A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

A model describing the response of the growth of single human cells in the absence and presence of the anti-cancer agent topotecan (TPT) is presented. The model includes a novel coupling of both the kinetics of TPT and cell cycle responses to the agent. By linking the models in this way, rather than using separate (disjoint) approaches, it is possible to illustrate how the drug perturbs the cell cycle. The model is compared to experimental in vitro cell cycle response data (comprising single cell descriptors for molecular and behavioural events), showing good qualitative agreement for a range of TPT dose levels

Psychiatric Evaluation of the Agitated Patient: Consensus Statement of the American Association for Emergency Psychiatry Project BETA Psychiatric Evaluation Workgroup

It is difficult to fully assess an agitated patient, and the complete psychiatric evaluation usually cannot be completed until the patient is calm enough to participate in a psychiatric interview. Nonetheless, emergency clinicians must perform an initial mental status screening to begin this process as soon as the agitated patient presents to an emergency setting. For this reason, the psychiatric evaluation of the agitated patient can be thought of as a 2-step process. First, a brief evaluation must be aimed at determining the most likely cause of agitation, so as to guide preliminary interventions to calm the patient. Once the patient is calmed, more extensive psychiatric assessment can be completed. The goal of the emergency assessment of the psychiatric patient is not necessarily to obtain a definitive diagnosis. Rather, ascertaining a differential diagnosis, determining safety, and developing an appropriate treatment and disposition plan are the goals of the assessment. This article will summarize what components of the psychiatric assessment can and should be done at the time the agitated patient presents to the emergency setting. The complete psychiatric evaluation of the patient whose agitation has been treated successfully is beyond the scope of this article and Project BETA (Best practices in Evaluation and Treatment of Agitation), but will be outlined briefly to give the reader an understanding of what a full psychiatric assessment would entail. Other issues related to the assessment of the agitated patient in the emergency setting will also be discussed

Retinal glia promote dorsal root ganglion axon regeneration.

Axon regeneration in the adult central nervous system (CNS) is limited by several factors including a lack of neurotrophic support. Recent studies have shown that glia from the adult rat CNS, specifically retinal astrocytes and Müller glia, can promote regeneration of retinal ganglion cell axons. In the present study we investigated whether retinal glia also exert a growth promoting effect outside the visual system. We found that retinal glial conditioned medium significantly enhanced neurite growth and branching of adult rat dorsal root ganglion neurons (DRG) in culture. Furthermore, transplantation of retinal glia significantly enhanced regeneration of DRG axons past the dorsal root entry zone after root crush in adult rats. To identify the factors that mediate the growth promoting effects of retinal glia, mass spectrometric analysis of retinal glial conditioned medium was performed. Apolipoprotein E and secreted protein acidic and rich in cysteine (SPARC) were found to be present in high abundance, a finding further confirmed by western blotting. Inhibition of Apolipoprotein E and SPARC significantly reduced the neuritogenic effects of retinal glial conditioned medium on DRG in culture, suggesting that Apolipoprotein E and SPARC are the major mediators of this regenerative response.This work was supported by a van Geest Fight for Sight Early Career Investigator Award, grant number 1868 [BL].This is the final version of the article. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.011599

Association Between Residential Greenness and Cardiovascular Disease Risk

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on β-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity

Aerosol trace metal leaching and impacts on marine microorganisms

Metal dissolution from atmospheric aerosol deposition to the oceans is important in enhancing and inhibiting phytoplankton growth rates and modifying plankton community structure, thus impacting marine biogeochemistry. Here we review the current state of knowledge on the causes and effects of the leaching of multiple trace metals from natural and anthropogenic aerosols. Aerosol deposition is considered both on short timescales over which phytoplankton respond directly to aerosol metal inputs, as well as longer timescales over which biogeochemical cycles are affected by aerosols

Cost analysis of noninvasive blood-based microRNA testing versus CT scans for follow-up in patients with testicular germ-cell tumors

BACKGROUND: Our group has developed a noninvasive blood-based microRNA (miRNA) test for improving diagnosis, disease monitoring, and relapse detection in malignant testicular germ-cell tumors (TGCTs). Performance analysis suggests the test is likely to have comparable sensitivity and specificity in detecting TGCT as computed tomography (CT), thus reducing the need for serial CT scans for follow-up monitoring, with associated reductions in cumulative radiation burden and second cancer risk. To facilitate clinical adoption, we undertook a cost analysis to identify the budget impact of replacing CT scans with miRNA testing within health care systems. METHODS: The TGCT aftercare pathway was mapped out using National Comprehensive Cancer Network guidelines. A Markov model was built to simulate the impact of the miRNA test on TGCT aftercare costs. Incidence, treatment probabilities, relapse rate, and death rate data were collected from published studies to populate the model. RESULTS: Applying our model to the US health care system, the miRNA test has the potential to save up to $69 million per year in aftercare expenses related to TGCT treatment, with exact savings depending on the adoption rate and test price. CONCLUSION: This analysis demonstrates the potential positive budget impact of adopting miRNA testing in place of CT scans in the clinical management of TGCTs

Synthesis and coordination chemistry of 2-(di-2-pyridylamino)pyrimidine; structural aspects of spin crossover in an Fe(II) complex

This paper was accepted on February 26 20122-(Di-2-pyridylamino)pyrimidine (L), a potentially ditopic tetradentate ligand, was synthesized from commercially available di-2-pyridylamine and 2-chloropyrimidine. Despite being capable of bridging two metal atoms with bidentate chelation of both metal centres, L prefers to chelate or bridge through the more basic pyridyl donors of the di-2-pyridylamine moiety. Mononuclear trans-[Fe(NCS)2(L)2] and [Cu(L)2(H2O)](BF4)2•H2O complexes, and a discrete [Ag2(L)4](PF6)2 metallomacrocycle were isolated and structurally characterized by X-ray crystallography. A mononuclear palladium complex [PdCl2(L)]•(solvate), where solvate = ½H2O or CH2Cl2, was also readily obtained in 71% yield. One example of the ligand acting as a bis(bidentate) bridging ligand was observed in a dinuclear [(PdCl2)2(L)]•¾H2O complex that was obtained only in very low yield (ca. 3%) from the reaction that produced [PdCl2(L)]•½H2O. trans-[Fe(NCS)2(L)2] undergoes a temperature dependent HS-LS (HS = high spin; LS = low spin) crossover at ca. 205 K that was 2 observed by X-ray crystallography and magnetic measurements and attempts were made to understand the structural basis of this process. Despite efforts to isolate examples of L bridging two iron(II) centres, only the mononuclear trans-[Fe(NCS)2(L)2] species could be obtained.Rachel S. Crees, Boujemma Moubaraki, Keith S. Murray, and Christopher J. Sumb

Skilled deaf readers have an enhanced perceptual span in reading

Recent evidence suggests that, compared with hearing people, deaf people have enhanced visual attention to simple stimuli viewed in the parafovea and periphery. Although a large part of reading involves processing the fixated words in foveal vision, readers also utilize information in parafoveal vision to preprocess upcoming words and decide where to look next. In the study reported here, we investigated whether auditory deprivation affects low-level visual processing during reading by comparing the perceptual span of deaf signers who were skilled and less-skilled readers with the perceptual span of skilled hearing readers. Compared with hearing readers, the two groups of deaf readers had a larger perceptual span than would be expected given their reading ability. These results provide the first evidence that deaf readers' enhanced attentional allocation to the parafovea is used during complex cognitive tasks, such as reading

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

Maintained physical activity and physiotherapy in the management of distal arm pain: A randomised controlled trial

Objectives: The epidemiology of distal arm pain and back pain are similar. However, management differs considerably: for back pain, rest is discouraged, whereas patients with distal arm pain are commonly advised to rest and referred to physiotherapy. We hypothesised that remaining active would reduce long-term disability and that fast-track physiotherapy would be superior to physiotherapy after time on a waiting list.Methods: Adults referred to community-based physiotherapy with distal arm pain were randomised to: advice to remain active while awaiting physiotherapy (typically delivered after 6-8 weeks); advice to rest while awaiting physiotherapy, or immediate treatment. Intention-to-treat analysis determined whether the probability of recovery at 26 weeks was greater among the active advice group, compared with those advised to rest and/or among those receiving immediate versus usually timed physiotherapy.Results: 538 of 1663 patients invited between February 2012 and February 2014 were randomised (active=178; rest=182; immediate physiotherapy=178). 81% provided primary outcome data, and complete recovery was reported by 60 (44%), 46 (32%) and 53 (35%). Those advised to rest experienced a lower probability of recovery (OR: 0.54; 95% CI 0.32 to 0.90) versus advice to remain active. However, there was no benefit of immediate physiotherapy (0.64; 95% CI 0.39 to 1.07).Conclusions: Among patients awaiting physiotherapy for distal arm pain, advice to remain active results in better 26-week functional outcome, compared with advice to rest. Also, immediate physiotherapy confers no additional benefit in terms of disability, compared with physiotherapy delivered after 6-8 weeks waiting time. These findings question current guidance for the management of distal arm pain