infected with a larger, tightly helical-shaped bacterium previously referred to as ‘Helicobacter heilmannii’ or ‘Gastrospirillum hominis’. Taxonomic classification of these bacteria has been hampered by the inability to cultivate them in vitro and by the inadequate discriminatory power of 16S rRNA gene sequence analysis. This study describes the detection and phylogenetic analysis of 26 different gastrospirillum isolates from humans and animals, which incorporates sequence data based on the 16S rRNA and urease genes. Fifteen gastrospirilla detected in humans, primates and pigs clustered with ‘Candidatus Helicobacter suis’, thus expanding the host range for this organism. By comparison, based on 16S rRNA data, the remaining 11 gastrospirilla could not be differentiated from Helicobacter felis, Helicobacter bizzozeronii and Helicobacter salomonis. However, urease gene sequence analysis allowed for the discrimination of this latter group into four discrete clusters, three of which contained the above recognized species. The fourth cluster contained isolates from human and feline hosts, and should provisionally be considered a unique bacterial species, for which the name ‘Candidatus Helicobacter heilmannii’ is proposed.

This study determined the test-retest reliability of a grip device that measures the contribution of individual fingers to grip strength and described the pattern of contribution in subjects without hand pathology. Subjects repeated a set of three maximal grip efforts on two occasions separated by two to seven days. Intraclass correlation reliability coefficients were high (>0.75) for eight out of ten strength measures. The percentage contributions of the index, middle, ring, and small fingers to grip were approximately 25%, 35%, 25%, and 14%, respectively. Grip and finger strengths were highly correlated. Anthropometric measures of body size or finger length were moderately correlated with strength measures. These data suggest that there is a predictable pattern by which individual fingers contribute to overall grip strength, which is partially related to body size. The ulnar side of the hand contributes to the smaller proportion of overall grip (approximately 60% radial, 40% ulnar). The clinical utility of finger strength measures should be explored.

Iron is an essential nutrient that is often found in extremely limited available quantities within eukaryotic hosts. Because of this, many pathogenic bacteria have developed regulated networks of genes important for iron uptake and storage. In addition, it has been shown that many bacteria use available iron concentrations as a signal to regulate virulence gene expression. We have utilized DNA microarray technology to identify genes of the human pathogen Helicobacter pylori that are differentially regulated on a growth-inhibiting shift to iron starvation conditions. In addition, the growth phase-dependent expression of these genes was investigated by examining both exponential and stationary growth phase cultures. We identified known iron-regulated genes, as well as a number of genes whose regulation by iron concentration was not previously appreciated. Included in the list of regulated factors were the known virulence genes cagA , vacA , and napA . We examined the effect of iron starvation on the motility of H. pylori and found that exponential- and stationary-phase cultures responded differently to the stress. We further found that while growing cells are rapidly killed by iron starvation, stationary-phase cells show a remarkable ability to survive iron depletion. Finally, bioinformatic analysis of the predicted promoter regions of the differentially regulated genes led to identification of several putative Fur boxes, suggesting a direct role for Fur in iron-dependent regulation of these genes.

Current combination therapies cure Helicobacter pylori infection in 75 to 85% of cases. However, many treatment failures are not explained by antibiotic resistance. Our goal was to explore treatment failures under in vivo conditions by using the H. pylori Sydney strain (SS1) mouse model. Mice infected with H. pylori (SS1) were treated with monotherapies or combination therapies used in human trials. Bacterial levels and distribution of organisms within the stomach were assessed 24 h after treatment to determine clearance and location of treatment failures and 29 days after treatment to determine cure rates. Except for treatment with metronidazole, mono- and dual therapies did not cure infection but resulted in decreases in bacterial levels and differences in distribution within the stomach. In cases of treatment failure when clarithromycin was used, omeprazole and dual therapy with omeprazole and amoxicillin resulted in organisms being cleared from the antrum, but organisms remained in the antrum-body transitional zone. The triple therapies of OMC and bismuth subcitrate, metronidazole, and tetracycline were successful in eradicating infection. Except for metronidazole monotherapy and triple therapy with OAC, there was good correlation between the Sydney strain mouse model and humans with respect to the success of antimicrobial therapy. The antrum-body transitional zone was identified as a sanctuary site in treatment failure. This could result from antimicrobial agents not functioning effectively at this site or bacteria in this location expressing products that protect them against antimicrobial agents. This is the first demonstration of a possible sanctuary site as a reason for failure of therapy.

The acceptance of Helicobacter pylori as a major human pathogen has necessitated the development of animal models to help elucidate the pathogenic mechanisms of this bacterium and aid in the development of improved strategies for the treatment of gastric disease. Appropriate models, utilising a range of animal species, have been developed to examine factors such as the influence of host responses and bacterial factors in disease development and the success of new therapeutic regimens, including vaccination, to cure infection.

Long-term colonization of humans with Helicobacter pylori can cause the development of gastric B cell mucosa-associated lymphoid tissue lymphoma, yet little is known about the sequence of molecular steps that accompany disease progression. We used microarray analysis and laser microdissection to identify gene expression profiles characteristic and predictive of the various histopathological stages in a mouse model of the disease. The initial step in lymphoma development is marked by infiltration of reactive lymphocytes into the stomach and the launching of a mucosal immune response. Our analysis uncovered molecular markers of both of these processes, including genes coding for the immunoglobulins and the small proline-rich protein Sprr 2A. The subsequent step is characterized histologically by the antigen-driven proliferation and aggregation of B cells and the gradual appearance of lymphoepithelial lesions. In tissues of this stage, we observed increased expression of genes previously associated with malignancy, including the laminin receptor-1 and the multidrug-resistance channel MDR-1. Finally, we found that the transition to destructive lymphoepithelial lesions and malignant lymphoma is marked by an increase in transcription of a single gene encoding calgranulin A/Mrp-8.

11536 Background: Liquid biopsy for plasma ctDNA NGS is a rapidly evolving science. Plasma ctDNA assays are commercially available and are increasingly adopted in the community with a paucity of evidence-based guidance. We set out to study the optimal timing and utility of plasma ctDNA NGS in clinic. Methods: Pts with advanced NSCLC who were driver unknown, defined as not having prior tissue NGS or clinical concern for tumor heterogeneity that may affect treatment decisions, were eligible. Peripheral blood was collected in a Streck tube (10mL), DNA extracted, and subjected to a bias-corrected hybrid-capture 21 gene targeted NGS assay in a CLIA lab with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1% (ResolutionBio Bellevue, WA). Pts also had concurrent tissue NGS via MSK IMPACT. Clinical endpoints included detection of oncogenic drivers in plasma, ability to match pts to targeted therapy, concordance and turnaround time of plasma and tissue NGS. Results: Forty-one pts were prospectively accrued. Plasma ctDNA detected an oncogenic driver in 39% (16/41) of pts, of whom 17% (7/41) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insertionYVMA, BRAF L597Q and MET exon14. Mean turnaround time for plasma was 7 days (4-12) and 28 days (20-43) for tissue. Plasma ctDNA was detected in 56% (23/41) of pts; detection was 40% (8/20) if blood was drawn on active therapy and 71% (15/21) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.28, 95% CI 0.06 - 1.16; p = 0.06). All pts had concurrent tissue NGS; of the 10 samples resulted, there was 100% driver concordance between tissue and plasma in pts drawn off therapy. Conclusions: In pts who were driver unknown or who had clinical concern for tumor heterogeneity, plasma ctDNA NGS identified a variety of oncogenic drivers with a short turnaround time and matched them to targeted therapy. Plasma ctDNA detection was more frequent at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific, but a negative finding may still require tissue biopsy.

The discovery of Helicobacter pylori changed forever our perception of the stomach as a habitat for specialized bacteria. It is now known that the stomachs of all animals are colonized by a wide range of highly adapted bacteria that belong to the genus Helicobacter. This chapter describes non-H. pylori gastric bacteria and considers the nature of these specialized adaptations that allow this very interesting group of organisms to inhabit the hostile gastric environment where no others can survive. It has been reported that the spiral organisms inhabited the gastric pits of the pyloric and fundic glands, with some of these bacteria closely associated with the acid-producing parietal cells and in some cases inside the canuliculi of these cells. Many of the in vivo culture techniques that were undertaken earlier are still widely used today, especially for the isolation and characterization of gastric helicobacters that have been unable to be cultivated in vitro, a classic example being ''H. heilmannii’’. New and more sophisticated techniques, especially in the field of molecular biology, have led to the discovery of many new organisms that inhabit the stomach, lower bowel, and liver. Like many of the other gastric helicobacters, H. heilmannii is free living and does not attach to the epithelial cell layer. In their natural host, most of the known gastric helicobacters do not induce a significant pathology. Just as the human has H. pylori inhabiting the stomach, most animal species have their own gastric helicobacters, many of which are described in this chapter.

© 2013 AFAANZ. Investors widely use contracts for difference (CFDs) to leverage and short sell underlying financial assets. We investigate the after cost performance of investors in Australian Securities Exchange listed share CFDs, and find that market order CFD trades earn small positive returns at the daily horizon, with negative returns reported for one month to one year horizons due to financing costs. Market orders also net sell positions, which suggests that investors use CFDs for shorting opportunities. Overall, we find that liquidity demanders in CFDs obtain favourable execution, which is inconsistent with the view that CFDs are used by naive individuals.

The discovery of Helicobacter pylori in 1982 increased interest in the range of other spiral bacteria that had been seen not only in the stomach but also in the lower bowel of many animal species.1 2 The power of technologies such as the polymerase chain reaction with genus specific primers revealed that many of these bacteria belong to the genus Helicobacter . These non-pylori helicobacters are increasingly being found in human clinical specimens. The purpose of this article is to introduce these microorganisms to the clinician, put them in an ecological perspective, and to reflect on their likely importance as human pathogens. In 1987, Dent et al described the presence of a novel bacterium in 3/1300 gastric biopsies.3The initial differentiation was based on morphology, the bacterium having a larger tight helical shape compared to the S shape of H pylori (fig 1). Subsequent studies have shown that while rarely found in humans it is the dominant gastric organism in a number of animal species including primates, pigs, cats, and dogs.4 Although first given the name Gastrospirillum hominis this gastric bacterium has subsequently been shown to belong to the Helicobacter genus and has been given the provisional name of Helicobacter heilmannii .5 6 Another bacterium, Helicobacter felis , which is morphologically similar to H heilmannii by light microscopy, has also been noted in three cases.7-9Its identification is based on the presence of periplasmic fibres which are only visible by electron microscopy. H felis has been used extensively in mouse models of H pylori infection.10 Figure 1 Light micrographs of gastric tissue from humans infected with (A) H pylori and (C) H heilmannii (× 1000). Insets show higher magnifications in which the characteristic S-shape morphology of H pylori (B) can be seen in comparison to the …

Spiral bacteria were isolated from the intestines of laboratory mice during a study examining the presence of Helicobacter species and other spiral organisms naturally infecting mice maintained at four different animal facilities in Sydney, Australia. One group of 17 isolates, cultured from mice from three of the four facilities, were found to be helicobacters but did not fall within any of the 18 currently recognized species. These isolates were unusual in that they only grew anaerobically at 37 degrees C and were incapable of growth under microaerobic conditions. Like Helicobacter rodentium, isolates possessed single, bipolar, unsheathed flagella and were urease-negative. They were positive for oxidase and reduced nitrate to nitrite but did not hydrolyse hippurate or indoxyl acetate, grew on charcoal agar and were resistant to cephalothin. 16S rDNA sequences from four strains were determined and found to be identical to one another. H. rodentium was the most closely related species in terms of 16S rDNA sequence similarity (98.2%). Numerical analysis of whole-cell proteins by SDS-PAGE for nine isolates was carried out with a comparison to all known Helicobacter species, including newly determined profiles from three H. rodentium strains. The new isolates were clearly differentiated from H. rodentium and other Helicobacter spp. On the basis of this data, including genetic, biochemical and protein analysis, it is proposed that these isolates belong to Helicobacter ganmani sp. nov. (type strain CMRI H02T = CCUG 43526T = CIP 106846T).

Helicobacter pylori is a human pathogen, whereas the natural hosts for 'Gastrospirillum hominis' and Helicobacter felis are animals. 'G. hominis' is occasionally found to cause infection in humans, whereas H. felis only rarely infects humans. The pathogenesis of H. pylori infection is not completely understood and in order to reveal differences in immune response to the three Helicobacter species, the upregulation of adherence molecule CD11b/CD18, chemotactic activity and oxidative burst response of neutrophils after stimulation with H. pylori, 'G. hominis' and H. felis sonicates, were compared. Like H. pylori, 'G. hominis' and H. felis induced upregulation of CD11b/CD18 and chemotaxis of neutrophils. 'G. hominis' demonstrated a more pronounced upregulation of CD11b/CD18, whereas H. felis was the strongest stimulant of neutrophil chemotaxis. H. felis was unable to stimulate neutrophils to oxidative burst response, whereas 'G. hominis' activated neutrophils in a dose-dependent way similar to H. pylori. 'G. hominis' and H. felis were both able to prime neutrophils for oxidative burst response similar to H. pylori. In conclusion, we observed clear differences in neutrophil responses to different Helicobacter species, which indicates that bacterial virulence factors may be important for the diversity in the pathogenetic outcome of Helicobacter infections.

Primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma may develop from chronic infection with Helicobacter sp. in the mouse model. The mechanisms of pathogenesis remain unclear. Regulation of B-cell proliferation and death are important features to investigate. Proteins encoded by bcl-2 family genes, e.g., Bcl-XL, regulate apoptosis; and alterations in the expression of these genes can contribute to the development of cancer. Our aim was to determine the role of Bcl-XL in B lymphocytes in the development of gastric MALT lymphoma associated with Helicobacter infection using the BALB/c mouse model. We analyzed 37 animals with Helicobacter-associated MALT (n = 25), low-grade MALT lymphoma (n = 10) and high-grade lymphoma (n = 2), investigating the in vivo distribution of Bcl-XL in B cells/B-lymphoma cells using immunohistochemical analysis. In vitro cultivation of B cells/B-lymphoma cells was employed to perform RT-PCR analysis of Bcl-XL mRNA expression after cell stimulation with Helicobacter antigen. We found significant Bcl-XL protein expression in B lymphocytes within MALT and low-grade MALT lymphoma, whereas there was no and minimal expression, respectively, of Bcl-XL in the 2 high-grade MALT lymphoma cases. Expression of bcl-XL mRNA in B lymphocytes was up-regulated in vitro upon Helicobacter-antigen stimulation and associated with prolonged cell survival. These findings support the hypothesis that Bcl-XL plays a role in the pathogenesis of B-cell MALT lymphoma by providing cell-survival signals and by triggering the acquisition of MALT. © 2001 Wiley-Liss, Inc.

This study describes the molecular makeup of the cell-wall lipopolysaccharides (LPSs) (O-chain polysaccharide-->core oligosaccharide-->lipid A) from five Helicobacter pylori strains: H. pylori 26695 and J99, the complete genome sequences of which have been published, the established mouse model Sydney strain (SS1), and the symptomatic strains P466 and UA915. All chemical and serological experiments were performed on the intact LPSs. H. pylori 26695 and SS1 possessed either a low-Mr semi-rough-form LPS carrying mostly a single Ley type-2 blood-group determinant in the O-chain region covalently attached to the core oligosaccharide or a high-Mr smooth-form LPS, as did strain J99, with an elongated partially fucosylated type-2 N-acetyllactosamine (polyLacNAc) O-chain polymer, terminated mainly by a Lex blood-group determinant, connected to the core oligosaccharide. In the midst of semi-rough-form LPS glycoforms, H. pylori 26695 and SS1 also expressed in the O-chain region a difucosylated antigen, alpha-L-Fucp(1-3)-alpha-L-Fucp(1-4)-beta-D-GlcpNAc, and the cancer-cell-related type-1 or type-2 linear B-blood-group antigen, alpha-D-Galp(1-3)-beta-D-Galp(1-3 or 4)-beta-D-GlcpNAc. The LPS of H. pylori strain P466 carried the cancer-associated type-2 sialyl Lex blood-group antigen, and the LPS from strain UA915 expressed a type-1 Leb blood-group unit. These findings should aid investigations that focus on identifying and characterizing genes responsible for LPS biosynthesis in genomic strains 26695 and J99, and in understanding the role of H. pylori LPS in animal model studies. The LPSs from the H. pylori strains studied to date were grouped into specific glycotype families.

The 5846-bp circular plasmid pHPS1 of Helicobacter pylori Sydney strain, SS1, was cloned, sequenced, and structurally characterized. The SS1 strain is widely used in animal studies of H. pylori infection. The sequence of pHPS1 revealed three open reading frames (ORFs), all of which are transcribed. Two ORFs encode putative plasmid replication proteins, RepA and RepB, similar to replicases resident on theta plasmids. In contrast, the function of ORF2 remains cryptic due to the absence of sequence similarity with any known protein in sequence databases. In addition, species specificity of these three coding regions was shown using DNA dot blot hybridization in 57 diverse clinical H. pylori isolates and 32 Helicobacter and Campylobacter strains. RepA appears to be the predominant plasmid replication protein of H. pylori and the deduced amino acid sequence was highly conserved (76-96%) in 8 H. pylori isolates, including SS1. RepB was detected in 3 H. pylori isolates examined in this study, 2 of which possess only the repB gene. Analysis of the protein sequences of these two replicases, together with previously characterized H. pylori plasmid replication proteins, supports the formation of a distinct class of H. pylori plasmid proteins. Moreover, comprehensive analysis of the whole genome sequence of H. pylori strain 26695, pHPS1, and other H. pylori plasmid sequences that are available revealed interesting insights as to the occurrence of plasmid-mediated recombination within H. pylori. Common regions between plasmids and chromosome sequences of H. pylori were identified in this study which could only have arisen by genetic recombination, thus providing the first line of evidence, albeit indirectly, of the contribution of H. pylori plasmids in generating an extensive genetic heterogeneity characteristic of this important gastroduodenal pathogen.

Accessibility indices (AIs) for public and private transport were estimated in a pilot study in northeast Hampshire, England. The AIs were based on a formulation relating travel time and cost between specified origins and destinations (O-Ds). Wider use of the role of the indices was examined, particularly for reducing car dependency as one element in improving sustainability within the North East Hampshire Transport Strategy. The indices, which can be presented in simplified graphical fashion to inform nontechnical audiences, are based on door-to-door travel times and costs, and the O-Ds represent trips between home and important destinations. Significantly, the only example in which travel-cost AIs for bus versus car travel were approximately equal was that in which a substantial car-parking charge was made. The AIs thus help to indicate the transport corridors where actions to improve equity in transport opportunities for users have the greatest priority and potential. These actions, such as improved bus priority and varying fare levels, parking charges, and other user charges, can be verified by prescriptive use of the AIs to illustrate the impacts. This approach provides a basis for using the AIs to quickly examine future transport scenarios and in associated decision making. It also helps in focusing on detailed modal shift analysis aimed at reshaping the transport system in a sustainable manner. This process is described within the context of strategic transport planning at county and regional levels, and continuing work on the theory and applications of the AIs is outlined.

Helicobacter pylori infection in humans has been shown to be associated with changes in gastric physiology, including exaggerated basal and meal-stimulated gastrin levels. This has been suggested to be due to the direct effects of the bacterium through inflammation and its urease enzyme. The gastric bacteria Helicobacter felis and Helicobacter heilmannii colonize the antrum of rats in large numbers and induce no significant inflammatory response. Thus, the direct effect of Helicobacter infection on gastric physiology, independent of gastritis, could be studied. Basal, freely fed and stimulated acid and gastrin levels were recorded from animals infected with H. felis, H. heilmannii or uninfected controls over a 30 week period. No significant difference was found between freely fed gastrin over 7 weeks or fasting gastrin over 24 weeks or basal and stimulated acid over 30 weeks between all three groups. Triple therapy did not alter gastrin or acid output. The antrum of all Helicobacter-infected rats was well colonized; triple therapy cleared H. felis but not H. heilmannii. Very little inflammation was seen in control or Helicobacter-infected animals. In conclusion, Helicobacter-induced effects on gastric physiology are unlikely to be due to direct bacterial effects, but are best explained by other factors (i.e. inflammatory damage).

There is no model of Helicobacter pylori infection that exactly mimics the human diseases. In a particular, there are no good models of ulceration or gastric adenocarcinoma. Patterns of gastritis induced in the animals tend to be lymphocytic and lack the neutrophil infiltration typical of H. pylori infection in the adult. However, the animal models are starting to provide valuable information with respect to factors involved in the colonisation of the gastric mucosa and the importance of host factors in the development of gastric atrophy, as well as making possible the screening of potential therapeutic agents and vaccine candidates. Models include gnotobiotic piglets, primates, cats, dogs, ferrets and a range of rodents. Recent advances in the mouse models mean that they will allow us to dissect bacterial host interactions in a novel manner due to the availability of a wide range of immunological reagents and numerous mutant or transgenic strains.

The detection of Helicobacter species by genus-specific polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) was compared with that by species-specific PCR in murine intestinal samples. Results suggest that, in samples containing multiple Helicobacter species, genus-specific PCR-DGGE may fail to detect all Helicobacter species present and that this relates to the initial template DNA ratio.

An allochthonous population of spiral-shaped bacteria was found colonizing the surfaces of the colonic mucosa of rats after they had been given magnesium sulphate (MgSO4)-induced diarrhea. These organisms were rarely seen in normal control rats and were not displaced when the treatment was ceased, remaining associated with the tissue for periods of up to 180 days. Similar bacteria were also found when specific pathogen-free rats, lacking mucosa-associated populations, were inoculated with homogenized rat intestine from conventional animals. Light and electron microscopic observations showed that the organisms were attached to the surface of the colon, orientated at right angles to the tissue, with one end inserted into the microvillus border. This is the first report of long-term colonization, following perturbation of the gut ecosystem, of a site on the gastrointestinal mucosa not normally associated with bacteria. The ultrastructure and mode of attachment of these organisms were very similar to that of spiral-shaped bacteria known to associate with the colonic mucosa in monkeys and man.

Prior to the American Civil War, white southern novelists had exhorted their countrymen to open your eyes to the danger of the North's encroaching ideals and not to be caught sleeping on your posts. After the war, new southern novelists, like George Washington Cable, Frances Watkins Harper, Sutton E. Griggs, and Charles Chesnutt, worked instead to awaken their region to the injustice of its treatment of African Americans. Each author came to realize, however, that white readers, North and South, had grown tired of novels about race. Consequently, these writers rejected their genre and turned to nonfiction to reinvigorate social reform. To goad genteel southern readers to see the race problem as a crisis demanding immediate action rather than merely an aesthetic diversion, Cable, Harper, Griggs, and Chesnutt wrote speeches, autobiographies, sermons, and nonfiction books that argued that white churches should behave as their African-American counterparts had, as sites for interracial communion. These authors, that is, sought to reform southern white society by reforming - still in words but no longer in novels - southern white churches. More specifically, these novelists focused on Social Christianity, based on the biblical principles of love and justice, to transform society, as evidenced by Cable's African-American Sunday School classroom, minister-novelist Griggs' National Baptist Convention, and Chesnutt's African Methodist Episcopal church community's work in education, urban missions, and settlement houses.

The discovery of the bacterium Helicobacter pylori by the Australians Warren and Marshall in 1982 has revolutionized the management of gastroduodenal diseases. Antimicrobial therapy is now an essential component of the treatment of all duodenal ulcers and most gastric ulcers. A causal role in gastric adenocarcinoma and low-grade B-cell gastric lymphomas has resulted in the investigation of strategies for large scale elimination of H. pylori from certain populations. However, interest in this fascinating bacterium amongst microbiologists in general, and infectious disease researchers and clinicians throughout the world in particular, has tended to be lukewarm. Helicobacter pylori diseases are not considered a priority in the developing world and are viewed as infections for which treatment is a luxury that can be afforded only by developed societies. A thesis of this article is that mass impacts of this ubiquitous pathogen on the developing world may be more than is thought and that, in the long term, intervention may be desirable as long as it can be made simple and cheap. Progress in Helicobacter research has come such a long way in the past 10 years that immunization may now be an attainable goal.

The only successful strategy for large-scale eradication of an infectious disease from whole populations has been through immunization. In societies fortunate enough to have a healthcare infrastructure that allows mass vaccination, diseases such as poliomyelitis, whooping cough and diphtheria have been virtually eliminated. But what about infection with Helicobacter pylori, which has now been proved to be a major worldwide pathogen? Infection by H. pylori is lifelong, despite a vigorous immune response. How, then, could immunization be feasible? Recent investigations using a mouse model of H. pylori infection have shown that protective immunity can indeed be induced with an oral vaccine. Furthermore, protection was lifelong in the animal model. Also, more importantly, the vaccine actually cured existing infection, raising the exciting possibility of therapeutic immunization. Stimulated by the medical need, the race is now on to produce the first vaccine. However, many critical questions remain to be answered before the first patients are immunized with the complete vaccine. For example, what is the best antigen to target? Urease is currently the favourite antigen, but others will be tested. What about the adjuvant? LT, the heat labile enterotoxin of diarrhoeaogenic strains of Escherichia coli, is the most likely candidate, but we need to examine alternatives. Is there any risk of immunopotentiation? The answer is probably no, but this has to be proved. A vaccine against H. pylori will be developed, and infection with H. pylori will be prevented--the question remains 'how long will it take'?

Helicobacter pylori is an important pathogen in humans, causing chronic gastritis and playing a major role in the development of peptic ulcers and gastric cancer. The organism is highly adapted to the human stomach, largely due to its motility and ability to produce large amounts of urease. It binds specifically to the gastric mucosa via adhesion pedestals; colonization of the duodenum only occurs in the presence of gastric metaplasia. Infection with H. pylori leads to gastritis, but the majority of infected patients are asymptomatic, and it is thought that the ability of H. pylori to cause more severe disease may be related to the presence of the cagA gene. With improvements in public health and living conditions, the prevalence of H. pylori infection in developed countries is decreasing, and this is associated with a decline in the incidence of peptic ulcer and gastric cancer.

Application of nested PCR for Helicobacter species to 416 samples obtained at colonoscopy from 15 patients with Crohn's disease, 12 with ulcerative colitis, and 43 controls revealed H. pylori DNA in only 6 individuals with no disease association. No other Helicobacter species were detected in ileal or colonic samples.

Following the demonstration of Helicobacter pylori as a major gastroduodenal pathogen there was a need to develop animal models in order to investigate mechanisms of pathogenesis and to be able to test new treatment strategies. Helicobacter pylori will only colonize a limited number of hosts including non-human primates, germ-free or barrier raised piglets, germ-free dogs and recently laboratory raised cats. Although these models have proved useful there is a need for more convenient small animal models. The ferret infected with its natural gastric organism, Helicobacter mustelae, is the only other animal to show peptic ulceration and has been successfully used to investigate gastritis and antimicrobial agents. The other commonly used animal model is the laboratory mouse or rat infected with either Helicobacter felis or Helicobacter heilmannii, bacteria that normally colonize cat or dog gastric mucosae. Active/chronic gastritis, gastric atrophy, and lymphoma-like lesions have been shown to develop in H. felis infected mice. The most recent and exciting use of an animal model has been the use of the H. felis mouse model in the development of human vaccines against H. pylori. Mice can be protected against infection with large doses of viable H. felis by oral immunization using sonicates of H. felis or H. pylori or recombinant H. pylori urease together with cholera toxin or cholera toxin-B subunit as the mucosal adjuvant. More importantly it has been shown that immunization of already infected animals results in eradication of infection. This raises the intriguing possibility that therapeutic immunization might be a viable option in the management of Helicobacter-associated disease. If immunization as a therapy of peptic ulcers was combined with short-term acid suppression, the possibility of reinfection may also be eliminated. In those countries where H. pylori infection rates are very high and infection occurs at an early age, large scale oral immunization of sections of the community would not only protect the young from the deleterious consequences of long-term H. pylori infection but could also cure existing disease.

Background/Objectives In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET. Methods Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling. Results Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72–1.27], PFS (RR 0.95; CI 0.81–1.13), or OS (RR 1.03; CI 0.77–1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04–1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27–0.82) and lower overall renal toxicity (RR 3.61; CI 1.24–10.51). Conclusion Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET.

The presence of Helicobacter spp. was examined in the liver and in different regions of the gastrointestinal tract (GIT) including the stomach, 3 cm above ileum, ileum, caecum, colon and rectum of 10 ringtail possums (RTPs) and 3 koalas using a combination of microscopy, culture and PCR. Helicobacter was detected in the distal end of the GIT of 7 of 10 RTPs by direct PCR and in all (10/10) RTPs by nested PCR. Five 'S' shaped isolates with bipolar sheathed flagella were isolated from the lower bowel of 3 of the 10 RTPs. 16S rRNA sequence analysis of these 5 isolates confirmed them as potentially novel Helicobacter species. No Helicobacter species were cultured from the koalas, however Helicobacter DNA was detected, in the majority of liver and/or stomach samples of the three koalas and in the colonic region of one koala, using nested PCR. The 16S rRNA gene was sequenced directly from DNA extracted from the homogenised livers and mucus scrapings of the stomach from koala 1 and were confirmed to be Helicobacter species. Based on histopathological examination of sections from the liver and intestine no evidence of infection could be related to the presence of helicobacters in either the RTP or koala. Based on our results, it is possible that diet may influence the detection of Helicobacter species; however this required further investigation.

An emulation fund is designed to reduce trading activity, thereby lowering costs, for a multi-manager fund. It does this by delaying, and potentially combining, trading decisions from each employed fund manager to eliminate offsetting trades (e.g. one manager may buy a stock for her fund while another manager sells the same stock at approximately the same time for his fund). While lowering transaction costs is a key benefit of an emulation strategy, there has been little research that compares the reduction in transaction costs with the opportunity costs of delaying trade. Using reported equity trades for a large Australian pension fund, we simulate the consequences of an emulation strategy. We find that simulated emulation trades underperform those trades made by the employed (or target) fund over our sample period. That is, the opportunity cost of delayed trading significantly outweighs transaction cost reductions. Overall, we do not find strong evidence to support emulation from a cost-benefit perspective before management fees and taxes. © The Author(s) 2012.

Investors widely use contracts for difference (CFDs) to leverage and short sell underlying financial assets. We investigate the after cost performance of investors in Australian Securities Exchange listed share CFDs, and find that market order CFD trades earn small positive returns at the daily horizon, with negative returns reported for one month to one year horizons due to financing costs. Market orders also net sell positions, which suggests that investors use CFDs for shorting opportunities. Overall, we find that liquidity demanders in CFDs obtain favourable execution, which is inconsistent with the view that CFDs are used by naive individuals.