Treatment with incretins does not increase the risk of pancreatic diseases compared to older anti-hyperglycaemic drugs, when added to metformin: real world evidence in people with Type 2 diabetes.

AIMS: In people with metformin-treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second-line anti-hyperglycaemic agent initiation. METHODS: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i, n = 50 095), glucagon-like peptide-1 receptor agonist (GLP-1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti-hyperglycaemic drug groups for appropriate confounders. RESULTS: In the DPP-4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP-4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP-1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups. CONCLUSIONS: No significant differences in the risk of developing pancreatic diseases in those treated with various anti-hyperglycaemic drug classes were found.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Heart failure following cancer treatment: characteristics, survival and mortality of a linked health data analysis.

BACKGROUND: Cardiotoxicity resulting in heart failure is a devastating complication of cancer therapy. A patient may survive cancer only to develop heart failure (HF), which has a higher mortality rate than some cancers. AIM: This study aimed to describe the characteristics and outcomes of HF in patients with blood or breast cancer after chemotherapy treatment. METHODS: Queensland Cancer Registry, Death Registry and Hospital Administration records were linked (1996-2009). Patients were categorised as those with an index HF admission (that occurred after cancer diagnosis) and those without an index HF admission (non-HF). RESULTS: A total of 15 987 patients was included, and 1062 (6.6%) had an index HF admission. Median age of HF patients was 67 years (interquartile range 58-75) versus 54 years (interquartile range 44-64) for non-HF patients. More men than women developed HF (48.6% vs 29.5%), and a greater proportion in the HF group had haematological cancer (83.1%) compared with breast cancer (16.9%). After covariate adjustment, HF patients had increased mortality risk compared with non-HF patients (hazard ratios 1.67 (95% confidence interval, 1.54-1.81)), and 47% of the index HF admission occurred within 1 year from cancer diagnosis and 70% within 3 years. CONCLUSION: Cancer treatment may place patients at a greater risk of developing HF. The onset of HF occurred soon after chemotherapy, and those who developed HF had a greater mortality risk.

Onset of photosynthesis in spring speeds up monoterpene synthesis and leads to emission bursts.

Emissions of biogenic volatile organic compounds (BVOC) by boreal evergreen trees have strong seasonality, with low emission rates during photosynthetically inactive winter and increasing rates towards summer. Yet, the regulation of this seasonality remains unclear. We measured in situ monoterpene emissions from Scots pine shoots during several spring periods and analysed their dynamics in connection with the spring recovery of photosynthesis. We found high emission peaks caused by enhanced monoterpene synthesis consistently during every spring period (monoterpene emission bursts, MEB). The timing of the MEBs varied relatively little between the spring periods. The timing of the MEBs showed good agreement with the photosynthetic spring recovery, which was studied with simultaneous measurements of chlorophyll fluorescence, CO2 exchange and a simple, temperature history-based proxy for state of photosynthetic acclimation, S. We conclude that the MEBs were related to the early stages of photosynthetic recovery, when the efficiency of photosynthetic carbon reactions is still low whereas the light harvesting machinery actively absorbs light energy. This suggests that the MEBs may serve a protective functional role for the foliage during this critical transitory state and that these high emission peaks may contribute to atmospheric chemistry in the boreal forest in springtime.

Technology-assisted congestive heart failure care.

The interface between eHealth technologies and disease management in chronic conditions such as chronic heart failure (CHF) has advanced beyond the research domain. The substantial morbidity, mortality, health resource utilization and costs imposed by chronic disease, accompanied by increasing prevalence, complex comorbidities and changing client and health staff demographics, have pushed the boundaries of eHealth to alleviate costs whilst maintaining services. Whilst the intentions are laudable and the technology is appealing, this nonetheless requires careful scrutiny. This review aims to describe this technology and explore the current evidence and measures to enhance its implementation.

Helicobacter pylori downregulates expression of human ß-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion.

Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hßDs) are antimicrobial peptides, hßD1 being constitutively expressed in the human stomach. We hypothesized that H. pylori may persist, in part, by downregulating gastric hßD1 expression. We measured hßD1 and hßD2 expression in vivo in relation to the presence, density and severity of H. pylori infection, investigated differential effects of H. pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hßD1 and higher hßD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hßD1 expression, but there were no differences in hßD2. H. pylori infection of human gastric epithelial cell lines also downregulated hßD1. Using wild-type strains and isogenic mutants, we showed that a functional cag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H. pylori usurped NF-κB signalling to modulate hßD1 expression. These data indicate that H. pylori downregulates hßD1 expression via NF-κB signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.

Astrocytes are important mediators of Aß-induced neurotoxicity and tau phosphorylation in primary culture.

Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of ß-amyloid (Aß) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aß-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aß-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aß-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aß-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aß in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy.

Observation of high soft x-ray drive in large-scale hohlraums at the National Ignition Facility.

The first soft x-ray radiation flux measurements from hohlraums using both a 96 and a 192 beam configuration at the National Ignition Facility have shown high x-ray conversion efficiencies of ∼85%-90%. These experiments employed gold vacuum hohlraums, 6.4 mm long and 3.55 mm in diameter, heated with laser energies between 150-635 kJ. The hohlraums reached radiation temperatures of up to 340 eV. These hohlraums for the first time reached coronal plasma conditions sufficient for two-electron processes and coronal heat conduction to be important for determining the radiation drive.

Comparison of a point of care device against current laboratory methodology using citrated and EDTA samples for the determination of D-dimers in the exclusion of proximal deep vein thrombosis.

UNLABELLED: D-dimer estimation is a routine part of diagnostic algorithms for the exclusion of venous thromboembolism (VTE). We evaluated a point of care device, Biosite Triage (Inverness Medical UK, Cheshire, UK) for the estimation of D-dimers in both samples taken into citrate and EDTA against our routine laboratory D-dimer (Liatest D-dimer, Diagnostica Stago, Reading, UK) performed on the STA-R Evolution. With informed consent, 102 consecutive patients presenting with possible deep vein thrombosis (DVT) were enrolled and D-dimers along with Wells scores and compression ultrasonography (CUS) were recorded. Using the manufacturers' recommended cut offs of 500 microg/l fibrinogen equivalent units and 400 microg/l for the Stago and Triage, respectively, sensitivity, specificity, positive and negative predictive values were calculated. These were 1.00, 0.42, 0.17, and 1.00 for the Triage machine using citrate samples, 1.00, 0.32, 0.14, and 1.00 using EDTA samples and 1.00, 0.29, 0.16, and 1.00 for the Stago Liatest assay, respectively. Three patients had significantly higher results for the Stago Liatest D-dimer assay compared with the Biosite Triage device although ultrasound scans were negative. CONCLUSION: The Biosite Triage D-dimer assay performed on either citrate or EDTA samples is comparable with the Stago Liatest laboratory D-dimer assay when used in conjunction with clinical pretest probability scoring and CUS for the exclusion of DVT.

Major conservation policy issues for biodiversity in Oceania.

Oceania is a diverse region encompassing Australia, Melanesia, Micronesia, New Zealand, and Polynesia, and it contains six of the world's 39 hotspots of diversity. It has a poor record for extinctions, particularly for birds on islands and mammals. Major causes include habitat loss and degradation, invasive species, and overexploitation. We identified six major threatening processes (habitat loss and degradation, invasive species, climate change, overexploitation, pollution, and disease) based on a comprehensive review of the literature and for each developed a set of conservation policies. Many policies reflect the urgent need to deal with the effects of burgeoning human populations (expected to increase significantly in the region) on biodiversity. There is considerable difference in resources for conservation, including people and available scientific information, which are heavily biased toward more developed countries in Oceania. Most scientific publications analyzed for four threats (habitat loss, invasive species, overexploitation, and pollution) are from developed countries: 88.6% of Web of Science publications were from Australia (53.7%), New Zealand (24.3%), and Hawaiian Islands (10.5%). Many island states have limited resources or expertise. Even countries that do (e.g., Australia, New Zealand) have ongoing and emerging significant challenges, particularly with the interactive effects of climate change. Oceania will require the implementation of effective policies for conservation if the region's poor record on extinctions is not to continue.

Iron-induced mucosal pathology of the upper gastrointestinal tract: a common finding in patients on oral iron therapy.

AIMS: Upper gastrointestinal injury from iron tablets at therapeutic dose is not widely recognized. The aim was to document cases of iron-related upper gastrointestinal (GI) pathology and to determine frequency of occurrence. METHODS AND RESULTS: We prospectively studied patients with iron deficiency anaemia undergoing upper GI endoscopy from November 2005 to July 2006. Cases of upper GI iron deposition from these and other cases extracted retrospectively between 1999 and 2006 were examined histopathologically and patient notes were reviewed. In the prospective study, 15/160 patients investigated for iron deficiency anaemia [16.1% (15/93) of those taking oral iron tablets] had iron deposition noted on routine haematoxylin and eosin staining. In this plus the retrospective series, 59 patients were identified with 64 episodes of iron deposition. Eighty-six percent (6/7) with oesophageal iron deposition had associated erosion. Sixty-three percent (29/46) with gastric iron deposition had erosion and 80% (37/46) had reactive gastritis. Duodenal deposition was usually (91%, 10/11) within macrophages in villous tips with no erosion. Ninety-eight percent (58/59) of iron deposition cases had documented oral iron intake. CONCLUSIONS: Iron deposition in the upper GI tract is common in patients taking iron tablets. It is frequently associated with mucosal disruption in the oesophagus and stomach.

Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses.

BACKGROUND AND AIMS: Helicobacter pylori infection is the major cause of peptic ulceration and gastric adenocarcinoma. To address the hypothesis that the human acquired immune response to H. pylori influences pathogenesis, we characterised the gastric T helper (Th) and regulatory T cell (Treg) response of infected patients. METHODS: The human gastric CD4(+) T cell response of 28 donors who were infected with H. pylori and 44 who were not infected was analysed using flow cytometry. The T cell associated mucosal cytokine response was analysed by real-time polymerase chain reaction assay of samples from 38 infected and 22 uninfected donors. Recombinant interleukin 10 (IL10) was added to co-cultures of H. pylori and AGS cells and its suppressive effects upon inflammatory responses were measured. RESULTS: We found that the H. pylori-specific response consists of both T helper 1 and 2 subsets with high levels of IL10-secreting Tregs. People with peptic ulcer disease had a 2.4-fold reduced CD4(+)CD25(hi)IL10(+) Treg response (p = 0.05) but increased Th1 and Th2 responses (Th1: 3.2-fold, p = 0.038; Th2: 6.1-fold, p = 0.029) compared to those without ulcers. In vitro studies showed that IL10 inhibited IL8 expression and activation of nuclear factor kappa B induced by H. pylori in gastric epithelial cells, and enhanced H. pylori growth in a bacterial-cell co-culture model. CONCLUSIONS: Together our data suggest that H. pylori induces a regulatory T cell response, possibly contributing to its peaceful coexistence with the human host, and that ulcers occur when this regulatory response is inadequate.

Individualized compared with conventional dosing of enoxaparin.

The aim of this study was to compare an individualized dosing regimen for enoxaparin to conventional dosing. Patients in the individualized arm were initially dosed according to weight: patients <100 kg using total body weight; patients >/=100 kg using lean body weight. Doses were adjusted at 48 h according to renal function. Patients in the conventional arm received enoxaparin according to current practice. Dose-individualized patients had fewer bleeding events (primary end point; relative risk (RR)=0.12, 95% confidence interval (CI)=0.01-0.89, P=0.03) and composite bleeding and bruising events (secondary end point; RR=0.30, 95% CI=0.12-0.71, P=0.003) than those who received conventional dosing. In both arms of the study, there were no recurrent thromboembolic events during treatment and no deaths had occurred at 30 days. Dose individualization of enoxaparin significantly reduces the prevalence of bleeding and bruising events, without apparent loss in effectiveness.

Developing public health nursing: barriers perceived by community nurses.

OBJECTIVES: To understand the key issues for field nursing in developing their public health role within five primary care trusts (PCTs) in Merseyside, in the North West of England. DESIGN: Qualitative study. METHODS: Fourteen school nurses and 30 health visitors participated in 11 focus groups consisting of others from their profession working within the same PCT, and 24 practitioners responded to a questionnaire. RESULTS: The findings suggest that there are a number of shared obstacles that need to be overcome before the public health approach can be fully developed within community nursing. These include: the need for facilitation to deal with organisational change, lack of clarity around the public health role, inadequate administrative support, general practitioner attachment problems, poor interprofessional partnerships, competing priorities and resistance to change. CONCLUSIONS: The development of public health nursing in England envisaged in current government policy will not occur in full unless the kind of issues identified in this study are adequately addressed. This will require participative, interprofessional approaches to redesigning services by all relevant public health practitioners.

De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis.

This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/- Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-kappaB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.

High-resolution magnification endoscopy can reliably identify normal gastric mucosa, Helicobacter pylori-associated gastritis, and gastric atrophy.

BACKGROUND AND STUDY AIMS: The aims of the study were to describe the magnified endoscopic findings in the gastric body, correlate these with histology, and evaluate their reproducibility in the assessment of the magnified endoscopic patterns seen. PATIENTS AND METHODS: A total of 95 consecutive dyspeptic patients underwent upper gastrointestinal endoscopy with a magnifying endoscope. The endoscopists classified the magnified endoscopic patterns and correlated them with the histological findings. In the second part of the study, 200 images were shown to five endoscopists in order to examine inter- and intraobserver variability in image assessment. RESULTS: The magnified endoscopic findings in the gastric body were categorized into four types: type 1, honeycomb-type subepithelial capillary network (SECN) with regular arrangement of collecting venules and regular, round pits; type 2, honeycomb-type SECN with regular, round pits, but loss of collecting venules; type 3, loss of normal SECN and collecting venules, with enlarged white pits surrounded by erythema; and type 4, loss of normal SECN and round pits, with irregular arrangement of collecting venules. The sensitivity, specificity, and positive and negative predictive values of the type 1 pattern for predicting normal gastric mucosa were 92.7% (95% confidence interval [CI] 93.2-97.3%), 100% (95% CI 83.9-100%), 100% (95% CI 92.9-100%), and 83.8% (95% CI 65.5-93.9%). The sensitivity, specificity, and positive and negative predictive values of types 2 and 3 patterns for predicting a Helicobacter pylori-infected stomach were 100% (95% CI 83.9-100%), 92.7% (95% CI 93.2-97.3%), 83.8% (95% CI 65.5-93.9%), and 100% (95% CI 92.9-100%). The sensitivity, specificity, and positive and negative predictive values of a type 4 pattern for predicting gastric atrophy were 90% (95% CI 66.8-98.2%), 96% (95% CI 87.9-98.9%), 85.7% (95% CI 62.6-96.2%), and 97.3% (95% CI 89.6-99.5%. The kappa values for inter- and intraobserver agreement in predicting normal gastric mucosa, H. pylori gastritis, and gastric atrophy were 0.864 and 0.913 respectively. CONCLUSION: High-resolution magnification endoscopy can reliably identify the normal gastric mucosa, H. pylori-associated gastritis, and gastric atrophy in a Western population.