207 research outputs found

    Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response

    Get PDF
    Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation

    Pharmacists in Pharmacovigilance: Can Increased Diagnostic Opportunity in Community Settings Translate to Better Vigilance?

    Get PDF
    The pharmacy profession has undergone substantial change over the last two to three decades. Whilst medicine supply still remains a central function, pharmacist’s roles and responsibilities have become more clinic and patient focused. In the community (primary care), pharmacists have become important providers of healthcare as Western healthcare policy advocates patient self-care. This has resulted in pharmacists taking on greater responsibility in managing minor illness and the delivery of public health interventions. These roles require pharmacists to more fully use their clinical skills, and often involve diagnosis and therapeutic management. Community pharmacists are now, more than ever before, in a position to identify, record and report medication safety incidents. However, current research suggests that diagnostic ability of community pharmacists is questionable and they infrequently report to local or national schemes. The aim of this paper is to highlight current practice and suggest ways in which community pharmacy can more fully contribute to patient safety

    Changes in multi-segment foot biomechanics with a heat-mouldable semi-custom foot orthotic device

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Semi-custom foot orthoses (SCO) are thought to be a cost-effective alternative to custom-made devices. However, previous biomechanical research involving either custom or SCO has only focused on rearfoot biomechanics. The purpose of this study was therefore to determine changes in multi-segment foot biomechanics during shod walking with and without an SCO. We chose to investigate an SCO device that incorporates a heat-moulding process, to further understand if the moulding process would significantly alter rearfoot, midfoot, or shank kinematics as compared to a no-orthotic condition. We hypothesized the SCO, whether moulded or non-moulded, would reduce peak rearfoot eversion, tibial internal rotation, arch deformation, and plantar fascia strain as compared to the no-orthoses condition.</p> <p>Methods</p> <p>Twenty participants had retroreflective markers placed on the right limb to represent forefoot, midfoot, rearfoot and shank segments. 3D kinematics were recorded using an 8-camera motion capture system while participants walked on a treadmill.</p> <p>Results</p> <p>Plantar fascia strain was reduced by 34% when participants walked in either the moulded or non-moulded SCO condition compared to no-orthoses. However, there were no significant differences in peak rearfoot eversion, tibial internal rotation, or medial longitudinal arch angles between any conditions.</p> <p>Conclusions</p> <p>A semi-custom moulded orthotic does not control rearfoot, shank, or arch deformation but does, however, reduce plantar fascia strain compared to walking without an orthoses. Heat-moulding the orthotic device does not have a measurable effect on any biomechanical variables compared to the non-moulded condition. These data may, in part, help explain the clinical efficacy of orthotic devices.</p

    Multiphysics simulation of a microfluidic perfusion chamber for brain slice physiology

    Get PDF
    Understanding and optimizing fluid flows through in vitro microfluidic perfusion systems is essential in mimicking in vivo conditions for biological research. In a previous study a microfluidic brain slice device (μBSD) was developed for microscale electrophysiology investigations. The device consisted of a standard perfusion chamber bonded to a polydimethylsiloxane (PDMS) microchannel substrate. Our objective in this study is to characterize the flows through the μBSD by using multiphysics simulations of injections into a pourous matrix to identify optimal spacing of ports. Three-dimensional computational fluid dynamic (CFD) simulations are performed with CFD-ACE + software to model, simulate, and assess the transport of soluble factors through the perfusion bath, the microchannels, and a material that mimics the porosity, permeability and tortuosity of brain tissue. Additionally, experimental soluble factor transport through a brain slice is predicted by and compared to simulated fluid flow in a volume that represents a porous matrix material. The computational results are validated with fluorescent dye experiments

    Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

    Get PDF
    Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

    Effect of Baseline HIV Disease Parameters on CD4+ T Cell Recovery After Antiretroviral Therapy Initiation in Kenyan Women

    Get PDF
    Antiretroviral therapy (ART) for HIV infection reconstitutes the immune system and improves survival. However, the rate and extent of CD4+ T cell recovery varies widely. We assessed the impact of several factors on immune reconstitution in a large Kenyan cohort.HIV-infected female sex workers from a longitudinal cohort, with at least 1 year of pre-ART and 6 months of post-ART follow-up (n = 79), were enrolled in the current study. The median pre-ART follow-up was 4,040 days. CD4 counts were measured biannually and viral loads where available. The median CD4 count at ART initiation was 180 cells/ul, which increased to 339 cells/ul at the most recent study visit. The rate of CD4+ T cell increase on ART was 7.91 cells/month (mean = 13, range -25.92 to 169.4). LTNP status prior to ART initiation did not associate with the rate of CD4 recovery on ART. In univariate analyses, associations were observed for CD4 recovery rate and duration of pre-ART immunosuppression (r = -0.326, p = 0.004) and CD4 nadir (r = 0.284, p = 0.012). In multivariate analysis including age, CD4 nadir, duration of HIV infection, duration of pre-ART immunosuppression, and baseline viral load, only CD4 nadir (p = 0.007) and not duration of immunosuppression (p = 0.87) remained significantly associated with the rate of CD4 recovery.These data suggest that prior duration of immune suppression does not predict subsequent recovery once ART is initiated and confirm the previous observation that the degree of CD4 depletion prior to ART initiation is the most important determinant of subsequent immune reconstitution

    Management of osteoporosis in central and eastern Europe (CEE): conclusions of the “2nd Summit on Osteoporosis—CEE”, 21–22 November 2008, Warsaw, Poland

    Get PDF
    In November 2008, the “2nd Summit on Osteoporosis—Central and Eastern Europe (CEE)” was held in Warsaw, Poland. Discussions at this meeting focused on the identification and discussion of diagnostic, preventive, and therapeutic measures used in CEE. Evaluated information was used to identify issues regarding diagnosis and therapy of osteoporosis in these countries to facilitate the subsequent setup of appropriate support and development strategies. The main debate was structured according to the following five subjects: (1) present status and future perspectives for implementation of FRAX® into local (CEE) diagnostic algorithms, (2) principles of drug selection in osteoporosis treatment in CEE countries, (3) nonpharmacological interventions in osteoporosis treatment and prophylaxis in CEE countries, (4) treatment benefit evaluation, and (5) cost–effectiveness and evaluation of reimbursement policies in CEE countries. The most important and substantial comments of the delegates are summarized in the present article. The multinational panel of experts with representatives from many CEE countries as well as Austria and Switzerland made the “2nd Summit on Osteoporosis—CEE” a perfect platform to identify issues and needs regarding diagnosis and therapy of osteoporosis as well as the cost–effectiveness of osteoporosis management in CEE countries. The information gained will serve as a basis for the development of strategies to resolve the identified issues at the “3rd Summit on Osteoporosis—CEE” in November 2009
    corecore