Impact of Cardiovascular Calcifications on the Detrimental Effect of Continued Smoking on Cardiovascular Risk in Male Lung Cancer Screening Participants

Background

Current smokers have an increased cardiovascular disease (CVD) risk compared to ex-smokers due to reversible as well as irreversible effects of smoking. We investigated if current smokers remain to have an increased CVD risk compared to ex-smokers in subjects with a long and intense smoking history. We in addition studied if the effect of smoking continuation on CVD risk is independent of or modified by the presence of cardiovascular calcifications.

Methods

The cohort used comprised a sample of 3559 male lung cancer screening trial participants. We conducted a case-cohort study using all CVD cases and a random sample of 10% (n = 341) from the baseline cohort (subcohort). A weighted Cox proportional hazards model was used to estimate the hazard ratios for current smoking status in relation to CVD events.

Results

During a median follow-up of 2.6 years (max. 3.7 years), 263 fatal and non-fatal cardiovascular events (cases) were identified. Age, packyears and cardiovascular calcification adjusted hazard ratio of current smokers compared to former smokers was 1.33 (95% confidence interval 1.00–1.77). In additional analyses that incorporated multiplicative interaction terms, neither coronary nor aortic calcifications modified the association between smoking status and cardiovascular risk (P = 0.08).

Conclusions

Current smokers have an increased CVD risk compared to former smokers even in subjects with a long and intense smoking history. Smoking exerts its hazardous effects on CVD risk by pathways partly independent of cardiovascular calcifications.     

Angiopoietin-2 Serum Levels Improve Noninvasive Fibrosis Staging in Chronic Hepatitis C: A Fibrogenic-Angiogenic Link

Aims

Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis.

Methods

Serum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test.

Results

Angiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity.

Conclusions

Our novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.     

CXCL12-Mediated Murine Neural Progenitor Cell Movement Requires PI3Kβ Activation

The migratory route of neural progenitor/precursor cells (NPC) has a central role in central nervous system development. Although the role of the chemokine CXCL12 in NPC migration has been described, the intracellular signaling cascade involved remains largely unclear. Here we studied the molecular mechanisms that promote murine NPC migration in response to CXCL12, in vitro and ex vivo. Migration was highly dependent on signaling by the CXCL12 receptor, CXCR4. Although the JAK/STAT pathway was activated following CXCL12 stimulation of NPC, JAK activity was not necessary for NPC migration in vitro. Whereas CXCL12 activated the PI3K catalytic subunits p110α and p110β in NPC, only p110β participated in CXCL12-mediated NPC migration. Ex vivo experiments using organotypic slice cultures showed that p110β blockade impaired NPC exit from the medial ganglionic eminence. In vivo experiments using in utero electroporation nonetheless showed that p110β is dispensable for radial migration of pyramidal neurons. We conclude that PI3K p110β is activated in NPC in response to CXCL12, and its activity is necessary for immature interneuron migration to the cerebral cortex.     

Midgut aminopeptidase N isoforms from Ostrinia nubilalis: Activity characterization and differential binding to Cry1Ab and Cry1Fa proteins from Bacillus thuringiensis

Aminopeptidase N (APN) isoforms from Lepidoptera are known for their involvement in the mode of action of insecticidal Cry proteins from Bacillus thuringiensis. These enzymes belong to a protein family with at least eight different members that are expressed simultaneously in the midgut of lepidopteran larvae. Here, we focus on the characterization of the APNs from Ostrinia nubilalis (OnAPNs) to identify potential Cry receptors. We expressed OnAPNs in insect cells using a baculovirus system and analyzed their enzymatic activity by probing substrate specificity and inhibitor susceptibility. The interaction with Cry1Ab and Cry1Fa proteins (both found in transgenic insect-resistant maize) was evaluated by ligand blot assays and immunocytochemistry. Ligand blots of brush border membrane proteins showed that both Cry proteins bound mainly to a 150 kDa-band, in which OnAPNs were greatly represented. Binding analysis of Cry proteins to the cell-expressed OnAPNs showed that OnAPN1 interacted with both Cry1Ab and Cry1Fa, whereas OnAPN3a and OnAPN8 only bound to Cry1Fa. Two isoforms, OnAPN2 and OnAPN3b, did not interact with any of these two proteins. This work provides the first evidence of a differential role of OnAPN isoforms in the mode of action of Cry proteins in O. nubilalis.     

Melatonin attenuates the effects of sub-acute administration of lead on kidneys in rats without altering the lead-induced reduction in nitric oxide

Exposure to lead induces oxidative stress and renal damage. Although most forms of oxidative stress are characterized by simultaneous elevation of nitrogen and oxidative species, lead-induced oxidative stress is unusual in that it is associated with a reduction in nitric oxide (NO) levels in the kidney. The role of NO in kidney injury is controversial; some studies suggest that it is associated with renal injury, whereas others show that it exerts protective effects. Concentration-dependent effects have also been proposed, linking low levels with vasodilatation and high levels with toxicity. The aim of this study was to evaluate the effects of melatonin co-exposure on the lead-induced reduction in renal NO levels. We found that sub-acute intraperitoneal administration of 10 mg/kg/day of lead for 15 days induced toxic levels of lead in the blood and caused renal toxicity (pathological and functional). Under our experimental conditions, lead induced an increase in lipid peroxidation and a decrease in NO. Melatonin co-treatment decreased lead-induced oxidative stress (peroxidation level) and toxic effects on kidneys without altering the lead-induced reduction in renal NO. These results suggest that, in our experimental model, the reduction in renal NO levels by lead exposure is not the only responsible factor for lead-induced kidney damage.     

Fish oil reverses the altered glucose transporter,phosphorylation, insulin receptor substrate-1 protein level and lipid contents in the skeletal muscle of sucrose-rich diet fed rats

The role and underlying mechanisms by which n?3 polyunsaturated fatty acids (PUFA) prevent/reverse SRD-induced insulin resistance (IR) in the muscle are not completely understood. Therefore, we examined: triglyceride, diacylglycerol, PKCθ, Glut-4, enzymatic hexokinase activity, IRS-1 protein mass level, and fatty acid composition of muscle phospholipids. Rats were fed a SRD during 6 months. Thereafter, half the animals continued with SRD up to 8 months; the other half was fed a SRD in which CO (8% wt/wt) was replaced by FO (7%+1% CO) for 2 months. Results were compared with those obtained in rats fed a control diet (CD). In SRD-fed rats, FO oil normalized/improved lipid storage and PKCθ protein mass level. Effects of insulin were comparable with those of CD-fed rats. FO reversed impaired glucose phosphorylation, IRS-1, and, under insulin stimulation, Glut-4 protein mass level. FO normalized insulin resistance and increased n?3 PUFAs in muscle phospholipids.     

Bifidobacterium CECT 7765 improves metabolic and immunological alterations associated with obesity in high‐fat diet‐fed mice

Objectives: To evaluate the effects of administration of Bifidobacterium pseudocatenulatum CECT 7765 on metabolic and immune alterations in obese mice. Design and Methods: Adult male wild‐type C57BL‐6 mice were fed a standard diet or high‐fat diet (HFD), supplemented or not with B. pseudocatenulatum CECT 7765 for 7 weeks. The assessments included biochemical and immunological parameters, insulin resistance, glucose tolerance, histology of liver, white‐adipose and intestinal tissues, immunocompetent cell functions, and microbiota‐related features. Results: B. pseudocatenulatum CECT 7765 reduced serum cholesterol, triglyceride, and glucose levels and decreased insulin resistance and improved glucose tolerance in obese mice. This strain reduced serum levels of leptin, interleukin (IL)‐6 and monocyte chemotactic protein‐1, while increased those of IL‐4 in HFD‐fed mice. B. pseudocatenulatum CECT7765 reduced liver steatosis and the number of larger adipocytes and number of fat micelles in enterocytes of obese mice. The strain also improved the function of macrophages and dendritic cells in relation to phagocytosis, cytokine production, and induction of T‐lymphocyte proliferation. The strain administration increased bifidobacteria and reduced enterobacteria and the inflammatory properties of the gut content in HFD‐fed mice. Conclusion: B. pseudocatenulatum CECT 7765 was shown to ameliorate both metabolic and immunological dysfunctions related to obesity in HFD‐fed mice.     

Predicting Summer Site Occupancy for an Invasive Species,the Common Brushtail Possum (Trichosurus vulpecula), in an Urban Environment

Invasive species are often favoured in fragmented, highly-modified, human-dominated landscapes such as urban areas. Because successful invasive urban adapters can occupy habitat that is quite different from that in their original range, effective management programmes for invasive species in urban areas require an understanding of distribution, habitat and resource requirements at a local scale that is tailored to the fine-scale heterogeneity typical of urban landscapes. The common brushtail possum (Trichosurus vulpecula) is one of New Zealand’s most destructive invasive pest species. As brushtail possums traditionally occupy forest habitat, control in New Zealand has focussed on rural and forest habitats, and forest fragments in cities. However, as successful urban adapters, possums may be occupying a wider range of habitats. Here we use site occupancy methods to determine the distribution of brushtail possums across five distinguishable urban habitat types during summer, which is when possums have the greatest impacts on breeding birds. We collected data on possum presence/absence and habitat characteristics, including possible sources of supplementary food (fruit trees, vegetable gardens, compost heaps), and the availability of forest fragments from 150 survey locations. Predictive distribution models constructed using the programme PRESENCE revealed that while occupancy rates were highest in forest fragments, possums were still present across a large proportion of residential habitat with occupancy decreasing as housing density increased and green cover decreased. The presence of supplementary food sources was important in predicting possum occupancy, which may reflect the high nutritional value of these food types. Additionally, occupancy decreased as the proportion of forest fragment decreased, indicating the importance of forest fragments in determining possum distribution. Control operations to protect native birds from possum predation in cities should include well-vegetated residential areas; these modified habitats not only support possums but provide a source for reinvasion of fragments.     

An Optimized Immunohistochemistry Technique Improves NMO-IgG Detection: Study Comparison with Cell-Based Assays

Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.     

Falling Victim to Wasps in the Air: A Fate Driven by Prey Flight Morphology?

In prey-predator systems where the interacting individuals are both fliers, the flight performance of both participants heavily influences the probability of success of the predator (the prey is captured) and of the prey (the predator is avoided). While the flight morphology (an estimate of flight performance) of predatory wasps has rarely been addressed as a factor that may contribute to explain prey use, how the flight morphology of potential prey influences the output of predator-prey encounters has not been studied. Here, we hypothesized that flight morphology associated with flight ability (flight muscle mass to body mass ratio (FMR) and body mass to wing area ratio (wing loading, WL)) of Diptera affect their probability of being captured by specialized Diptera-hunting wasps (Bembix merceti and B. zonata), predicting a better manoeuvrability and acceleration capacity achieved by higher FMR and lower WL, and flight speed achieved by higher WL. In addition, wasp species with better flight morphology should be less limited by an advantageous Diptera flight morphology. Overall, the abundance of dipterans in the environment explained an important part of the observed variance in prey capture rate. However, it was not the only factor shaping prey capture. First, higher prey abundance was associated with greater capture rate for one species (B. merceti), although not for the other one. Second, the interaction observed between the environmental dipteran availability and dipteran WL for B. zonata suggests that greater dipteran WL (this probably meaning high cruising speed) decreased the probability of being captured, as long as fly abundance was high in the environment. Third, greater dipteran FMR (which likely means high manoeuvrability and acceleration capacity) helped to reduce predation by B. merceti if, again, dipterans were abundant in the environment. Wasp WL only varied with body mass but not between species, thereby hardly accounting for inter-specific differences in the wasps’ predatory patterns. However, the greater FMR of B. zonata, which implies better flight performance and greater load-lifting capacity, may explain why the capture rate in the two wasp species is affected by different factor interactions. In conclusion, although prey availability remains the primary factor shaping prey use, prey flight morphology seems to gain an additional role under conditions of abundant prey, when wasps can avoid flies with better flight ability.