Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Molecular and phylogenetic analysis of HIV-1 variants circulating in Italy

<p>Abstract</p> <p>Objective</p> <p>The continuous identification of HIV-1 non-B subtypes and recombinant forms in Italy indicates the need of constant molecular epidemiology survey of genetic forms circulating and transmitted in the resident population.</p> <p>Methods</p> <p>The distribution of HIV-1 subtypes has been evaluated in 25 seropositive individuals residing in Italy, most of whom were infected through a sexual route during the 1995–2005 period. Each sample has been characterized by detailed molecular and phylogenetic analyses.</p> <p>Results</p> <p>18 of the 25 samples were positive at HIV-1 PCR amplification. Three samples showed a nucleotide divergence compatible with a non-B subtype classification. The phylogenetic analysis, performed on both HIV-1 <it>env </it>and <it>gag </it>regions, confirms the molecular sub-typing prediction, given that 1 sample falls into the C subtype and 2 into the G subtype. The B subtype isolates show high levels of <it>intra</it>-subtype nucleotide divergence, compatible with a long-lasting epidemic and a progressive HIV-1 molecular diversification.</p> <p>Conclusion</p> <p>The Italian HIV-1 epidemic is still mostly attributable to the B subtype, regardless the transmission route, which shows an increasing nucleotide heterogeneity. Heterosexual transmission and the interracial blending, however, are slowly introducing novel HIV-1 subtypes. Therefore, a molecular monitoring is needed to follow the constant evolution of the HIV-1 epidemic.</p

Understanding intra-neighborhood patterns in PM<inf>2.5</inf> and PM <inf>10</inf> using mobile monitoring in Braddock, PA

Background: Braddock, Pennsylvania is home to the Edgar Thomson Steel Works (ETSW), one of the few remaining active steel mills in the Pittsburgh region. An economically distressed area, Braddock exceeds average annual (>15 μg/m§ssup§3§esup§) and daily (>35 μg/ m§ssup§3§esup§) National Ambient Air Quality Standards (NAAQS) for particulate matter (PM2.5). Methods. A mobile air monitoring study was designed and implemented in morning and afternoon hours in the summer and winter (2010-2011) to explore the within-neighborhood spatial and temporal (within-day and between-day) variability in PM2.5 and PM10. Results: Both pollutants displayed spatial variation between stops, and substantial temporal variation within and across study days. For summer morning sampling runs, site-specific mean PM2.5 ranged from 30.0 (SD = 3.3) to 55.1 (SD = 13.0) μg/m§ssup§3§esup§. Mean PM10 ranged from 30.4 (SD = 2.5) to 69.7 (SD = 51.2) μg/m§ssup§3§esup§, respectively. During summer months, afternoon concentrations were significantly lower than morning for both PM 2.5 and PM10, potentially owing to morning subsidence inversions. Winter concentrations were lower than summer, on average, and showed lesser diurnal variation. Temperature, wind speed, and wind direction predicted significant variability in PM2.5 and PM10 in multiple linear regression models. Conclusions: Data reveals significant morning versus afternoon variability and spatial variability in both PM2.5 and PM10 concentrations within Braddock. Information obtained on peak concentration periods, and the combined effects of industry, traffic, and elevation in this region informed the design of a larger stationary monitoring network. © 2012 Tunno et al.; licensee BioMed Central Ltd

Polymorphism in Gag Gene Cleavage Sites of HIV-1 Non-B Subtype and Virological Outcome of a First-Line Lopinavir/Ritonavir Single Drug Regimen

Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (p = 0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial

Use of a total traffic count metric to investigate the impact of roadways on asthma severity: a case-control study

<p>Abstract</p> <p>Background</p> <p>This study had two principal objectives: (i) to investigate the relationship between asthma severity and proximity to major roadways in Perth, Western Australia; (ii) to demonstrate a more accurate method of exposure assessment for traffic pollutants using an innovative GIS-based measure that fully integrates all traffic densities around subject residences.</p> <p>Methods</p> <p>We conducted a spatial case-control study, in which 'cases' were defined as individuals aged under 19 years of age with more severe asthma (defined here as two or more emergency department contacts with asthma in a defined 5-year period) versus age- and gender-matched 'controls' with less severe asthma (defined here as one emergency department contact for asthma). Traffic exposures were measured using a GIS-based approach to determine the lengths of the roads falling within a buffer area, and then multiplying them by their respective traffic counts.</p> <p>Results</p> <p>We examined the spatial relationship between emergency department contacts for asthma at three different buffer sizes: 50 metres, 100 metres and 150 metres. No effect was noted for the 50 metre buffer (OR = 1.07; 95% CI: 0.91-1.26), but elevated odds ratios were observed with for crude (unadjusted) estimates OR = 1.21 (95% CI: 1.00-1.46) for 100 metre buffers and OR = 1.25 (95% CI: 1.02-1.54) for 150 metre buffers. For adjusted risk estimates, only the 150 metre buffer yielded a statistically significant finding (OR = 1.24; 95% CI:1.00-1.52).</p> <p>Conclusions</p> <p>Our study revealed a significant 24% increase in the risk of experiencing multiple emergency department contacts for asthma for every log-unit of traffic exposure. This study provides support for the hypothesis that traffic related air pollution increases the frequency of health service contacts for asthma. This study used advanced GIS techniques to establish traffic-weighted buffer zones around the geocoded residential location of subjects to provide an accurate assessment of exposure to traffic emissions, thereby providing a quantification of the ranges over which pollutants may exert a health effect.</p

Active Site Conformational Dynamics in Human Uridine Phosphorylase 1

Uridine phosphorylase (UPP) is a central enzyme in the pyrimidine salvage pathway, catalyzing the reversible phosphorolysis of uridine to uracil and ribose-1-phosphate. Human UPP activity has been a focus of cancer research due to its role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil (5-FU) and capecitabine. Additionally, specific molecular inhibitors of this enzyme have been found to raise endogenous uridine concentrations, which can produce a cytoprotective effect on normal tissues exposed to these drugs. Here we report the structure of hUPP1 bound to 5-FU at 2.3 Å resolution. Analysis of this structure reveals new insights as to the conformational motions the enzyme undergoes in the course of substrate binding and catalysis. The dimeric enzyme is capable of a large hinge motion between its two domains, facilitating ligand exchange and explaining observed cooperativity between the two active sites in binding phosphate-bearing substrates. Further, a loop toward the back end of the uracil binding pocket is shown to flexibly adjust to the varying chemistry of different compounds through an “induced-fit” association mechanism that was not observed in earlier hUPP1 structures. The details surrounding these dynamic aspects of hUPP1 structure and function provide unexplored avenues to develop novel inhibitors of this protein with improved specificity and increased affinity. Given the recent emergence of new roles for uridine as a neuron protective compound in ischemia and degenerative diseases, such as Alzheimer's and Parkinson's, inhibitors of hUPP1 with greater efficacy, which are able to boost cellular uridine levels without adverse side-effects, may have a wide range of therapeutic applications

Residential exposure to motor vehicle emissions and the risk of wheezing among 7-8 year-old schoolchildren: a city-wide cross-sectional study in Nicosia, Cyprus

<p>Abstract</p> <p>Background</p> <p>Several studies have reported associations between respiratory outcomes in children and a range of self-reported, administrative or geographical indicators of traffic pollution. First-time investigation into the frequency of asthmatic symptoms among 7-8 year-old Cypriot children in 1999-2000 showed increased prevalence in the capital Nicosia compared to other areas. Geographical differences on an island the size of Cyprus may reflect environmental and/or lifestyle factors. This study investigates the relationship between self-reported symptoms and residential exposure to motor vehicle emissions among Nicosia schoolchildren.</p> <p>Methods</p> <p>The addresses of children in the metropolitan area of Nicosia who participated in the original survey (N = 1,735) were geo-coded and the level of exposure of each child was assessed using distance- and emission-based indicators (i.e. estimated levels of particulate matter and nitrogen oxides emissions due to motor vehicles on main roads around the residence). Odds ratios of wheezing and asthma diagnosis in relation to levels of exposure were estimated in logistic regression models adjusting for person-based factors, co-morbidity and intra-school clustering.</p> <p>Results</p> <p>We found an increased risk of wheezing at distances less than 50 m from a main road and/or only among those experiencing the highest levels of exposure. The strongest effect estimates were observed when exposure was defined in terms of the cumulative burden at all roads around the residence. Adjusted odds ratios for current wheezing were 2.33 (95% CI 1.27, 4.30) amongst the quartile of participants exposed to the highest levels of PM at all roads 50 m of their residence and 2.14 (95% CI 1.05, 4.35) for NOx, with no effect at intermediate levels of exposure. While the direction of effect was apparent at longer distances, differences were generally not statistically significant.</p> <p>Conclusions</p> <p>Children experiencing the highest burden of emissions in Nicosia seem to be at a higher risk of reporting asthmatic symptoms. Due to the small number of children residing at close proximity to main roads and lack of evidence of risk at intermediate levels of exposure or longer distances, the observed pattern alone does not explain the generally higher prevalence observed in urban Nicosia compared to other areas.</p

Identification of a large, fast-expanding HIV-1 subtype B transmission cluster among MSM in Valencia, Spain

We describe and characterize an exceptionally large HIV-1 subtype B transmission cluster occurring in the Comunidad Valenciana (CV, Spain). A total of 1806 HIV-1 protease-reverse transcriptase (PR/RT) sequences from different patients were obtained in the CV between 2004 and 2014. After subtyping and generating a phylogenetic tree with additional HIV-1 subtype B sequences, a very large transmission cluster which included almost exclusively sequences from the CV was detected (n = 143 patients). This cluster was then validated and characterized with further maximum-likelihood phylogenetic analyses and Bayesian coalescent reconstructions. With these analyses, the CV cluster was delimited to 113 patients, predominately men who have sex with men (MSM). Although it was significantly located in the city of Valencia (n = 105), phylogenetic analyses suggested this cluster derives from a larger HIV lineage affecting other Spanish localities (n = 194). Coalescent analyses estimated its expansion in Valencia to have started between 1998 and 2004. From 2004 to 2009, members of this cluster represented only 1.46% of the HIV-1 subtype B samples studied in Valencia (n = 5/143), whereas from 2010 onwards its prevalence raised to 12.64% (n = 100/791). In conclusion, we have detected a very large transmission cluster in the CV where it has experienced a very fast growth in the recent years in the city of Valencia, thus contributing significantly to the HIV epidemic in this locality. Its transmission efficiency evidences shortcomings in HIV control measures in Spain and particularly in Valencia