A dominant function of p38 mitogen-activated protein kinase signaling in receptor activator of nuclear factor-κB ligand expression and osteoclastogenesis induction by Aggregatibacter actinomycetemcomitans and Escherichia coli lipopolysaccharide

Lipopolysaccharide from gram-negative bacteria is one of the microbial-associated molecular patterns that initiate the immune/inflammatory response, leading to the tissue destruction observed in periodontitis. The aim of this study was to evaluate the role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in lipopolysaccharide-induced receptor activator of nuclear factor-κB ligand (RANKL) expression by murine periodontal ligament cells. Material and Methods:  Expression of RANKL and osteoprotegerin mRNA was studied by reverse transcription-polymerase chain reaction upon stimulation with lipopolysaccharide from Escherichia coli and Aggregatibacter actinomycetemcomitans . The biochemical inhibitor SB203580 was used to evaluate the contribution of the p38 MAPK signaling pathway to lipopolysaccharide-induced RANKL and osteoprotegerin expression. Stable cell lines expressing dominant-negative forms of MAPK kinase (MKK)-3 and MKK6 were generated to confirm the role of the p38 MAPK pathway. An osteoclastogenesis assay using a coculture model of the murine monocytic cell line RAW 264.7 was used to determine if osteoclast differentiation induced by lipopolysaccharide-stimulated periodontal ligament was correlated with RANKL expression. Results:  Inhibiting p38 MAPK prior to lipopolysaccharide stimulation resulted in a significant decrease of RANKL mRNA expression. Osteoprotegerin mRNA expression was not affected by lipopolysaccharide or p38 MAPK. Lipopolysaccharide-stimulated periodontal ligament cells increased osteoclast differentiation, an effect that was completely blocked by osteoprotegerin and significantly decreased by inhibition of MKK3 and MKK6, upstream activators of p38 MAPK. Conditioned medium from murine periodontal ligament cultures did not increase osteoclast differentiation, indicating that periodontal ligament cells produced membrane-bound RANKL. Conclusion:  Lipopolysaccharide resulted in a significant increase of RANKL in periodontal ligament cells. The p38 MAPK pathway is required for lipopolysaccharide-induced membrane-bound RANKL expression in these cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65788/1/j.1600-0765.2007.01013.x.pd

Evaporative cooling and vasodilation mediate thermoregulation in naked mole-rats during normoxia but not hypoxia

Naked mole-rats are among the most hypoxia-tolerant mammals but have a poor thermoregulatory capacity due to their lack of insulating fur and fat, and small body size. In acute hypoxia, naked mole-rat body temperature (Tb) decreases to ambient temperature (Ta) but the mechanisms that underlie this thermoregulatory response are unknown. We hypothesized 1) that naked mole-rat blood vessels vasodilate during hypoxia to shunt heat toward the body surface and/or 2) that they augment heat loss through evaporative cooling. Using open-flow re- spirometry (indirect calorimetry) we explored metabolic and thermoregulatory strategies of naked mole-rats exposed to hypoxia (7% O2 for 1 h) at two relative humidities (RH; 50 or 100% water saturation), and in two Ta's (25 and 30 °C), alone, and following treatment with the vasoconstrictor angiotensin II (ANGII). We found that Tb and metabolic rate decreased in hypoxia across all treatment groups but that neither RH nor ANGII effected either variable in hypoxia. Conversely, both Tb and metabolic rate were reduced in 100% RH or by ANGII treatment in normoxia at 25 °C, and therefore the absolute change in both variables with the onset of hypoxia was reduced when vasodilation or evaporative cooling were prevented. We conclude that naked mole-rats employ evaporative cooling and vasodilation to thermoregulate in normoxia and in 25 °C but that neither mechanism is involved in thermoregulatory changes during acute hypoxia. These findings suggest that NMRs may employ passive strategies such as reducing thermogenesis to reduce Tb in hypoxia, which would support metabolic rate suppression

Experimental study of pH effect on uranium (UVI) particle formation and transport through quartz sand in alkaline 0.1 M sodium chloride solutions

A thorough understanding of the aqueous uranium VI (UVI) chemistry in alkaline, sodium containing solutions is imperative to address a wide range of critical challenges in environmental engineering, including nuclear waste management. The aim of the present study was to characterise experimentally in more detail the control of pH on the removal of UVI from aqueous alkaline solutions through particle formation and on subsequent transport through porous media. We conducted first static batch experiments in the pH range between 10.5 and 12.5 containing 10 ppm UVI in 0.1 M NaCl solutions and examined the particles formed using filtration, dynamic light scattering, transition electron microscopy and X-ray powder diffraction. We found that at pH 10.5 and 11.5, between 75 and 96 % of UVI was removed from the solutions as clarkeite and studtite over a period of 48 h, forming particles with hydrodynamic diameters of 640 ± 111 nm and 837 ± 142 nm, respectively and representing aggregates of 10′s nm sized crystals randomly orientated. At pH 12.5, the formation of particles >0.2 μm became insignificant and no UVI was removed from solution. The mobility of UVI in these solutions was further studied using column experiments through quartz sand. We found that at pH 10.5 and 11.5, UVI containing particles were immobilised near the column inlet, likely due physical immobilisation of the particles (particle straining). At pH 12.5, however, UVI quantitatively eluted from the columns in the filter fraction <0.2 μm. The findings of our study reinforce a strong control of solution pH on particle size and U removal in alkaline solutions and subsequently on mobility of U through quartz porous media

Simvastatin improves the sexual health-related quality of life in men aged 40 years and over with erectile dysfunction : Additional data from the Erectile Dysfunction and Statin trial

© 2014 Trivedi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background: Erectile dysfunction is prevalent in men over 40 years, affecting their quality of life and that of their partners. The aims of this study were:a)To evaluate the internal reliability of the male erectile dysfunction specific quality of life (MED-QoL) scale and explore its factor structure.b)To evaluate the effect of simvastatin on subscales of the MED-QoL in men over forty years with erectile dysfunction. Methods: This is a double blind randomised controlled trial of 40 mg simvastatin or placebo given once daily for six months to men over forty years with untreated erectile dysfunction, who were not at high cardiovascular risk and were not on anti-hypertensive or lipid-lowering medication. 173 eligible men were recruited from 10 general practices in East of England. Data were collected at two points over 30 weeks. We report on the factor structure of MED-QoL, the internal reliability of the scale and the derived subscales, and the effect of simvastatin on MED-QoL subscales. Results: An initial analysis of the MED-QoL items suggested that a number of items should be removed (MED-QoL-R). Exploratory factor analysis identified three subscales within the MED-QoL-R which accounted for 96% of the variance, related to feelings of Control, initiating Intimacy, and Emotional response to erectile dysfunction. The alpha value for the revised scale (MED-Qol-R) was >0.95 and exceeded .82 for each subscale. Regression analysis showed that patients in the placebo group experienced a significantly reduced feeling of Control over erectile dysfunction than those in the statin group. Those in the placebo group had significantly lower Emotional response than those in the statin group at the close of trial, but there was no significant treatment effect on Intimacy. Conclusions: Our revised MED-QoL-R identified three subscales. Secondary analysis showed a significant improvement in sexual health related quality of life, specifically in relation to perception of control and emotional health in men with untreated erectile dysfunction given 40 mg simvastatin for six months. Trial registration: Current Controlled Trials ISRCTN66772971.Peer reviewe

Projections of the healthcare costs and disease burden due to hepatitis C infection under different treatment policies in Malaysia, 2018-2040

The World Health Organisation (WHO) has set ambitious goals to reduce the global disease burden associated with, and eventually eliminate, viral hepatitis

Potential for Energy Production from Farm Wastes Using Anaerobic Digestion in the UK: An Economic Comparison of Different Size Plants

© 2017 by the authors. Anaerobic digestion (AD) plants enable renewable fuel, heat, and electricity production, with their efficiency and capital cost strongly dependent on their installed capacity. In this work, the technical and economic feasibility of different scale AD combined heat and power (CHP) plants was analyzed. Process configurations involving the use of waste produced in different farms as feedstock for a centralized AD plant were assessed too. The results show that the levelized cost of electricity are lower for large-scale plants due to the use of more efficient conversion devices and their lower capital cost per unit of electricity produced. The levelized cost of electricity was estimated to be 4.3 p/kWhe for AD plants processing the waste of 125 dairy cow sized herds compared to 1.9 p/kWhe for AD plants processing waste of 1000 dairy cow sized herds. The techno-economic feasibility of the installation of CO2 capture units in centralized AD-CHP plants was also undertaken. The conducted research demonstrated that negative CO2 emission AD power generation plants could be economically viable with currently paid feed-in tariffs in the UK.The authors would like to acknowledge the funding received from the Research Councils UK (RCUK) and particularly the Engineering and Physical Sciences Research Council (EPSRC) under Grant Number: EP/K011820/1 (Centre for Sustainable Energy Use in Food Chains-CSEF) and EP/M007359/1 (Recovery and re-use of energy, water and nutrients from waste in the food chain-Redivivus)

Promoting STI testing among senior vocational students in Rotterdam, the Netherlands: effects of a cluster randomized study

Background: Adolescents are a risk group for acquiring sexually transmitted infections (STIs). In the Netherlands, senior vocational school students are particular at risk. However, STI test rates among adolescents are low and interventions that promote testing are scarce. To enhance voluntary STI testing, an intervention was designed and evaluated in senior vocational schools. The intervention combined classroom health education with sexual health services at the school site. The purpose of this study was to assess the combined and single effects on STI testing of health education and school-based sexual health services. Methods. In a cluster-randomized study the intervention was evaluated in 24 schools, using three experimental conditions: 1) health education, 2) sexual health services; 3) both components; and a control group. STI testing was assessed by self reported behavior and registrations at regional sexual health services. Follow-up measurements were performed at 1, 3, and 6-9 months. Of 1302 students present at baseline, 739 (57%) completed at least 1 follow-up measurement, of these students 472 (64%) were sexually experienced, and considered to be susceptible for the intervention. Multi-level analyses were conducted. To perform analyses according to the principle of intention-to-treat, missing observations at follow-up on the outcome measure were imputed with multiple imputation techniques. Results were compared with the complete cases analysis. Results: Sexually experienced students that received the combined intervention of health education and sexual health services reported more STI testing (29%) than students in the control group (4%) (OR = 4.3, p < 0.05). Test rates in the group that received education or sexual health services only were 5.7% and 19.9%, not reaching statistical significance in multilevel analyses. Female students were more often tested then male students: 21.5% versus 5.4%. The STI-prevalence in the study group was low with 1.4%. Conclusions: Despite a low dose of intervention that was received by the students and a high attrition, we were able to show an intervention effect among sexually experienced students on STI testing. This study confirmed our hypothesis that offering health education to vocational students in combination with sexual health services at school sites is more effective in enhancing STI testing than offering services or education only

Monitoring changes in malaria epidemiology and effectiveness of interventions in Ethiopia and Uganda: Beyond Garki Project baseline survey.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Scale-up of malaria interventions seems to have contributed to a decline in the disease but other factors may also have had some role. Understanding changes in transmission and determinant factors will help to adapt control strategies accordingly. METHODS: Four sites in Ethiopia and Uganda were set up to monitor epidemiological changes and effectiveness of interventions over time. Here, results of a survey during the peak transmission season of 2012 are reported, which will be used as baseline for subsequent surveys and may support adaptation of control strategies. Data on malariometric and entomological variables, socio-economic status (SES) and control coverage were collected. RESULTS: Malaria prevalence varied from 1.4 % in Guba (Ethiopia) to 9.9 % in Butemba (Uganda). The most dominant species was Plasmodium vivax in Ethiopia and Plasmodium falciparum in Uganda. The majority of human-vector contact occurred indoors in Uganda, ranging from 83 % (Anopheles funestus sensu lato) to 93 % (Anopheles gambiae s.l.), which is an important factor for the effectiveness of insecticide-treated nets (ITNs) or indoor residual spraying (IRS). High kdr-L1014S (resistance genotype) frequency was observed in A. gambiae sensu stricto in Uganda. Too few mosquitoes were collected in Ethiopia, so it was not possible to assess vector habits and insecticide resistance levels. ITN ownership did not vary by SES and 56-98 % and 68-78 % of households owned at least one ITN in Ethiopia and Uganda, respectively. In Uganda, 7 % of nets were purchased by households, but the nets were untreated. In three of the four sites, 69-76 % of people with access to ITNs used them. IRS coverage ranged from 84 to 96 % in the three sprayed sites. Half of febrile children in Uganda and three-quarters in Ethiopia for whom treatment was sought received diagnostic tests. High levels of child undernutrition were detected in both countries carrying important implications on child development. In Uganda, 7-8 % of pregnant women took the recommended minimum three doses of intermittent preventive treatment. CONCLUSION: Malaria epidemiology seems to be changing compared to earlier published data, and it is essential to have more data to understand how much of the changes are attributable to interventions and other factors. Regular monitoring will help to better interpret changes, identify determinants, modify strategies and improve targeting to address transmission heterogeneity.UK aid (PPA

Bioassay studies support the potential for latrogenic transmission of variant Creutzfeldt Jakob disease through dental procedures

Background: Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient? Methods: BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice. Findings: Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days). Interpretation: Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments

A Functional Nuclear Localization Sequence in the C. elegans TRPV Channel OCR-2

The ability to modulate gene expression in response to sensory experience is critical to the normal development and function of the nervous system. Calcium is a key activator of the signal transduction cascades that mediate the process of translating a cellular stimulus into transcriptional changes. With the recent discovery that the mammalian Cav1.2 calcium channel can be cleaved, enter the nucleus and act as a transcription factor to control neuronal gene expression, a more direct role for the calcium channels themselves in regulating transcription has begun to be appreciated. Here we report the identification of a nuclear localization sequence (NLS) in the C. elegans transient receptor potential vanilloid (TRPV) cation channel OCR-2. TRPV channels have previously been implicated in transcriptional regulation of neuronal genes in the nematode, although the precise mechanism remains unclear. We show that the NLS in OCR-2 is functional, being able to direct nuclear accumulation of a synthetic cargo protein as well as the carboxy-terminal cytosolic tail of OCR-2 where it is endogenously found. Furthermore, we discovered that a carboxy-terminal portion of the full-length channel can localize to the nucleus of neuronal cells. These results suggest that the OCR-2 TRPV cation channel may have a direct nuclear function in neuronal cells that was not previously appreciated