Mosquito Infection Responses to Developing Filarial Worms

Human lymphatic filariasis is a mosquito-vectored disease caused by the nematode parasites Wuchereria bancrofti, Brugia malayi and Brugia timori. These are relatively large roundworms that can cause considerable damage in compatible mosquito vectors. In order to assess how mosquitoes respond to infection in compatible mosquito-filarial worm associations, microarray analysis was used to evaluate transcriptome changes in Aedes aegypti at various times during B. malayi development. Changes in transcript abundance in response to the different stages of B. malayi infection were diverse. At the early stages of midgut and thoracic muscle cell penetration, a greater number of genes were repressed compared to those that were induced (20 vs. 8). The non-feeding, intracellular first-stage larvae elicited few differences, with 4 transcripts showing an increased and 9 a decreased abundance relative to controls. Several cecropin transcripts increased in abundance after parasites molted to second-stage larvae. However, the greatest number of transcripts changed in abundance after larvae molted to third-stage larvae and migrated to the head and proboscis (120 induced, 38 repressed), including a large number of putative, immunity-related genes (∼13% of genes with predicted functions). To test whether the innate immune system of mosquitoes was capable of modulating permissiveness to the parasite, we activated the Toll and Imd pathway controlled rel family transcription factors Rel1 and Rel2 (by RNA interference knockdown of the pathway's negative regulators Cactus and Caspar) during the early stages of infection with B. malayi. The activation of either of these immune signaling pathways, or knockdown of the Toll pathway, did not affect B. malayi in Ae. aegypti. The possibility of LF parasites evading mosquito immune responses during successful development is discussed

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

BACKGROUND: Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR). Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. METHODS: We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh) to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. RESULTS: The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. CONCLUSION: These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR

Phenomenon of declining blood pressure in elderly - high systolic levels are undervalued with Korotkoff method

<p>Abstract</p> <p>Background</p> <p>Systolic blood pressure (SBP) decline has been reported in octogenarians. The aim was to study if it could be observed while measuring SBP with two methods: Korotkoff (K-BP) and Strain-Gauge-Finger-Pletysmography (SG-BP), and which of them were more reliable in expressing vascular burden.</p> <p>Methods</p> <p>A cohort of 703 men from a population of Malmö, Sweden, were included in "Men born in 1914-study" and followed-up at ages: 68 and 81 years. 176 survivors were examined with K-BP and SG-BP at both ages, and 104 of them with Ambulatory Blood Pressure at age 81/82. Ankle Brachial Index (ABI) was measured on both occasions, and Carotid Ultrasound at age 81.</p> <p>Results</p> <p>From age 68 to 81, mean K-BP decreased in the cohort with mean 8.3 mmHg, while SG-BP increased with 13.4 mmHg. K-BP decreased in 55% and SG-BP in 31% of the subjects. At age 81, K-BP was lower than SG-BP in 72% of subjects, and correlated to high K-BP at age 68 (r = --.22; p < .05). SG-BP at age 81 was correlated with mean ambulatory 24-h SBP (r = .480; p < .0001), daytime SBP (r = .416; p < .0001), nighttime SBP (r = .395; p < .0001), and daytime and nighttime Pulse Pressure (r = .452; p < .0001 and r = .386; p < .0001). KB-BP correlated moderately only with nighttime SBP (r = .198; p = .044), and daytime and nightime pulse pressure (r = .225; p = .021 and r = .264; p = .007). Increasing SG-BP from age 68 to 81, but not K-BP, correlated with: 24-h, daytime and nighttime SBP, and mean daytime and nighttime Pulse Pressure. Increasing SG-BP was also predicted by high B-glucose and low ABI at age 68, and correlated with carotid stenosis and low ABI age 81, and the grade of ABI decrease over 13 years.</p> <p>Conclusion</p> <p>In contrast to K-BP, values of SG-BP in octogenarians strongly correlated with Ambulatory Blood Pressure. The SG-BP decline in the last decade was rare, and increasing SG-BP better than K-BP reflected advanced atherosclerosis. It should be aware, that K-BP underdetected 46% of subjects with SG-BP equal/higher than 140 mmHg at age 81, which may lead to biased associations with risk factors due to differential misclassification by age.</p

Development of an In Vivo RNAi Protocol to Investigate Gene Function in the Filarial Nematode, Brugia malayi

Our ability to control diseases caused by parasitic nematodes is constrained by a limited portfolio of effective drugs and a paucity of robust tools to investigate parasitic nematode biology. RNA interference (RNAi) is a reverse-genetics tool with great potential to identify novel drug targets and interrogate parasite gene function, but present RNAi protocols for parasitic nematodes, which remove the parasite from the host and execute RNAi in vitro, are unreliable and inconsistent. We have established an alternative in vivo RNAi protocol targeting the filarial nematode Brugia malayi as it develops in an intermediate host, the mosquito Aedes aegypti. Injection of worm-derived short interfering RNA (siRNA) and double stranded RNA (dsRNA) into parasitized mosquitoes elicits suppression of B. malayi target gene transcript abundance in a concentration-dependent fashion. The suppression of this gene, a cathepsin L-like cysteine protease (Bm-cpl-1) is specific and profound, both injection of siRNA and dsRNA reduce transcript abundance by 83%. In vivo Bm-cpl-1 suppression results in multiple aberrant phenotypes; worm motility is inhibited by up to 69% and parasites exhibit slow-moving, kinked and partial-paralysis postures. Bm-cpl-1 suppression also retards worm growth by 48%. Bm-cpl-1 suppression ultimately prevents parasite development within the mosquito and effectively abolishes transmission potential because parasites do not migrate to the head and proboscis. Finally, Bm-cpl-1 suppression decreases parasite burden and increases mosquito survival. This is the first demonstration of in vivo RNAi in animal parasitic nematodes and results indicate this protocol is more effective than existing in vitro RNAi methods. The potential of this new protocol to investigate parasitic nematode biology and to identify and validate novel anthelmintic drug targets is discussed

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

What matters for life satisfaction among the oldest-old? Evidence from China

The world population is aging rapidly and the well-being of older people is of great interest. Therefore, this study investigates the determinants of life satisfaction among the oldest-old (i.e. individuals aged 80 or over) in China. Materials and methods We use the 2011/2012 Chinese Longitudinal Healthy Longevity Survey data (n = 6530) for this paper. Logistic regression is used to analyse the effects of socio-demographic, economic, health, instrumental activities of daily living, family and community factors on life satisfaction and depression among the oldest-old in China. Results Our analysis confirms the significance of many factors affecting life satisfaction among the oldest-old in China. Factors that are correlated with life satisfaction include respondent’s sex, education, place of residence, self-rated health status, cognitive ability (using mini mental state examination), regular physical examination, perceived relative economic status, access to social security provisions, commercialized insurances, living arrangements, and number of social services available in the community (p<0.05 for all these variables). Although life satisfaction is negatively associated with instrumental activities of daily living (β = -0.068, 95%CI = -.093—.043), and depression (β = -0.463, 95%CI = -.644—.282), the overall effect of self-rated health status is positive (p<0.001). This confirms the primacy of health as the determinant of well-being among the oldest-old. Conclusions Majority of the oldest-old in China rated their life satisfaction as good or very good. Our findings show that health and economic status are by far the most significant predictors of life satisfaction. Our finding on the primacy of health and relative income as determinants of well-being among the oldest-old, and the greater influence of self-rated health status over objective health measures is consistent with the findings of many past studies. Our results suggest that efforts should be directed at enhancing family support as well as health and social service provisions in the community to improve life satisfaction of older people

Copper distribution in a river system that receives coal mine-affected water releases in the Fitzroy River Basin, Central QLD

The Mackenzie River sub-basin in the Fitzroy Basin (Central Queensland) is a turbid river system associated with significant coal mining. Coal mine-affected water (CMAW) releases do not occur during low flow conditions. Copper (Cu) is one of the heavy metals found in CMAW. The median annual dissolved Cu concentrations in the Mackenzie basin during low flow conditions in 2010-2014, calculated from data reported by the Fitzroy Partnership for River Health, were 3.0, 2.0, 1.5 and 1.2 µg/L (n = 43–264), respectively, with concentrations for 3 years being greater than the ANZECC (2000) toxicant trigger value for Cu (1.4 µg/L) for slightly-moderately disturbed freshwater systems. This study sought to determine the potential bioavailability and the distribution of Cu in the Mackenzie River environment. Two field trips were conducted: sediment core samples were taken in August 2014 and water samples in March 2015, both during low flow conditions and no recent CMAW releases. Three sites were sampled: one, in an upstream tributary, where no coal mining activity existed (called “Ref” site), and two downstream Mackenzie River sites (Site 5b and Site 6), that could receive cumulative mine-affected water releases, from numerous upstream coal mines. DGT-labile Cu (using DGT devices), total dissolved Cu (grab water samples filtered through 0.45µm at the site) and Cu in suspended particulate matter (retained on large diameter 0.45 µm filters, in field) were measured at each site. Triplicate DGT samplers were deployed for 48 h, and triplicate grab water samples were taken during deployment and retrieval of the DGT devices at each site. There was no significant difference in the total dissolved Cu concentration at deployment vs at retrieval at the Ref site and at Site 6 (furthest downstream). The average dissolved Cu concentration over 48 h at these two sites were 0.91 ±0.10 µg/L and 1.6 ±0.26 µg/L, respectively. In contrast a significant difference in the Cu concentration at deployment vs at retrieval was observed at Site 5b (2.1 ±0.14 µg/L vs 3.2 ±0.42 µg/L). Total dissolved Cu at Ref site was below the ANZECC (2000) trigger value, whereas concentrations at downstream sites were greater than the trigger value. The time-averaged DGT-labile (or potentially-bioavailable) Cu concentrations were low overall, being greatest at Site 5b (0.37 ±0.04 µg/L) and similar at Ref site and Site 6 (0.20 ±0.09 vs 0.18 ±0.01 µg/L, respectively). The Ref site had 4.3 mg/kg of particulate Cu on deployment and 1.3 mg/kg on retrieval; the respective values for Site 5b were 2.8 and 9.8 mg/kg, and for Site 6 were 1.2 and 2.1 mg/kg. Turbidity readings on retrieval were 27.4, 163 and 127 NTU at the three sites, respectively. A 10-cm sediment core from Ref site and a 12-cm core from Site 6 were analysed; Site 5b had rocks and pebbles and was unsuitable for coring. Cu concentration (<60 µm fraction) in the 2-cm core slices from Ref site ranged from 16.9-37.7 mg/kg dry weight (dw), and in Site 6 from 19.5-28.3 mg/kg dw. This preliminary study has demonstrated that total dissolved Cu in grab water samples may overestimate the potential impact of Cu on the aquatic environment. Cu distribution in different phases of the turbid Mackenzie River system indicated low bioavailable-Cu levels during low flow conditions. Comparative testing during CMAW releases is recommended. Cu concentrations (<60 µm fraction) in sediment cores were relatively low

Hepatitis C infection in an Irish antenatal population.

The aim of this study was to characterise the current trends of HCV in an Irish antenatal population. Hepatitis C infection (HCV) has an estimated seroprevalence of 1-2% in women of child-bearing age and a vertical transmission rate of 5-15%. Infants of HCV seropositive women, born 1994 to 1999, were referred to the Paediatric Infectious Diseases service. Maternal details were collected retrospectively. In all 296 HCV seropositive women were studied. 244 (82%) were infected through intravenous drug use (IVDU), 25 (8%) through heterosexual contact and 13 (7) vial blood products. Nine women had no identifiable risk factors. Co-infection with other blood borne viruses was uncommon (4.7% HIV, 3.4% hepatitis B). Of 84 women tested for HCV-RNA, 46 (55%) were positive. Eighty three (26%) delivered prematurely; the caesarean section rate was 11%. HCV is increasinly detected in antenatal clinics. Heterosexual contact is a mode of spread. Maternal viraemia can be variable in pregnancy. Further study of HCV in pregnancy is needed to define the impart of pregnancy on HCV, accurately predict infant outcome and selectively target interventions at greatest risk of transmission

Copper distribution in a river system that receives coal mine-affected water releases in the Fitzroy River Basin, Central QLD

The Mackenzie River sub-basin in the Fitzroy Basin (Central Queensland) is a turbid river system associated with significant coal mining. Coal mine-affected water (CMAW) releases do not occur during low flow conditions. Copper (Cu) is one of the heavy metals found in CMAW. The median annual dissolved Cu concentrations in the Mackenzie basin during low flow conditions in 2010-2014, calculated from data reported by the Fitzroy Partnership for River Health, were 3.0, 2.0, 1.5 and 1.2 µg/L (n = 43–264), respectively, with concentrations for 3 years being greater than the ANZECC (2000) toxicant trigger value for Cu (1.4 µg/L) for slightly-moderately disturbed freshwater systems. This study sought to determine the potential bioavailability and the distribution of Cu in the Mackenzie River environment. Two field trips were conducted: sediment core samples were taken in August 2014 and water samples in March 2015, both during low flow conditions and no recent CMAW releases. Three sites were sampled: one, in an upstream tributary, where no coal mining activity existed (called “Ref” site), and two downstream Mackenzie River sites (Site 5b and Site 6), that could receive cumulative mine-affected water releases, from numerous upstream coal mines. DGT-labile Cu (using DGT devices), total dissolved Cu (grab water samples filtered through 0.45µm at the site) and Cu in suspended particulate matter (retained on large diameter 0.45 µm filters, in field) were measured at each site. Triplicate DGT samplers were deployed for 48 h, and triplicate grab water samples were taken during deployment and retrieval of the DGT devices at each site. There was no significant difference in the total dissolved Cu concentration at deployment vs at retrieval at the Ref site and at Site 6 (furthest downstream). The average dissolved Cu concentration over 48 h at these two sites were 0.91 ±0.10 µg/L and 1.6 ±0.26 µg/L, respectively. In contrast a significant difference in the Cu concentration at deployment vs at retrieval was observed at Site 5b (2.1 ±0.14 µg/L vs 3.2 ±0.42 µg/L). Total dissolved Cu at Ref site was below the ANZECC (2000) trigger value, whereas concentrations at downstream sites were greater than the trigger value. The time-averaged DGT-labile (or potentially-bioavailable) Cu concentrations were low overall, being greatest at Site 5b (0.37 ±0.04 µg/L) and similar at Ref site and Site 6 (0.20 ±0.09 vs 0.18 ±0.01 µg/L, respectively). The Ref site had 4.3 mg/kg of particulate Cu on deployment and 1.3 mg/kg on retrieval; the respective values for Site 5b were 2.8 and 9.8 mg/kg, and for Site 6 were 1.2 and 2.1 mg/kg. Turbidity readings on retrieval were 27.4, 163 and 127 NTU at the three sites, respectively. A 10-cm sediment core from Ref site and a 12-cm core from Site 6 were analysed; Site 5b had rocks and pebbles and was unsuitable for coring. Cu concentration (<60 µm fraction) in the 2-cm core slices from Ref site ranged from 16.9-37.7 mg/kg dry weight (dw), and in Site 6 from 19.5-28.3 mg/kg dw. This preliminary study has demonstrated that total dissolved Cu in grab water samples may overestimate the potential impact of Cu on the aquatic environment. Cu distribution in different phases of the turbid Mackenzie River system indicated low bioavailable-Cu levels during low flow conditions. Comparative testing during CMAW releases is recommended. Cu concentrations (<60 µm fraction) in sediment cores were relatively low