Capillary pressure may predict preclinical changes in the eye

This is the final version. Available on open access from Springer Verlag via the DOI in this recordAIMS/HYPOTHESIS: Microvascular dysfunction is associated with end-organ damage. Macular oedema is an important component of diabetic retinopathy. Macular thickness can be accurately quantified by optical coherence tomography (OCT), enabling accurate assessment of the macular prior to clinically apparent abnormalities. We investigated whether macular (fovea) thickness in non-diabetic individuals is related to the microvascular variables controlling fluid filtration across a blood vessel wall, in particular capillary pressure and the microvascular filtration capacity (Kf). METHODS: We recruited 50 non-diabetic individuals (25 men, 25 women; age range: 26-78 years; BMI range: 20-46 kg/m(2)). Fovea thickness was assessed by OCT. Microvascular assessments included: finger nailfold capillary pressure; Kf; microvascular structural assessments, i.e. skin vasodilatory capacity, minimum vascular resistance (MVR) and microvascular distensibility; and endothelial function. RESULTS: At 214.6 (19.9) microm (mean [SD]), fovea thickness was within normal range. Capillary pressure, adjusted for BMI, was associated with fovea thickness (standardised beta 0.573, p = 0.006, linear regression). Fovea thickness was not associated with Kf, microvascular structural assessments or endothelial function. Capillary pressure was still associated with fovea thickness when adjusted for microvascular variables (Kf, vasodilatory capacity, MVR, microvascular distensibility or endothelial function), or for risk factors for diabetes (systemic blood pressure, insulin sensitivity, inflammation, glycaemic status and lipids) and age. CONCLUSIONS/INTERPRETATION: Capillary pressure, a key determinant of movement of fluid across a blood vessel wall, is associated with fovea thickness in non-diabetic individuals. This suggests that with regard to potential preventative or therapeutic targets, attention should be directed at the mechanisms determining retinal microvascular pressure.Diabetes UKNational Institute for Health Research (NIHR

Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

A 1.5-million-year record of orbital and millennial climate variability in the North Atlantic

Climate during the last glacial period was marked by abrupt instability on millennial timescales that included large swings of temperature in and around Greenland (Daansgard-Oeschger events) and smaller, more gradual changes in Antarctica (AIM events). Less is known about the existence and nature of similar variability during older glacial periods, especially during the early Pleistocene when glacial cycles were dominantly occurring at 41 kyr intervals compared to the much longer and deeper glaciations of the more recent period. Here, we report a continuous millennially resolved record of stable isotopes of planktic and benthic foraminifera at IODP Site U1385 (the "Shackleton Site") from the southwestern Iberian margin for the last 1.5 million years, which includes the Middle Pleistocene Transition (MPT). Our results demonstrate that millennial climate variability (MCV) was a persistent feature of glacial climate, both before and after the MPT. Prior to 1.2 Ma in the early Pleistocene, the amplitude of MCV was modulated by the 41 kyr obliquity cycle and increased when axial tilt dropped below 23.5° and benthic δ18O exceeded ∼3.8 ‰ (corrected to Uvigerina), indicating a threshold response to orbital forcing. Afterwards, MCV became focused mainly on the transitions into and out of glacial states (i.e. inceptions and terminations) and during times of intermediate ice volume. After 1.2 Ma, obliquity continued to play a role in modulating the amplitude of MCV, especially during times of glacial inceptions, which are always associated with declining obliquity. A non-linear role for obliquity is also indicated by the appearance of multiples (82, 123 kyr) and combination tones (28 kyr) of the 41 kyr cycle. Near the end of the MPT (∼0.65 Ma), obliquity modulation of MCV amplitude wanes as quasi-periodic 100 kyr and precession power increase, coinciding with the growth of oversized ice sheets on North America and the appearance of Heinrich layers in North Atlantic sediments. Whereas the planktic δ18O of Site U1385 shows a strong resemblance to Greenland temperature and atmospheric methane (i.e. Northern Hemisphere climate), millennial changes in benthic δ18O closely follow the temperature history of Antarctica for the past 800 kyr. The phasing of millennial planktic and benthic δ18O variation is similar to that observed for MIS 3 throughout much of the record, which has been suggested to mimic the signature of the bipolar seesaw - i.e. an interhemispheric asymmetry between the timing of cooling in Antarctica and warming in Greenland. The Iberian margin isotopic record suggests that bipolar asymmetry was a robust feature of interhemispheric glacial climate variations for at least the past 1.5 Ma despite changing glacial boundary conditions. A strong correlation exists between millennial increases in planktic δ18O (cooling) and decreases in benthic δ13C, indicating that millennial variations in North Atlantic surface temperature are mirrored by changes in deep-water circulation and remineralization of carbon in the abyssal ocean. We find strong evidence that climate variability on millennial and orbital scales is coupled across different timescales and interacts in both directions, which may be important for linking internal climate dynamics and external astronomical forcing. Copyright

Branding the nation: Towards a better understanding

This paper aims to clarify some misunderstanding about nation branding. It examines the origins and interpretations of the concept, and draws a comparison between nation branding and commercial branding. A new definition is offered that emphasises the need to shift from “branding” the nation to nation image management

Managing change in the nursing handover from traditional to bedside handover – a case study from Mauritius

BACKGROUND: The shift handover forms an important part of the communication process that takes place twice within the nurses' working day in the gynaecological ward. This paper addresses the topic of implementing a new system of bedside handover, which puts patients central to the whole process of managing care and also addresses some of the shortcomings of the traditional handover system. METHODS: A force field analysis in terms of the driving forces had shown that there was dissatisfaction with the traditional method of handover which had led to an increase in the number of critical incidents and complaints from patients, relatives and doctors. The restraining forces identified were a fear of accountability, lack of confidence and that this change would lead to more work. A 3 – step planned change model consisting of unfreezing, moving and refreezing was used to guide us through the change process. Resistance to change was managed by creating a climate of open communication where stakeholders were allowed to voice opinions, share concerns, insights, and ideas thereby actively participating in decision making. RESULTS: An evaluation had shown that this process was successfully implemented to the satisfaction of patients, and staff in general. CONCLUSION: This successful change should encourage other nurses to become more proactive in identifying areas for change management in order to improve our health care system

Elliptic Curves over Real Quadratic Fields are Modular

We prove that all elliptic curves defined over real quadratic fields are modular.Comment: 38 pages. Magma scripts available as ancillary files with this arXiv versio

Genome-Wide Analysis of a TaLEA-Introduced Transgenic Populus simonii × Populus nigra Dwarf Mutant

A dwarf mutant (dwf1) was obtained among 15 transgenic lines, when TaLEA (Tamarix androssowii late embryogenesis abundant gene) was introduced into Populus simonii × Populus nigra by Agrobacterium tumefaciens-mediated transformation. Under the same growth conditions, dwf1 height was significantly reduced compared with the wild type and the other transgenic lines. Because only one transgenic line (dwf1) displayed the dwarf phenotype, we considered that T-DNA insertion sites may play a role in the mutant formation. The mechanisms underlying this effect were investigated using TAIL-PCR (thermal asymmetric interlaced PCR) and microarrays methods. According to the TAIL-PCR results, two flanking sequences located on chromosome IV and VIII respectively, were cloned. The results indicated the integration of two independent T-DNA copies. We searched for the potential genes near to the T-DNA insertions. The nearest gene was a putative poplar AP2 transcription factor (GI: 224073210). Expression analysis showed that AP2 was up-regulated in dwf1 compared with the wild type and the other transgenic lines. According to the microarrays results, a total of 537 genes involved in hydrolase, kinase and transcription factor activities, as well as protein and nucleotide binding, showed significant alterations in gene expression. These genes were expressed in more than 60 metabolic pathways, including starch, sucrose, galactose and glycerolipid metabolism and phenylpropanoids and flavonoid biosyntheses. Our transcriptome and T-DNA insertion sites analyses might provide some useful insights into the dwarf mutant formation

Localized Populations of CD8low/− MHC Class I Tetramer+ SIV-Specific T Cells in Lymphoid Follicles and Genital Epithelium

CD8 T cells play an important role in controlling viral infections. We investigated the in situ localization of simian immunodeficiency virus (SIV)-specific T cells in lymph and genital tissues from SIV-infected macaques using MHC-class I tetramers. The majority of tetramer-binding cells localized in T cell zones and were CD8+. Curiously, small subpopulations of tetramer-binding cells that had little to no surface CD8 were detected in situ both early and late post-infection, and in both vaginally and rectally inoculated macaques. These tetramer+CD8low/− cells were more often localized in apparent B cell follicles relative to T cell zones and more often found near or within the genital epithelium than the submucosa. Cells analyzed by flow cytometry showed similar populations of cells. Further immunohistological characterization revealed small populations of tetramer+CD20− cells inside B cell follicles and that tetramer+ cells did not stain with γδ-TCR nor CD4 antibodies. Negative control tetramer staining indicated that tetramer+CD8low/− cells were not likely NK cells non-specifically binding to MHC tetramers. These findings have important implications for SIV-specific and other antigen-specific T cell function in these specific tissue locations, and suggest a model in which antigen-specific CD8+ T cells down modulate CD8 upon entering B cell follicles or the epithelial layer of tissues, or alternatively a model in which only antigen-specific CD8 T cells that down-modulate CD8 can enter B cell follicles or the epithelium

Turnover rate of cerebrospinal fluid in female sheep: changes related to different light-dark cycles

<p>Abstract</p> <p>Background</p> <p>Sheep are seasonal breeders. The key factor governing seasonal changes in the reproductive activity of the ewe is increased negative feedback of estradiol at the level of the hypothalamus under long-day conditions. It has previously been demonstrated that when gonadotropin secretions are inhibited during long days, there is a higher concentration of estradiol in the cerebrospinal fluid (CSF) than during short days. This suggests an involvement of the CSF and choroid plexus in the neuroendocrine regulatory loop, but the mechanisms underlying this phenomenon remain unknown. One possible explanation of this difference in hormonal content is an effect of concentration or dilution caused by variations in CSF secretion rate. The aim of this study was thus to investigate changes in the CSF turnover rate related to light-dark cycles.</p> <p>Methods</p> <p>The turnover rate of the CSF was estimated by measuring the time taken for the recovery of intraventricular pressure (IVP) after removal of a moderate volume (0.5 to 2 ml) of CSF (slope in mmHg/min). The turnover rate was estimated three times in the same group of sheep: during a natural period of decreasing day-length corresponding to the initial period when gonadotropin activity is stimulated (SG1), during a long-day inhibitory period (IG), and finally during a short-day stimulatory period (SG2).</p> <p>Results</p> <p>The time taken and the speed of recovery of initial IVP differed between groups: 8 min 30 sec, 0.63 ± 0.07 mmHg/min(SG1), 11 min 1 sec, 0.38 ± 0.06 mmHg/min (IG) and 9 min 0 sec, 0.72 ± 0.15 mmHg/min (SG2). Time changes of IVP differed between groups (ANOVA, p < 0.005, SG1 different from IG, <it>p </it>< 0.05). The turnover rate in SG2: 183.16 ± 23.82 μl/min was not significantly different from SG1: 169. 23 ± 51.58 μl/min (Mann-Whitney test, <it>p </it>= 0.41), but was significantly different from IG: 71.33 ± 16.59 μl/min (<it>p </it>= 0.016).</p> <p>Conclusion</p> <p>This study shows that the turnover rate of CSF in ewes changes according to the light-dark cycle; it is increased during short day periods and reduced in long day periods. This phenomenon could account for differences in hormonal concentrations in the CSF in this seasonal species.</p