Interferon dysregulation and virus-induced cell death in avian influenza H5N1 virus infections.

1. Hyper-induction of cytokines and chemokines was found in human blood macrophages infected with the avian influenza H5N1 and H9N2/G1 viruses, as compared to those infected with human influenza H1N1 virus. 2. IRF3 played a significant role in the hyperinduction of cytokines including IFN-β, IFN-λ1,IFN-α subtypes, MCP-1, and TNF-α, and also played a part in subsequent cytokine-induced cell signalling cascades. 3. Compared with H1N1 viruses, avian influenza viruses including H5N1/97 and its precursors triggered a caspase-mediated but delayed apoptotic response in human macrophages. 4. Therapies that can minimise immunopathology-associated dysregulation of innate immunity without impairing effective host defence may be valuable adjuncts to antiviral therapy.published_or_final_versio

CCL18 synergises with high concentrations of glucose in stimulating fibronectin production in human renal tubuloepithelial cells.

Background: Diabetic nephropathy is the leading cause of end stage kidney disease worldwide. The pathogenesis of this disease remains elusive and multiple factors have been implicated. These include the effects of hyperglycaemia, haemodynamic and metabolic factors, and an inflammatory process that stimulates cellular signalling pathways leading to disease progression and severe fibrosis. Fibronectin (Fn) is an important protein of the extracellular matrix that is essential in fibrosis and its presence in increased amounts has been identified in the kidney in diabetic nephropathy. Methods: Proximal tubuloepithelial (HK-2) cells were stimulated with high glucose (30mM D-glucose) or glycated albumin (500μg/mmol) + 4mM D-glucose or their controls, Mannitol (26mM+4mM D-glucose) and 4mM D-glucose, respectively. Following 48 hours of stimulation the supernatant was collected and MTT [3-(4,5-dimethylthiazole-2,5-diphenyltetrazolium bromide] assay performed to assess cell viability. HK-2 cells were also stimulated in the above environments with recombinant CCL18 (rCCL18) or MCP-1 (rMCP-1) for 48 hours with quantification of Fn levels using ELISA. Results: Co-stimulation of HK-2 cells with high concentrations of glucose and rCCL18 significantly increased Fn (p<0.001), in comparison to high concentrations of glucose alone. HK-2 cells stimulated with glycated albumin consistently produced Fn and this did not alter following co-stimulation with rCCL18 or rMCP-1. Conclusion: This study demonstrates how stimulation with a specific chemokine CCL18 in high glucose upregulates the production of Fn from proximal tubuloepithelial cells. This may be relevant to the development of renal fibrosis in diabetic nephropath

Initiating head development in mouse embryos: integrating signalling and transcriptional activity

The generation of an embryonic body plan is the outcome of inductive interactions between the progenitor tissues that underpin their specification, regionalization and morphogenesis. The intercellular signalling activity driving these processes is deployed in a time- and site-specific manner, and the signal strength must be precisely controlled. Receptor and ligand functions are modulated by secreted antagonists to impose a dynamic pattern of globally controlled and locally graded signals onto the tissues of early post-implantation mouse embryo. In response to the WNT, Nodal and Bone Morphogenetic Protein (BMP) signalling cascades, the embryo acquires its body plan, which manifests as differences in the developmental fate of cells located at different positions in the anterior–posterior body axis. The initial formation of the anterior (head) structures in the mouse embryo is critically dependent on the morphogenetic activity emanating from two signalling centres that are juxtaposed with the progenitor tissues of the head. A common property of these centres is that they are the source of antagonistic factors and the hub of transcriptional activities that negatively modulate the function of WNT, Nodal and BMP signalling cascades. These events generate the scaffold of the embryonic head by the early-somite stage of development. Beyond this, additional tissue interactions continue to support the growth, regionalization, differentiation and morphogenesis required for the elaboration of the structure recognizable as the embryonic head

Fine-structure diagnostics of neutral carbon toward HE 0515-4414

New high-resolution high signal-to-noise spectra of the $z=1.15$ damped Lyman $\alpha$ (DLA) system toward the quasi-stellar object HE 0515-4414 reveal absorption lines of the multiplets 2 and 3 in \ion{C}{i}. The resonance lines are seen in two components with total column densities of $\log N=13.79\pm0.01$ and $\log N=13.36\pm0.01$, respectively. The comparision of theoretical calculations of the relative fine-structure population with the ratios of the observed column densities suggests that the \ion{C}{i} absorbing medium is either very dense or exposed to very intense UV radiation. The upper limit on the local UV energy density is 100 times the galactic UV energy density, while the upper limit on the \ion{H}{i} number density is 110 cm$^{-3}$. The excitation temperatures of the ground state fine-structure levels of $T=15.7$ and $T=11.1$ K, respectively, are consistent with the temperature-redshift relation predicted by the standard Friedmann cosmology. The cosmic microwave background radiation (CMBR) is only a minor source of the observed fine-structure excitation.Comment: 5 pages, 5 figures, uses A&A macro package, gzipped tar archive, accepted by A&

Lung Cancer Decreased Sharply in First 5 Years After Smoking Cessation in Chinese Men

BackgroundThe rate of decline in lung cancer risk after smoking cessation among male population and the importance of the magnitude of the early decline were not sufficiently defined in the earlier studies. We evaluated the detailed duration-response relationship between years since smoking cessation and lung cancer risk across major histological types in a population-based case-referent study.MethodsWe recruited 1208 consecutive incident cases of primary lung cancer among Chinese males from the largest oncology center in Hong Kong during 2004–2006, and 1069 male community referents frequency-matched in 5-year age groups. We performed unconditional multiple logistic regression and generalized additive model incorporating smoothing spline to model the potential nonlinear effect of years since cessation on lung cancer.ResultsAll histological types of lung cancer were strongly associated with current smoking. We observed a rapidly decreasing odds ratio of lung cancer (>50%) across all major histological types of lung cancer (except for the large cell type) within the first 5 years of quitting; the odds ratio continued to decrease but at a slower rate in the subsequent years.ConclusionThe substantial benefits obtainable within a short period of 5 years' abstinence should convey an encouraging message to chronic smokers, clinicians, and public health workers

Mortality following Campylobacter infection: a registry-based linkage study

BACKGROUND: Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality. METHODS: Mortality among a cohort of Campylobacter cases were compared with the general population 0–1, 1–3, 3–12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad. RESULTS: The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9–4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest). In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04–0.8) was shown for the first month after diagnosis compared to what would be expected in the general population. CONCLUSION: Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases

Community incidence of pathogen-specific gastroenteritis: reconstructing the surveillance pyramid for seven pathogens in seven European Union member states.

By building reconstruction models for a case of gastroenteritis in the general population moving through different steps of the surveillance pyramid we estimated that millions of illnesses occur annually in the European population, leading to thousands of hospitalizations. We used data on the healthcare system in seven European Union member states in relation to pathogen characteristics that influence healthcare seeking. Data on healthcare usage were obtained by harmonized cross-sectional surveys. The degree of under-diagnosis and underreporting varied by pathogen and country. Overall, underreporting and under-diagnosis were estimated to be lowest for Germany and Sweden, followed by Denmark, The Netherlands, UK, Italy and Poland. Across all countries, the incidence rate was highest for Campylobacter spp. and Salmonella spp. Incidence estimates resulting from the pyramid reconstruction approach are adjusted for biases due to different surveillance systems and are therefore a better basis for international comparisons than reported data

A combination of hard and soft templating for the fabrication of silica hollow microcoils with nanostructured walls

Hollow silica microcoils have been prepared by using functionalized carbon microcoils as hard templates and surfactant or amphiphilic dye aggregates as soft templates. The obtained materials have been characterized by electron and optical microscopy, nitrogen sorption and small angle X-ray scattering. The obtained hollow microcoils resemble the original hard templates in shape and size. Moreover, they have mesoporous walls (pore size ≈ 3 nm) with some domains where pores are ordered in a hexagonal array, originated from surfactant micelles. The obtained silica microcoils also show preferential adsorption of cationic fluorescent dyes. A mechanism for the formation of silica microcoils is proposed

Quality assessment of an interferon-gamma release assay for tuberculosis infection in a resource-limited setting

<p>Abstract</p> <p>Background</p> <p>When a test for diagnosis of infectious diseases is introduced in a resource-limited setting, monitoring quality is a major concern. An optimized design of experiment and statistical models are required for this assessment.</p> <p>Methods</p> <p>Interferon-gamma release assay to detect tuberculosis (TB) infection from whole blood was tested in Hanoi, Viet Nam. Balanced incomplete block design (BIBD) was planned and fixed-effect models with heterogeneous error variance were used for analysis. In the first trial, the whole blood from 12 donors was incubated with nil, TB-specific antigens or mitogen. In 72 measurements, two laboratory members exchanged their roles in harvesting plasma and testing for interferon-gamma release using enzyme linked immunosorbent assay (ELISA) technique. After intervention including checkup of all steps and standard operation procedures, the second trial was implemented in a similar manner.</p> <p>Results</p> <p>The lack of precision in the first trial was clearly demonstrated. Large within-individual error was significantly affected by both harvester and ELISA operator, indicating that both of the steps had problems. After the intervention, overall within-individual error was significantly reduced (<it>P </it>< 0.0001) and error variance was no longer affected by laboratory personnel in charge, indicating that a marked improvement could be objectively observed.</p> <p>Conclusion</p> <p>BIBD and analysis of fixed-effect models with heterogeneous variance are suitable and useful for objective and individualized assessment of proficiency in a multistep diagnostic test for infectious diseases in a resource-constrained laboratory. The action plan based on our findings would be worth considering when monitoring for internal quality control is difficult on site.</p

Heart rate variability and the relationship between trauma exposure age, and psychopathology in a post-conflict setting

BACKGROUND: Cumulative exposure to potentially traumatic events (PTEs) increases risk for mental distress in conflict-affected settings, but the psychophysiological mechanisms that mediate this dose-response relationship are unknown. We investigated diminished heart rate variability (HRV) - an index of vagus nerve function and a robust predictor of emotion regulation capacity - as a vulnerability marker that potentially mediates the association between PTE exposure, age and symptoms of posttraumatic stress disorder (PTSD), psychological distress and aggressive behavior, in a community sample from Timor-Leste - a post-conflict country with a history of mass violence. METHOD: Resting state heart rate data was recorded from 45 cases of PTSD, depression and intermittent explosive disorder (IED); and 29 non-case controls. RESULTS: Resting HRV was significantly reduced in the combined case group compared with non-cases (p = .021; Cohen's d = 0.5). A significant mediation effect was also observed, whereby a sequence of increased age, reduced HRV and elevated PTSD symptoms mediated the association between PTE exposure and distress (B = .06, SE = .05, 95% CI = [.00-.217]) and aggression (B = .02, SE = .02, 95% CI = [.0003-.069])). CONCLUSION: The findings demonstrate an association between diminished resting HRV and psychopathology. Moreover, age-related HRV reductions emerged as a potential psychophysiological mechanism that underlies enhanced vulnerability to distress and aggression following cumulative PTE exposure