Abstract Background Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing ...outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). Method Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. Results HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS ( p < 0.0001) and OS ( p = 0.002). Conclusion In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.
•Vascular endothelial growth factor and angiopoietin-1 are pro-angiogenic factors.•Bisphosphonates (BPs) suppress the osteoblastic production of the 2 angiogenic factors.•Calcitriol mitigates the ...BP-induced inhibition of these angiogenic factors.•BPs have anti-angiogenic properties.
Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽−2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10−12–10−6M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34–39% (p<0.01) following treatment with zoledronate (10−9–10−6M). Treatment of the MG-63 cells with alendronate (10−7 and 10−6) led to a smaller decrease (25–28%) in VEGF (p<0.05). Zoledronate (10−10–10−6M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43–49% (p<0.01). Co-treatment with calcitriol (10−8M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects.
There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not ...known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both.
We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size.
Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after d(B). d(B) increased across blocks of trials, while d(A) was manipulated across phases of the experiment. Indifference delay d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d(B(50)) vs d(A)) derived.
d(B(50)) increased linearly with d(A) (r(2) > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC.
The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.
Alginate rafts and their characterisation Hampson, F.C.; Farndale, A.; Strugala, V. ...
International journal of pharmaceutics,
04/2005, Letnik:
294, Številka:
1
Journal Article
Recenzirano
Alginate/antacid anti-reflux preparations are designed to provide symptom relief by forming a physical barrier on top of the stomach contents in the form of a neutral floating gel or raft. This study ...tested the in vitro effectiveness of a range of liquid products in forming rafts that were cohesive, buoyant, voluminous, resistant to reflux and durable under conditions of movement (resilient). The products tested had a wide range of acid neutralising capacities (ANCs). It was found that products with a high ANC and no calcium ion source formed rafts of low strength, weight and volume, which appeared more as floating precipitates than coherent gels. Products with a high ANC and a calcium ion source formed medium strength, weight and volume rafts. Products with a low ANC formed strong coherent rafts with medium to large weight and volume, and those with low ANC and a calcium ion source formed the strongest rafts. Products with stronger rafts were found to be more resilient and more resistant to reflux in an in vitro reflux model. Significant overall differences in raft buoyancy were found between products forming coherent rafts but these could not be related to the product formulation or amount of available carbon dioxide.
The dynamic genome of Hydra Rokhsar, Daniel S; Steele, Robert E; Chapman, Jarrod A ...
Nature,
03/2010, Letnik:
464, Številka:
7288
Journal Article
Recenzirano
Odprti dostop
The freshwater cnidarian Hydra was first described in 1702 and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual ...reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals. Today, Hydra is an important model for studies of axial patterning, stem cell biology and regeneration. Here we report the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensis and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann-Mangold organizer, pluripotency genes and the neuromuscular junction.
•Isolates of Brachyspira hyodysenteriae recovered from 2003 to 2012 in Italy were analysed.•Susceptibility to pleuromutilins (tiamulin and valnemulin) was significantly associated with genetic ...group.•Susceptibility to pleuromutilins (tiamulin and valnemulin) was significantly associated with year of isolation.•Isolates in clonal clusters 2 and 7 were more than five times more likely to be sensitive than those in the other clonal clusters.
Swine dysentery is a mucohaemorrhagic colitis of pigs caused by infection with Brachyspira hyodysenteriae. The disease can be controlled by treatment with antimicrobial agents, with the pleuromutilins tiamulin and valnemulin being widely used. In recent years, the occurrence of B. hyodysenteriae with reduced susceptibility to these drugs has been increasing. The aim of this study was to determine temporal changes in genetic groups and pleuromutilin susceptibility amongst B. hyodysenteriae isolates from Italy. Multilocus sequence typing (MLST) was performed on 108 isolates recovered from 87 farms in different regions of Italy from 2003 to 2012, and their minimum inhibitory concentrations (MICs) for tiamulin and valnemulin were determined. Logistic regression was performed to assess associations between susceptibility to the two antimicrobial agents and genetic group, year and region of isolation. The isolates were allocated to 23 sequence types (STs), with five clonal clusters (Ccs) and seven singletons. More than 50% of isolates were resistant to both pleuromutilins (MIC >2.0 µg/mL for tiamulin and >1.0 µg/mL for valnemulin). All 10 isolates in ST 83 were resistant; these were first isolated in 2011 and came from nine farms, suggesting recent widespread dissemination of a resistant strain. Significant associations were found between the proportion of pleuromutilin susceptible isolates and the genetic group and year of isolation. Although resistant isolates were found in all Ccs, isolates in Ccs 2 and 7 were over five times more likely to be susceptible than those in the other Ccs. A significant trend in the reduction of susceptibility over time also was observed.
The need to predict accurately the volume, timing and location of sediments that are transported from an erosional source region into a basin-depocentre sink is important for many aspects of pure and ...applied sedimentological research. In this study, the results of three widely used methods to estimate sediment flux in ancient sediment routing systems are compared, using rich input datasets from two systems (Eocene South Pyrenean Foreland Basin, Spain and late-Pleistocene-to-Holocene Gulf of Corinth Rift Basin, Greece) for which mapped, dated sediment volumes provide an independent reference value of sediment accumulation rates. The three methods are: (1) the empirical BQART model, which uses values of drainage basin area, relief, temperature, lithology and water discharge; (2) empirical scaling relationships between characteristic geomorphological parameters of sediment-routing-system segments; and (3) the “fulcrum” model, which uses the palaeohydrological parameters of trunk river channels to estimate downsystem sediment discharge. The BQART model and empirical geomorphological scaling relationships were originally developed using modern sediment routing systems, and have subsequently been applied to ancient systems. In contrast, the “fulcrum” model uses hydrological scaling relationships from modern systems, but was developed principally for application in ancient systems.
Our comparative analysis quantifies the sensitivity of the three methods to their input parameters, and identifies the data required to make plausible estimates of sediment flux for ancient sediment routing systems. All three methods can generate estimates of sediment flux that are comparable with each other, and are accurate to at least one order of magnitude relative to independent reference values. The BQART model uses palaeoclimatic and palaeocatchment input data, which are accurate for sub-modern systems but may be highly uncertain in deep-time systems. Corresponding estimates of sediment flux are most sensitive to the accuracy with which the palaeocatchment area is constrained and to palaeoclimatic parameters that reflect temperature and precipitation. The “fulcrum” model uses palaeohydrological input data; its sediment-flux estimates are sensitive to palaeochannel dimensions and, in particular, the duration of bankfull discharge, which is invariably difficult to constrain accurately in deep-time sediment routing systems. This uncertainty can give rise to large potential ranges of sediment-flux estimates. Geomorphological scaling relationships offer comparable, order-of-magnitude accuracy for both sub-modern and deep-time sediment routing systems in which geomorphological segments can be identified, but when used on relatively small sediment routing systems the ranges of sediment volumes deposited can vary greatly, limiting the utility of the technique.
We suggest that methods to estimate sediment flux should be chosen for a particular sediment routing system based on the types and uncertainty of available data. Where input parameter values are highly uncertain, such as in deep-time systems, Monte Carlo simulation is an effective tool to calculate probability distributions of estimated sediment flux.
Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. ...Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species provide a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. We analyzed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonosis which in nature exhibits both dead-end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer- to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which are also expected to impede onward transmission. All effects were modulated by infection dose. Taken together, these results suggest that as host species become more dissimilar, increased virulence might act as a limiting factor preventing onward transmission. These results can explain observed constraints on rabies virus host shifts, describe a previously unrecognized role of host body temperature, and provide a potential explanation for host shifts being less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.
Microbial monitoring in marine recreational waterways often overlooks environmental variables associated with pathogen occurrence. This study employs a predictive boosted regression trees (BRT) model ...to predict Staphylococcus aureus abundance in the Tampa Bay estuary and identify related environmental variables associated with the microbial pathogen’s occurrence. We provide evidence that the BRT model’s adaptability and ability to capture complex interactions among predictors make it invaluable for research on microbial indicator research. Over 18 months, water samples from 7 recreational sites underwent microbial quantitation and S. aureus isolation, followed by genetic validation. BRT analysis of S. aureus occurrence and environmental variables revealed month, precipitation, salinity, site, temperature, and year as relevant predictors. In addition, the BRT model accurately predicted S. aureus occurrence, setting a precedent for pathogen–environment research. The approach described here is novel and informs proactive management strategies and community health initiatives in marine recreational waterways.
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