Comparison of Plasmodium berghei challenge models for the evaluation of pre-erythrocytic malaria vaccines and their effect on perceived vaccine efficacy

<p>Abstract</p> <p>Background</p> <p>The immunological mechanisms responsible for protection against malaria infection vary among <it>Plasmodium </it>species, host species and the developmental stage of parasite, and are poorly understood. A challenge with live parasites is the most relevant approach to testing the efficacy of experimental malaria vaccines. Nevertheless, in the mouse models of <it>Plasmodium berghei </it>and <it>Plasmodium yoelii</it>, parasites are usually delivered by intravenous injection. This route is highly artificial and particularly in the <it>P. berghei </it>model produces inconsistent challenge results. The initial objective of this study was to compare an optimized intravenous (IV) delivery challenge model with an optimized single infectious mosquito bite challenge model. Finding shortcomings of both approaches, an alternative approach was explored, <it>i.e</it>., the subcutaneous challenge.</p> <p>Methods</p> <p>Mice were infected with <it>P. berghei </it>sporozoites by intravenous (tail vein) injection, single mosquito bite, or subcutaneous injection of isolated parasites into the subcutaneous pouch at the base of the hind leg. Infection was determined in blood smears 7 and 14 days later. To determine the usefulness of challenge models for vaccine testing, mice were immunized with circumsporozoite-based DNA vaccines by gene gun.</p> <p>Results</p> <p>Despite modifications that allowed infection with a much smaller than reported number of parasites, the IV challenge remained insufficiently reliable and reproducible. Variations in the virulence of the inoculum, if not properly monitored by the rigorous inclusion of sporozoite titration curves in each experiment, can lead to unacceptable variations in reported vaccine efficacies. In contrast, mice with different genetic backgrounds were consistently infected by a single mosquito bite, without overwhelming vaccine-induced protective immune responses. Because of the logistical challenges associated with the mosquito bite model, the subcutaneous challenge route was optimized. This approach, too, yields reliable challenge results, albeit requiring a relatively large inoculum.</p> <p>Conclusions</p> <p>Although a single bite by <it>P. berghei </it>infected <it>Anopheles </it>mosquitoes was superior to the IV challenge route, it is laborious. However, any conclusive evaluation of a pre-erythrocytic malaria vaccine candidate should require challenge through the natural anatomic target site of the parasite, the skin. The subcutaneous injection of isolated parasites represents an attractive compromise. Similar to the mosquito bite model, it allows vaccine-induced antibodies to exert their effect and is, therefore not as prone to the artifacts of the IV challenge.</p

Breast cancer incidence and mortality in Tyrol/Austria after fifteen years of opportunistic mammography screening

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to analyse breast cancer incidence and mortality in Tyrol from 1970 to 2006, namely after performing more than a decade of opportunistic mammography screening and just before piloting an organised screening programme. Our investigation was conducted on a population level.</p> <p>Methods</p> <p>To study time trends in breast cancer incidence and mortality, we applied the age-period-cohort model by Poisson regression to the official mortality data covering more than three decades from 1970 to 2006 and to the incidence data ranging from 1988 to 2006. In addition, for incidence data we analysed data on breast cancer staging and compared these with EU guidelines.</p> <p>Results</p> <p>For the analysis of time trend in breast cancer mortality in age groups 40-79, an age-period-cohort model fits well and shows for years 2002-2006 a statistically significant reduction of 26% (95% CI 13%-36%) in breast cancer mortality as compared to 1992-1996.</p> <p>We see only slight non-significant increases in breast cancer incidence. For the past five years, incidence data show a 10% proportion of in situ cases, and of 50% for cases in stages II+.</p> <p>Conclusions</p> <p>The opportunistic breast cancer screening programme in Tyrol has only in part exploited the mortality reduction known for organised screening programmes. There seems to be potential for further improvement, and we recommend that an organised screening programme and a detailed screening database be introduced to collect all information needed to analyse the quality indicators suggested by the EU guidelines.</p

Emission of Volatile Organic Compounds After Herbivory from Trifolium pratense (L.) Under Laboratory and Field Conditions

Plants emit a wide range of volatile organic compounds in response to damage by herbivores, and many of the compounds have been shown to attract the natural enemies of insect herbivores or serve for inter- and intra-plant communication. Most studies have focused on volatile emission in the laboratory while little is known about emission patterns in the field. We studied the emission of volatiles by Trifolium pratense (red clover) under both laboratory and field conditions. The emission of 24 compounds was quantified in the laboratory, of which eight showed increased emission rates after herbivory by Spodoptera littoralis caterpillars, including (E)-β-ocimene, the most abundant compound, (Z)-β-ocimene, linalool, (E)-β-caryophyllene, (E,E)-α-farnesene, 4,8-dimethyl-1,3,7-nonatriene (DMNT), 1-octen-3-ol, and methyl salicylate (MeSA). While most of these compounds have been reported as herbivore-induced volatiles from a wide range of plant taxa, 1-octen-3-ol seems to be a characteristic volatile of legumes. In the field, T. pratense plants with varying herbivore damage growing in established grassland communities emitted only 13 detectable compounds, and the correlation between herbivore damage and volatile release was more variable than in the laboratory. For example, the emission of (E)-β-ocimene, (Z)-β-ocimene, and DMNT actually declined with damage, while decanal exhibited increased emission with increasing herbivory. Elevated light and temperature increased the emission of many compounds, but the differences in light and temperature conditions between the laboratory and the field could not account for the differences in emission profiles. Our results indicate that the release of volatiles from T. pratense plants in the field is likely to be influenced by additional biotic and abiotic factors not measured in this study. The elucidation of these factors may be important in understanding the physiological and ecological functions of volatiles in plants

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million personyears of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eG FR values 105 mL.min(-1).1.73 m(-2), compared with those with eG FR between 60 and 105 mL.min(-1).1.73 m(-2). Mendelian randomization analyses for CHD showed an association among participants with eGFR 105 mL.min(-1).1.73 m(-2). Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin Alc, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function