Metastases: the glycan connection

An association between protein glycosylation and tumorigenesis has been recognized for over 10 years. Associations linking the importance of glycosylation events to tumor biology, especially the progression to metastatic disease, have been noted over many years, Recently, a mouse model in which β1,6-N-acetylglucosaminyltransferase V (a rate-limiting enzyme in the N-glycan pathway) has been knocked out, was used to demonstrate the importance of glycosylation in tumor progression. By crossing mice lacking this enzyme with a transgenic mouse model of metastatic breast cancer, metastatic progression of the disease was dramatically reduced. These experiments provide in vivo evidence for the role of N-linked glycosylation in metastatic breast cancer and have significant implications for the development of new treatment strategies

Stochastic population growth in spatially heterogeneous environments

Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in $n$ patches: the conditional law of $X_{t+dt}$ given $X_t=x$ is such that when $dt$ is small the conditional mean of $X_{t+dt}^i-X_t^i$ is approximately $[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt$, where $X_t^i$ and $\mu_i$ are the abundance and per capita growth rate in the $i$-th patch respectivly, and $D_{ij}$ is the dispersal rate from the $i$-th to the $j$-th patch, and the conditional covariance of $X_{t+dt}^i-X_t^i$ and $X_{t+dt}^j-X_t^j$ is approximately $x^i x^j \sigma_{ij}dt$. We show for such a spatially extended population that if $S_t=(X_t^1+...+X_t^n)$ is the total population abundance, then $Y_t=X_t/S_t$, the vector of patch proportions, converges in law to a random vector $Y_\infty$ as $t\to\infty$, and the stochastic growth rate $\lim_{t\to\infty}t^{-1}\log S_t$ equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of $Y_\infty$, find which choice of the dispersal mechanism $D$ produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure

A generic method for estimating and smoothing multispecies biodiversity indices using intermittent data

Biodiversity indicators summarise extensive, complex ecological data sets and are important in influencing government policy. Component data consist of time-varying indices for each of a number of different species. However, current biodiversity indicators suffer from multiple statistical shortcomings. We describe a state-space formulation for new multispecies biodiversity indicators, based on rates of change in the abundance or occupancy probability of the contributing individual species. The formulation is flexible and applicable to different taxa. It possesses several advantages, including the ability to accommodate the sporadic unavailability of data, incorporate variation in the estimation precision of the individual species’ indices when appropriate, and allow the direct incorporation of smoothing over time. Furthermore, model fitting is straightforward in Bayesian and classical implementations, the latter adopting either efficient Hidden Markov modelling or the Kalman filter. Conveniently, the same algorithms can be adopted for cases based on abundance or occupancy data—only the subsequent interpretation differs. The procedure removes the need for bootstrapping which can be prohibitive. We recommend which of two alternatives to use when taxa are fully or partially sampled. The performance of the new approach is demonstrated on simulated data, and through application to three diverse national UK data sets on butterflies, bats and dragonflies. We see that uncritical incorporation of index standard errors should be avoided

The influence on survival of delay in the presentation and treatment of symptomatic breast cancer

The aim of this study was to examine the possible influence on survival of delays prior to presentation and/or treatment among women with breast cancer. Duration of symptoms prior to hospital referral was recorded for 2964 women who presented with any stage of breast cancer to Guy's Hospital between 1975 and 1990. Median follow-up is 12.5 years. The impact of delay (defined as having symptoms for 12 or more weeks) on survival was measured from the date of diagnosis and from the date when the patient first noticed symptoms to control for lead-time bias. Thirty-two per cent (942/2964) of patients had symptoms for 12 or more weeks before their first hospital visit and 32% (302/942) of patients with delays of 12 or more weeks had locally advanced or metastatic disease, compared with only 10% (210/2022) of those with delays of less than 12 weeks (P< 0.0001). Survival measured both from the date of diagnosis (P< 0.001) and from the onset of the patient's symptoms (P= 0.003) was worse among women with longer delays. Ten years after the onset of symptoms, survival was 52% for women with delays less than 12 weeks and 47% for those with longer delays. At 20 years the survival rates were 34% and 24% respectively. Furthermore, patients with delays of 12–26 weeks had significantly worse survival rates than those with delays of less than 12 weeks. Multivariate analyses indicated that the adverse impact of delay in presentation on survival was attributable to an association between longer delays and more advanced stage. However, within individual stages, longer delay had no adverse impact on survival. Analyses based on ‘total delay’ (i.e. the interval between a patient first noticing symptoms and starting treatment) yielded very similar results in terms of survival to those based on delay to first hospital visit (delay in presentation). © 1999 Cancer Research Campaig

Building social capital through breastfeeding peer support: Insights from an evaluation of a voluntary breastfeeding peer support service in North-West England

Background: Peer support is reported to be a key method to help build social capital in communities. To date there are no studies that describe how this can be achieved through a breastfeeding peer support service. In this paper we present findings from an evaluation of a voluntary model of breastfeeding peer support in North-West England to describe how the service was operationalized and embedded into the community. This study was undertaken from May, 2012 to May, 2013. Methods: Interviews (group or individual) were held with 87 participants: 24 breastfeeding women, 13 peer supporters and 50 health and community professionals. The data contained within 23 monthly monitoring reports (January, 2011 to February 2013) compiled by the voluntary peer support service were also extracted and analysed. Results: Thematic analysis was undertaken using social capital concepts as a theoretical lens. Key findings were identified to resonate with ’bonding’, ‘bridging’ and ‘linking’ forms of social capital. These insights illuminate how the peer support service facilitates ‘bonds’ with its members, and within and between women who access the service; how the service ‘bridges’ with individuals from different interests and backgrounds, and how ‘links’ were forged with those in authority to gain access and reach to women and to promote a breastfeeding culture. Some of the tensions highlighted within the social capital literature were also identified. Conclusions: Horizontal and vertical relationships forged between the peer support service and community members enabled peer support to be embedded into care pathways, helped to promote positive attitudes to breastfeeding and to disseminate knowledge and maximise reach for breastfeeding support across the community. Further effort to engage with those of different ethnic backgrounds and to resolve tensions between peer supporters and health professionals is warranted

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al

Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility : a randomized trial

Q1Q18-18BACKGROUND: Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients. OBJECTIVE: To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients. DESIGN: Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753) SETTING: 370 sites in 20 countries across North and South America, Europe, and Asia. PATIENTS: Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates. INTERVENTION: Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 +/- 4 days after receiving open-label enoxaparin for an initial 10 +/- 4 days. MEASUREMENTS: Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose. RESULTS: Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility. LIMITATION: Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial. CONCLUSION: Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women. PRIMARY FUNDING SOURCE: Sanofi-aventis

\u3ci\u3eSenecio Conrathii\u3c/i\u3e N.E.Br. (Asteraceae), a New Hyperaccumulator of Nickel from Serpentinite Outcrops of the Barberton Greenstone Belt, South Africa

Five nickel hyperaccumulators belonging to the Asteraceae are known from ultramafic outcrops in South Africa. Phytoremediation applications of the known hyperaccumulators in the Asteraceae, such as the indigenous Berkheya coddii Roessler, are well reported and necessitate further exploration to find additional species with such traits. This study targeted the most frequently occurring species of the Asteraceae on eight randomly selected serpentinite outcrops of the Barberton Greenstone Belt. Twenty species were sampled, including 12 that were tested for nickel accumulation for the first time. Although the majority of the species were excluders, the known hyperaccumulators Berkheya nivea N.E.Br. and B. zeyheri (Sond. & Harv.) Oliv. & Hiern subsp. rehmannii (Thell.) Roessler var. rogersiana (Thell.) Roessler hyperaccumulated nickel in the leaves at expected levels. A new hyperaccumulator of nickel was discovered, Senecio conrathii N.E.Br., which accumulated the element in its leaves at 1695 ± 637 µg g−1 on soil with a total and exchangeable nickel content of 503 mg kg−1 and 0.095 µg g−1, respectively. This makes it the third known species in the Senecioneae of South Africa to hyperaccumulate nickel after Senecio anomalochrous Hilliard and Senecio coronatus (Thunb.) Harv., albeit it being a weak accumulator compared with the latter. Seven tribes in the Asteraceae have now been screened for hyperaccumulation in South Africa, with hyperaccumulators only recorded for the Arctoteae and Senecioneae. This suggests that further exploration for hyperaccumulators should focus on these tribes as they comprise all six species (of 68 Asteraceae taxa screened thus far) to hyperaccumulate nickel

Investigation of first ray mobility during gait by kinematic fluoroscopic imaging-a novel method

<p>Abstract</p> <p>Background</p> <p>It is often suggested that sagittal instability at the first tarso-metatarsal joint level is a primary factor for hallux valgus and that sagittal instability increases with the progression of the deformity. The assessment of the degree of vertical instability is usually made by clinical evaluation while any measurements mostly refer to a static assessment of medial ray mobility (i.e. the plantar/dorsal flexion in the sagittal plane). Testing methods currently available cannot attribute the degree of mobility to the corresponding anatomical joints making up the medial column of the foot. The aim of this study was to develop a technique which allows for a quantification of the in-vivo sagittal mobility of the joints of the medial foot column during the roll-over process under full weight bearing.</p> <p>Methods</p> <p>Mobility of first ray bones was investigated by dynamic distortion-free fluoroscopy (25 frames/s) of 14 healthy volunteers and 8 patients with manifested clinical instability of the first ray. A CAD-based evaluation method allowed the determination of mobility and relative displacements and rotations of the first ray bones within the sagittal plane during the stance phase of gait.</p> <p>Results</p> <p>Total flexion of the first ray was found to be 13.63 (SD 6.14) mm with the healthy volunteers and 13.06 (SD 8.01) mm with the patients (resolution: 0.245 mm/pixel). The dorsiflexion angle was 5.27 (SD 2.34) degrees in the healthy volunteers and increased to 5.56 (SD 3.37) degrees in the patients. Maximum rotations were found at the naviculo-cuneiform joints and least at the first tarso-metatarsal joint level in both groups.</p> <p>Conclusions</p> <p>Dynamic fluoroscopic assessment has been shown to be a valuable tool for characterisation of the kinematics of the joints of the medial foot column during gait.</p> <p>A significant difference in first ray flexion and angular rotation between the patients and healthy volunteers however could not be found.</p