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A family of Shear-thinning Hydrogels for Injectable Encapsulation and Long-term Delivery (SHIELD) has been designed and synthesized with controlled in situ stiffening properties to regulate the stem cell secretome. We demonstrate that SHIELD with an intermediate stiffness (200 – 400 Pa) could significantly promote the angiogenic potential of human adipose-derived stem cells (hASCs).

ObjectivesThe goal of this study was to retrospectively evaluate the clinical impact of an accurate autocorrecting blood glucose monitoring system in children with severe burns. Blood glucose monitoring system accuracy is essential for providing appropriate intensive insulin therapy and achieving tight glycemic control in critically ill patients. Unfortunately, few comparison studies have been performed to evaluate the clinical impact of accurate blood glucose monitoring system monitoring in the high-risk pediatric burn population.DesignRetrospective analysis of an electronic health record system.SettingPediatric burn ICU at an academic medical center.PatientsChildren (aged < 18 yr) with severe burns (≥ 20% total body surface area) receiving intensive insulin therapy guided by either a noncorrecting (blood glucose monitoring system-1) or an autocorrecting blood glucose monitoring system (blood glucose monitoring system-2).Measurements and main resultsPatient demographics, insulin rates, and blood glucose monitoring system measurements were collected. The frequency of hypoglycemia and glycemic variability was compared between the two blood glucose monitoring system groups. A total of 122 patient charts from 2001 to 2014 were reviewed. Sixty-three patients received intensive insulin therapy using blood glucose monitoring system-1 and 59 via blood glucose monitoring system-2. Patient demographics were similar between the two groups. Mean insulin infusion rates (5.1 ± 3.8 U/hr; n = 535 paired measurements vs 2.4 ± 1.3 U/hr; n = 511 paired measurements; p < 0.001), glycemic variability, and frequency of hypoglycemic events (90 vs 12; p < 0.001) were significantly higher in blood glucose monitoring system-1-treated patients. Compared with laboratory measurements, blood glucose monitoring system-2 yielded the most accurate results (mean ± SD bias: -1.7 ± 6.9 mg/dL [-0.09 ± 0.4 mmol/L] vs 7.4 ± 13.5 mg/dL [0.4 ± 0.7 mmol/L]). Blood glucose monitoring system-2 patients achieve glycemic control more quickly (5.7 ± 4.3 vs 13.1 ± 6.9 hr; p< 0.001) and stayed within the target glycemic control range longer compared with blood glucose monitoring system-1 patients (85.2% ± 13.9% vs 57.9% ± 29.1%; p < 0.001).ConclusionsAccurate autocorrecting blood glucose monitoring system optimizes intensive insulin therapy, improves tight glycemic control, and reduces the risk of hypoglycemia and glycemic variability. The use of an autocorrecting blood glucose monitoring system for intensive insulin therapy may improve glycemic control in severely burned children.

Relatedness strongly influences social behaviors in a wide variety of species. For most species, the highest typical degree of relatedness is between full siblings with 50% shared genes. However, this is poorly understood in species with unusually high relatedness between individuals: clonal organisms. Although there has been some investigation into clonal invertebrates and yeast, nothing is known about kin selection in clonal vertebrates. We show that a clonal fish, the Amazon molly (Poecilia formosa), can distinguish between different clonal lineages, associating with genetically identical, sister clonals, and use multiple sensory modalities. Also, they scale their aggressive behaviors according to the relatedness to other females: they are more aggressive to non-related clones. Our results demonstrate that even in species with very small genetic differences between individuals, kin recognition can be adaptive. Their discriminatory abilities and regulation of costly behaviors provides a powerful example of natural selection in species with limited genetic diversity.

In this first paper in a series we present 1298 low-redshift (z\leq0.2) optical spectra of 582 Type Ia supernovae (SNe Ia) observed from 1989 through 2008 as part of the Berkeley SN Ia Program (BSNIP). 584 spectra of 199 SNe Ia have well-calibrated light curves with measured distance moduli, and many of the spectra have been corrected for host-galaxy contamination. Most of the data were obtained using the Kast double spectrograph mounted on the Shane 3 m telescope at Lick Observatory and have a typical wavelength range of 3300-10,400 Ang., roughly twice as wide as spectra from most previously published datasets. We present our observing and reduction procedures, and we describe the resulting SN Database (SNDB), which will be an online, public, searchable database containing all of our fully reduced spectra and companion photometry. In addition, we discuss our spectral classification scheme (using the SuperNova IDentification code, SNID; Blondin & Tonry 2007), utilising our newly constructed set of SNID spectral templates. These templates allow us to accurately classify our entire dataset, and by doing so we are able to reclassify a handful of objects as bona fide SNe Ia and a few other objects as members of some of the peculiar SN Ia subtypes. In fact, our dataset includes spectra of nearly 90 spectroscopically peculiar SNe Ia. We also present spectroscopic host-galaxy redshifts of some SNe Ia where these values were previously unknown. [Abridged]

The ability to sense mechanical forces is vital to cell physiology. Yet, the molecular basis of mechano-signaling remains unclear. Previous studies have shown that zyxin, a focal adhesion protein, is recruited at force-bearing sites on the actin cytoskeleton and, therefore, identifying zyxin as a mechano-sensing protein candidate. Furthermore, zyxin accumulation at force-bearing sites requires the LIM domain located at the C-terminus of zyxin. The zyxin LIM domain consists of three LIM motifs, each containing two zinc-binding sites. Since individual LIM motifs do not accumulate at focal adhesions or force-bearing sites, we hypothesize that multiple zyxin LIM domains increase force sensitivity. Using a miniature force sensor and GFP-tagged LIM variants, we quantified the relationship between single, tandem dimer and trimer LIM protein localization and traction forces. While the presence of extra LIM domains affected VASP recruitment to focal adhesions, force sensitivity was not enhanced over the single LIM domain. Therefore, zyxin force sensitivity is optimal with a single LIM domain, while additional LIM domains fail to enhance force sensitivity.

The purpose of this study was to develop a faster approach to phase contrast magnetic resonance imaging. This article proposes a phase contrast imaging scheme called single scan phase contrast in which the polarity of the velocity-encoding gradient is alternated between phase encoding steps. In single scan phase contrast, ghost images due to moving spins form. The signal intensity of the ghost images is modulated by the sine of the motion-induce phase shift. Prior to image acquisition, the region of interest containing moving spins is identified, and the field of view is configured so to avoid overlap between the object in the image and the ghost image(s) due to motion in the region of interest. The image values of the region of interest and the ghost image are used to quantify velocity. At best, single scan phase contrast reduces the total acquisition time by a factor of two when compared to phase contrast. In this study, single scan phase contrast is validated against phase contrast in phantom and in vivo. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

This paper combines a generalized viscoelastic model with a one-dimensional (1D) fluid dynamics model for the prediction of blood flow, pressure, and vessel area in systemic arteries. The 1D fluid dynamics model is derived from the Navier–Stokes equations for an incompressible Newtonian flow through a network of cylindrical vessels. This model predicts pressure and flow and is combined with a viscoelastic constitutive equation derived using the quasilinear viscoelasticity theory that relates pressure and vessel area. This formulation allows for inclusion of an elastic response as well as an appropriate creep function allowing for the description of the viscoelastic deformation of the arterial wall. Three constitutive models were investigated: a linear elastic model and two viscoelastic models. The Kelvin and sigmoidal viscoelastic models provide linear and nonlinear elastic responses, respectively. For the fluid domain, the model assumes that a given flow profile is prescribed at the inlet, that flow is c...

Objective Although the mammalian heart's ability to fully regenerate is debated, its potential to extensively repair itself is gaining support. We hypothesized that heart regeneration relies on rapid angiogenesis to support myocardial regrowth and sought to characterize the timeline for angiogenesis and cell proliferation in regeneration. Methods One-day-old CD-1 mice (P1, N = 60) underwent apical resection or sham surgery. Hearts were explanted at serial time points from 0 to 30 days postresection and analyzed with immunohistochemistry to visualize vessel ingrowth and cardiomyocyte migration into the resected region. Proliferating cells were labeled with 5-ethynyl-2′-deoxyuridine injections 12 hours before explant. 5-Ethynyl-2′-deoxyuridine–positive cells were counted in both the apex and remote areas of the heart. Masson's trichrome was used to assess fibrosis. Results By 30 days postresection, hearts regenerated with minimal fibrosis. Compared with sham surgery, apical resection stimulated a significant increase in proliferation of preexisting cardiomyocytes between 3 and 11 days after injury. Capillary migration into the apical thrombus was detected as early as 2 days postresection, with development of mature arteries by 5 days postresection. New vessels became perfused by 5 days postresection as evidenced by lectin injection. Vessel density and diameter significantly increased within the resected area over 21 days, and vessel ingrowth always preceded cardiomyocyte migration, with coalignment of most migrating cardiomyocytes with ingrowing vessels. Conclusions Endothelial cells migrate into the apical thrombus early after resection, develop into functional arteries, and precede cardiomyocyte ingrowth during mammalian heart regeneration. This endogenous neonatal response emphasizes the importance of expeditious angiogenesis required for neomyogenesis.

SN 2006bt displays characteristics unlike those of any other known Type Ia supernova (SN Ia). We present optical light curves and spectra of SN 2006bt which demonstrate the peculiar nature of this object. SN 2006bt has broad, slowly declining light curves indicative of a hot, high-luminosity SN, but lacks a prominent second maximum in the i band as do low-luminosity SNe Ia. Its spectra are similar to those of low-luminosity SNe Ia, containing features that are only present in cool SN photospheres. Light-curve fitting methods suggest that SN 2006bt is reddened by a significant amount of dust; however, it occurred in the outskirts of its early-type host galaxy and has no strong Na D absorption in any of its spectra, suggesting a negligible amount of host-galaxy dust absorption. C II is possibly detected in our pre-maximum spectra, but at a much lower velocity than other elements. The progenitor was likely very old, being a member of the halo population of a galaxy that shows no signs of recent star formation. SNe Ia have been very successfully modeled as a one-parameter family, and this is fundamental to their use as cosmological distance indicators. SN 2006bt is a challenge to that picture, yet its relatively normal light curves allowed SN 2006bt to be included in cosmological analyses. We generate mock SN Ia datasets which indicate that contamination by similar objects will both increase the scatter of a SN Ia Hubble diagram and systematically bias measurements of cosmological parameters. However, spectra and rest-frame i-band light curves should provide a definitive way to identify and eliminate such objects., ApJ, accepted. 13 pages, 13 figures

We have recently completed a 64-night spectroscopic monitoring campaign at the Lick Observatory 3-m Shane telescope with the aim of measuring the masses of the black holes in 12 nearby (z < 0.05) Seyfert 1 galaxies with expected masses in the range ~10^6-10^7 M_sun and also the well-studied nearby active galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including NGC 5548) showed optical variability of sufficient strength during the monitoring campaign to allow for a time lag to be measured between the continuum fluctuations and the response to these fluctuations in the broad Hbeta emission. We present here the light curves for the objects in this sample and the subsequent Hbeta time lags for the nine objects where these measurements were possible. The Hbeta lag time is directly related to the size of the broad-line region, and by combining the lag time with the measured width of the Hbeta emission line in the variable part of the spectrum, we determine the virial mass of the central supermassive black hole in these nine AGNs. The absolute calibration of the black hole masses is based on the normalization derived by Onken et al. We also examine the time lag response as a function of velocity across the Hbeta line profile for six of the AGNs. The analysis of four leads to ambiguous results with relatively flat time lags as a function of velocity. However, SBS 1116+583A exhibits a symmetric time lag response around the line center reminiscent of simple models for circularly orbiting broad-line region (BLR) clouds, and Arp 151 shows an asymmetric profile that is most easily explained by a simple gravitational infall model. Further investigation will be necessary to fully understand the constraints placed on physical models of the BLR by the velocity-resolved response in these objects., 24 pages, 16 figures and 13 tables, submitted to ApJ

We present optical photometry and spectroscopy of SN2005ip for the first 3yr after discovery, showing an underlying Type II-L SN interacting with a steady wind to yield an unusual Type IIn spectrum. For the first 160d, it had a fast linear decline from a modest peak absolute magnitude of about -17.4 (unfiltered), followed by a plateau at roughly -14.8 for more than 2yr. Initially having a normal broad-lined spectrum superposed with sparse narrow lines from the photoionized CSM, it quickly developed signs of strong CSM interaction with a spectrum similar to that of SN1988Z. As the underlying SNII-L faded, SN2005ip exhibited a rich high-ionization spectrum with a dense forest of narrow coronal lines, unprecedented among SNe but reminiscent of some active galactic nuclei. The line-profile evolution of SN 2005ip confirms that dust formation caused its recently reported infrared excess, but these lines reveal that it is the first SN to show clear evidence for dust in both the fast SN ejecta and the slower post-shock gas. SN2005ip's complex spectrum confirms the origin of the strange blue continuum in SN2006jc, which also had post-shock dust formation. We suggest that SN2005ip's late-time plateau and coronal spectrum result from rejuvenated CSM interaction between a sustained fast shock and a clumpy stellar wind, where X-rays escape through the optically thin interclump regions to heat the pre-shock CSM to coronal temperatures., Comment: 18 pages, several color figs, ApJ accepted

Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing.

INTRODUCTION The fast-track assessment clinic (FTAC) is a process to select patients who are very likely to require primary total hip replacement. Selected patients can then be seen in a one-off clinic reducing the number of hospital visits, cost to primary care trusts and delay between referral and treatment. PATIENTS AND METHODS Fifty patients on the waiting list for hip replacement were analysed to see if there were common parameters that led to their inclusion. From these data, fast-track selection criteria (FTSCs) were generated. These FTSCs were used to make a dual comparison of outcomes between 52 patients seen in a traditional clinic. Finally, a pilot study was conducted in which patients fulfilling FTSCs were seen in a designated clinic. RESULTS An Oxford hip score (OHS) of 34 and above combined with severe loss of joint space, severe marginal osteophytes, or both was common to most patients on the waiting list (84%). FTSCs correctly predicted the outcome of the orthopaedic clinic in 38 patients out of a total of 52. During the pilot stage, positive FTSCs were shown to have a positive predictive value of 92% for joint replacement being carried out and a negative predictive value of 46%. CONCLUSIONS An OHS of 34 or above combined with complete loss of joint space and/or severe marginal osteophyte formation can be used to select patients who are very likely to need total hip replacement. These patients can be seen in a clinic that combines assessment of surgical indication with medical fitness for surgery.

We present a one-dimensional (1D) fluid dynamic model that can predict blood flow and blood pressure during exercise using data collected at rest. To facilitate accurate prediction of blood flow, we developed an impedance boundary condition using morphologically derived structured trees. Our model was validated by computing blood flow through a model of large arteries extending from the thoracic aorta to the profunda arteries. The computed flow was compared against measured flow in the infrarenal (IR) aorta at rest and during exercise. Phase contrast-magnetic resonance imaging (PC-MRI) data was collected from 11 healthy volunteers at rest and during steady exercise. For each subject, an allometrically-scaled geometry of the large vessels was created. This geometry extends from the thoracic aorta to the femoral arteries and includes the celiac, superior mesenteric, renal, inferior mesenteric, internal iliac and profunda arteries. During rest, flow was simulated using measured supraceliac (SC) flow at the inlet and a uniform set of impedance boundary conditions at the 11 outlets. To simulate exercise, boundary conditions were modified. Inflow data collected during steady exercise was specified at the inlet and the outlet boundaries were adjusted as follows. The geometry of the structured trees used to compute impedance was scaled to simulate the effective change in the cross-sectional area of resistance vessels and capillaries due to exercise. The resulting computed flow through the IR aorta was compared to measured flow. This method produces good results with a mean difference between paired data to be 1.1 +/- 7 cm(3) s(- 1) at rest and 4.0 +/- 15 cm(3) s(- 1) at exercise. While future work will improve on these results, this method provides groundwork with which to predict the flow distributions in a network due to physiologic regulation.

Objective: The clinical efficacy of neuregulin (NRG), a ligand of the Her family receptors, is hindered by off-target exposure and requisite daily systemic infusions. We recently encapsulated NRG in a hydrogel (HG) for targeted and sustained myocardial delivery; beneficial results in a murine model of ischemic cardiomyopathy were clear. Here, we evaluate NRG-HG’s translational potential for myocardial regeneration and functional improvement in the clinical realm using a preclinical ovine model of ischemic cardiomyopathy. Methods: Male Dorset sheep (n=30) underwent baseline cardiac assessment with MRI and pressure-volume (PV) catheterization. Myocardial infarction (MI) was induced by ligating the 2 nd and 3 rd diagonal artery branches, and sheep were randomized to receive myocardial borderzone injection of 1mL saline, HG alone, NRG alone, or NRG-HG. Eight weeks post-infarction, repeat hemodynamic assessment was performed followed by tissue acquisition. A subset underwent sacrifice at 1 week for molecular analyses. Results: Analysis of myocardial borderzone 1-week post-infarction revealed NRG-HG augmented phosphorylated ErbB4, ErbB2, ERK, and histone h3 compared with all other groups. This marker activation suggests receptor activation, downstream signaling, and cardiac cell-cycle entry. At 8 weeks, NRG-HG significantly reduced scar size and augmented ventricular function (Table). There was no evidence of off-target NRG at 1 and 8 weeks, and no evidence of gel embolization or neurologic insult (by brain MRI) from intramyocardial hydrogel delivery. Conclusion: Targeted and sustained intramyocardial delivery of NRG with an engineered hydrogel platform triggers regeneration of mammalian heart muscle and augments ventricular function in a large animal model of ischemic cardiomyopathy. This novel, engineered delivery system realizes the true potential of NRG and its translation to clinical regenerative therapeutics.

Objective: The treatment for acute myocardial infarction (MI) is prompt revascularization. Our goal is to develop a novel therapy that mimics perfusion, but is not reliant on restitution of blood flow. We hypothesized that targeted delivery of a photosynthetic agent to the ischemic heart would restore myocardial energetics, attenuate damage, and improve long-term performance. Methods: Ten-week old male Wistar rats were used for the ischemia-reperfusion model. The left anterior descending artery (LAD) was temporarily ligated 2mm below the left atrial appendage via a left thoracotomy. Following ligation, animals were randomized to receive direct intramyocardial injection of 200μL PBS (n=7), 10x10 6 photosynthetic Synechecoccus elongatus (SE) of equivalent volume (n=10), or sham surgery (n=7). A light source illuminated the ischemic region for 1 hr after injection. The LAD tourniquet was subsequently removed and the heart reperfused. Ventricular function, geometry, and hemodynamics were assessed 4 weeks after surgery with MRI and LV catheterization. Results: Myocardial injury was attenuated by the photosynthetic agent: troponin-I concentration in peripheral blood was significantly lower in SE treated animals compared with controls 24 hrs post MI (6.5±4.8 vs. 16.5±10.5 ng/mL, P =0.05). Four weeks after MI, the mean LV ejection fraction was significantly greater in SE treated rats compared with controls (36.9±4.7 vs. 48.3±10.5%, P =0.02). Similarly, SE treated animals demonstrated a decreased end-systolic volume (327±133 vs. 487±140 μL, P =0.03) and a steeper slope of the end-systolic pressure-volume relationship (0.35±0.12 vs. 0.19±0.08, P =0.01). Histologic analyses revealed no evidence of intramyocardial abscess formation or persistent SE. Furthermore, the photosynthetic agent prevented upregulation of genes associated with hypoxia (downregulated Hsp-1b 11 fold). Conclusions: Delivery of a photosynthetic agent to ischemic myocardium creates a localized symbiotic relationship that safely attenuates myocardial injury and improves long-term ventricular function in a rat model of ischemia-reperfusion. Energizing myocardium with light in the absence of perfusion is a completely novel strategy for treating cardiac ischemia.

Background Early detection of acute kidney injury (AKI) in severely burn-injured patients can help alter treatment to prevent progression to acute failure and reduce the need for renal replacement therapy. We hypothesized that whole blood neutrophil gelatinase–associated lipocalin (NGAL) will be increased in severely burn-injured patients who develop AKI during acute resuscitation. Materials and methods We performed a prospective observation study of adult burn patients with a 20% total body surface area (TBSA) burned or greater burn injury. Two-hour serial measurements of NGAL, serum creatinine (Cr), and hourly urine output (UO) were collected for 48 h after admission. Our primary goal was to correlate the risk of AKI in the first week after burn injury with serial NGAL levels in the first 48 h after admission. Our secondary goal was to determine if NGAL was an earlier independent predictor of AKI compared with Cr and UO. Results We enrolled 30 adult (age ≥ 18 y) burn patients with the mean ± standard deviation age of 40.9 ± 15.4 and mean TBSA of 46.4 ± 22.4. Fourteen patients developed AKI within the first 7 d after burn injury. There were no differences in age, TBSA, fluid administration, mean arterial pressure, UO, and Cr between AKI and no-AKI patients. NGAL was significantly increased as early as 4 h after injury (182.67 ± 83.3 versus 107.37 ± 46.15) in the AKI group. Controlling for age, TBSA, and inhalation injury, NGAL was a predictor of AKI at 4 h after injury (odds ratio, 1.02) and remained predictive of AKI for the period of more than the first 24 h after admission. UO and Cr were not predictive of AKI in the first 24 h after admission. Conclusions Whole blood NGAL is markedly increased in burn patients who develop AKI in the first week after injury. In addition, NGAL is an early independent predictor of AKI during acute resuscitation for severe burn injury. UO and Cr are not predictive of AKI during this time period.

Spatial and temporal variation in critical life history traits differ markedly between two co-occurring, rare and endangered annual plants, Gilia tenuiflora arenaria and Chorizanthe pungens pungens, that have restricted, but overlapping geographic distributions in coastal habitats of central California, USA. Environmental variation was extreme during the 6-year study (1997–2002), with the greatest differences between an intense wet, warm El Nino year (1998), followed by a very dry, cool La Nina (1999). Both species have similar increases in adult survival and seed set with wetter, warmer weather in spring, but they differed in other traits: more Gilia germinated in years with high rainfall and temperature, while more Chorizanthe germinated in dry, cooler years; Gilia abundance increased with the number of years since the previous large El Nino event, while Chorizanthe abundance declined; and Gilia abundance was independent of the previous year’s seed set, while Chorizanthe density was directly related to the previous year’s seed set. The strong negative associations of Chorizanthe abundance with warm, wet weather and with time since the previous El Nino probably reflect the particular sequence of annual weather patterns from 1997 through 2002, especially the extremes in 1998 and 1999. Since it germinates readily in most years under a wide range of winter conditions and does not develop a long-lived seed bank, Chorizanthe seedling abundance reflects recent additions and depletions of its seed bank, rather than prevailing weather, per se. In contrast, Gilia seeds may remain in the seed bank for many years, until relatively rare winter conditions trigger significant germination. These species-specific demographies enhance persistence and coexistence of these species, but the mechanisms differ from each other and from those described for annuals in other highly variable environments.

We prospectively studied the outcome of a protocol of prophylaxis for deep vein thrombosis (DVT) in 103 consecutive patients undergoing surgical stabilisation of pelvic and acetabular fractures. Low-molecular-weight heparin (LMWH) was administered within 24 hours of injury or on achieving haemodynamic stability. Patients were screened for proximal DVT by duplex ultrasonography performed ten to 14 days after surgery. The incidence of proximal DVT was 10% and of pulmonary embolus 5%. Proximal DVT developed in two of 64 patients (3%) who had received LMWH within 24 hours of injury, but in eight of 36 patients (22%) who received LMWH more than 24 hours after the injury (p < 0.01). We conclude that LMWH, when begun without delay, is a safe and effective method of thromboprophylaxis in high-risk patients with major pelvic or acetabular fractures.

During infection withChlamydia trachomatis, CD8+T cells are primed, even though the bacteria remain confined to a host cell vacuole throughout their developmental cycle. Because CD8+T cells recognize antigens processed from cytosolic proteins, theChlamydiaantigens recognized by these CD8+T cells very likely have access to the host cell cytoplasm during infection. The identity of theseC. trachomatisproteins has remained elusive, even though their localization suggests they may play important roles in the biology of the organism. Here we use a retroviral expression system to identify Cap1, a 31-kDa protein fromC. trachomatisrecognized by protective CD8+T cells. Cap1 contains no strong homology to any known protein. Immunofluorescence microscopy by using Cap1-specific antibody demonstrates that this protein is localized to the vacuolar membrane. Cap1 is virtually identical among the humanC. trachomatisserovars, suggesting that a vaccine incorporating Cap1 might enable the vaccine to protect against allC. trachomatisserovars. The identification of proteins such as Cap1 that associate with the inclusion membrane will be required to fully understand the interaction ofC. trachomatiswith its host cell.

Leaves were collected from 21 different grapevine (Vitis ssp.) genotypes with varying resistance to powdery mildew disease caused by Uncinula necator. For leaves collected from field‐grown vines in spring there was a correlation between resistance rating and activity of chitinase and β‐1,3‐glucanase. The correlation was greater with the sum of the two enzyme activities. In contrast, no correlation was obtained for leaves collected during summer. With leaves from glasshouse grown vines, wounding or infection with powdery mildew increased both chitinase and β‐1,3‐glucanase activity. Light microscope examination of detached leaves inoculated with U. necator conidia showed that germination appeared to occur at the same rate on leaves of a susceptible (Sultana) and a resistant (Seyval) genotype. Subsequent development of mycelia was severely restricted on the resistant genotype but it was prolific on the sensitive genotype. A bioassay was developed based on germination and extension of the germ tube of U. necator conidia on agar plates. Agar preparations containing desalted crude extracts of grapevine leaves inhibited growth and caused the tips of the hyphae to rupture. The effect was not observed with boiled extracts and was greater with extracts from resistant genotypes. Chitinase and β‐1,3‐glucanase were purified 760‐fold and 46‐fold respectively from leaves of Seyval grapevines. The purified enzyme preparations inhibited germ tube growth, with the effect being more prominent in the presence of both enzymes. The results demonstrate that these two enzymes have antifungal activity against U. necator, and are consistent with these pathogenesis‐related proteins having a role in defence of grapevines against powdery mildew.

A population of 96 doubled haploid lines (DHLs) was prepared from F1 plants of the hexaploid wheat cross Chinese Spring x SQ1 (a high abscisic acid-expressing breeding line) and was mapped with 567 RFLP, AFLP, SSR, morphological and biochemical markers covering all 21 chromosomes, with a total map length of 3,522 cM. Although the map lengths for each genome were very similar, the D genome had only half the markers of the other two genomes. The map was used to identify quantitative trait loci (QTLs) for yield and yield components from a combination of 24 site x treatment x year combinations, including nutrient stress, drought stress and salt stress treatments. Although yield QTLs were widely distributed around the genome, 17 clusters of yield QTLs from five or more trials were identified: two on group 1 chromosomes, one each on group 2 and group 3, five on group 4, four on group 5, one on group 6 and three on group 7. The strongest yield QTL effects were on chromosomes 7AL and 7BL, due mainly to variation in grain numbers per ear. Three of the yield QTL clusters were largely site-specific, while four clusters were largely associated with one or other of the stress treatments. Three of the yield QTL clusters were coincident with the dwarfing gene Rht-B1 on 4BS and with the vernalisation genes Vrn-A1 on 5AL and Vrn-D1 on 5DL. Yields of each DHL were calculated for trial mean yields of 6 g plant(-1) and 2 g plant(-1) (equivalent to about 8 t ha(-1) and 2.5 t ha(-1), respectively), representing optimum and moderately stressed conditions. Analyses of these yield estimates using interval mapping confirmed the group-7 effects on yield and, at 2 g plant(-1), identified two additional major yield QTLs on chromosomes 1D and 5A. Many of the yield QTL clusters corresponded with QTLs already reported in wheat and, on the basis of comparative genetics, also in rice. The implications of these results for improving wheat yield stability are discussed.

To evaluate the efficacy of nil, three or six treatments of penethamate hydriodide on successive days for treatment of subclinical mastitis on the bacteriological cure proportion and subsequent somatic cell count (SCC).Milk samples were collected from all glands of 102 cows with SCC of200,000 cells/mL, and at least one gland with a rapid mastitis test (RMT) score0. Cows from which a bacterial pathogen was isolated were treated (Day 0) with either three (3 × PH; n=31 cows), six (6 × PH; n=30) or no (Control; n=31) daily I/M injections of 5 g of penethamate hydriodide. Milk samples were collected on Days 21 and 28 for bacteriology. Bacteriological cure was defined as having occurred when the pathogen isolated pre-treatment was isolated from neither of the post-treatment samples. Post-treatment, cow-level composite SCC data were collated. The identity of Staphylococcus aureus isolates was confirmed by PCR and antimicrobial resistance patterns for these isolates were determined by zone diffusion testing.Corynebacterium spp. (40%) and S. aureus (32%) were the most common isolates pre-treatment. The proportion of glands cured increased from 0.16 (SE 0.04) for the Control, to 0.32 (SE 0.06) for the 3 × PH, and 0.56 (SE 0.02) for the 6 × PH groups (p0.001); decreased with increasing age (p=0.02); and was lower for S. aureus than for other isolates (p0.001). Of the 60 isolates defined as S. aureus by phenotypic bacteriology, 55 were confirmed as S. aureus by PCR. Of these, 24 (45%) were resistant to penicillin. One of 24 (4%) glands with S. aureus resistant to penicillin was cured compared with 7/29 (24%) sensitive isolates (p=0.04). The geometric mean SCC at the subsequent herd test declined from 481 (95% CI=350-659) × 10(3) cells/mL in Control, to 352 (95% CI=255-486) × 10(3) cells/mL in 3 × PH, and 276 (95% CI=199-383) × 10(3) cells/mL in 6× PH cows (p=0.05).Increasing the duration of treatment of subclinical mastitis using penethamate hydriodide in dairy cows resulted in a higher bacteriological cure proportion, a lower proportion of glands infected post-treatment, and a reduced SCC. Cure proportion was reduced in older cows, and for glands infected with S. aureus, especially when resistant to penicillin.This study demonstrated that bacteriological cure of subclinical intramammary infections can be increased by increasing the duration of therapy, but a number of cow and pathogen factors also affected the probability of cure.

Owing to their utility for measurements of cosmic acceleration, Type Ia supernovae (SNe) are perhaps the best-studied class of SNe, yet the progenitor systems of these explosions largely remain a mystery. A rare subclass of SNe Ia show evidence of strong interaction with their circumstellar medium (CSM), and in particular, a hydrogen-rich CSM; we refer to them as SNe Ia-CSM. In the first systematic search for such systems, we have identified 16 SNe Ia-CSM, and here we present new spectra of 13 of them. Six SNe Ia-CSM have been well-studied previously, three were previously known but are analyzed in-depth for the first time here, and seven are new discoveries from the Palomar Transient Factory. The spectra of all SNe Ia-CSM are dominated by H{\alpha} emission (with widths of ~2000 km/s) and exhibit large H{\alpha}/H{\beta} intensity ratios (perhaps due to collisional excitation of hydrogen via the SN ejecta overtaking slower-moving CSM shells); moreover, they have an almost complete lack of He I emission. They also show possible evidence of dust formation through a decrease in the red wing of H{\alpha} 75-100 d past maximum brightness, and nearly all SNe Ia-CSM exhibit strong Na I D absorption from the host galaxy. The absolute magnitudes (uncorrected for host-galaxy extinction) of SNe Ia-CSM are found to be -21.3, Comment: 24 pages, 18 figures, 6 tables, submitted to ApJ

We present Hubble Space Telescope (HST) and ground-based optical and near-infrared observations of SN 2005hk and SN 2008A, typical members of the Type Iax class of supernovae (SNe). Here we focus on late-time observations, where these objects deviate most dramatically from all other SN types. Instead of the dominant nebular emission lines that are observed in other SNe at late phases, spectra of SNe 2005hk and 2008A show lines of Fe II, Ca II, and Fe I more than a year past maximum light, along with narrow [Fe II] and [Ca II] emission. We use spectral features to constrain the temperature and density of the ejecta, and find high densities at late times, with n_e >~ 10^9 cm^-3. Such high densities should yield enhanced cooling of the ejecta, making these objects good candidates to observe the expected "infrared catastrophe," a generic feature of SN Ia models. However, our HST photometry of SN 2008A does not match the predictions of an infrared catastrophe. Moreover, our HST observations rule out a "complete deflagration" that fully disrupts the white dwarf for these peculiar SNe, showing no evidence for unburned material at late times. Deflagration explosion models that leave behind a bound remnant can match some of the observed properties of SNe Iax, but no published model is consistent with all of our observations of SNe 2005hk and 2008A., 20 pages, 15 figures

Histone deacetylation and DNA methylation have a central role in the control of gene expression, including transcriptional repression of tumour suppressor genes. Loss of DNA mismatch repair due to methylation of the hMLH1 gene promoter results in resistance to cisplatin in vitro and in vivo . The cisplatin-resistant cell line A2780/cp70 is 8-fold more resistant to cisplatin than the non-resistant cell line, and has the hMLH1 gene methylated. Treatment with an inhibitor of DNA methyltransferase, DAC (2-deoxy-5′-azacytidine), results in a partial reversal of DNA methylation, re-expression of MLH1 (mutL homologue 1) and sensitization to cisplatin both in vitro and in vivo . PXD101 is a novel hydroxamate type histone deacetylase inhibitor that shows antitumour activity in vivo and is currently in phase I clinical evaluation. Treatment of A2780/cp70 tumour-bearing mice with DAC followed by PXD101 results in a marked increase in the number of cells that re-express MLH1. Since the clinical use of DAC may be limited by toxicity and eventual re-methylation of genes, we suggest that the combination of DAC and PXD101 could have a role in increasing the efficacy of chemotherapy in patients with tumours that lack MLH1 expression due to hMLH1 gene promoter methylation. Abbreviations: DAC, 2-deoxy-5′-azacytidine; MLH1, mutL homologue 1; MMR, mismatch repair; TSA, trichostatin A

This study aimed to determine the prevalence of genital ulcer and urethral pathogens, as well as their association with clinical features, in men with genital ulcer disease (GUD) enrolled in a clinical trial.Clinical data were collected by questionnaire. Ulcer swabs were tested for herpes simplex viruses (HSV-1/2), Treponema pallidum, Haemophilus ducreyi, and Chlamydia trachomatis L1-L3. First-pass urine was tested for urethral pathogens, namely Neisseria gonorrhoeae, C. trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium. Pathogens were detected by real-time molecular assays. Blood was tested for HIV, HSV-2, and syphilis-associated antibodies. Pathogens and clinical associations were investigated using the χ test.A total of 615 men with GUD were recruited. Herpes simplex virus (HSV-1, 4.2%; HSV-2, 98.2%) and bacterial pathogens were detected in 451 (73.6%) and 48 (7.8%) of genital ulcers, respectively. Human immunodeficiency virus, HSV-2, and treponemal antibodies were detected in 387 (62.9%), 434 (70.6%), and 141 (23.0%) men, respectively, whereas 54 men (8.8%) were rapid plasmin reagin (RPR) seropositive. A total of 223 urethral infections were diagnosed in 188 men (30.6%), including 69 (11.2%) M. genitalium, 64 (10.4%) T. vaginalis, 60 (9.8%) C. trachomatis, and 30 (4.9%) N. gonorrhoeae infections. Dysuria was reported by 170 men (27.6%), and 69 men (11.5%) had urethral discharge on examination. Urethral pathogens were detected in 102/409 (24.9%) men without these clinical features.Herpes accounted for most GUD cases and urethral pathogen coinfections were common. Erythromycin, dispensed to treat infrequent chancroid and lymphogranuloma venereum cases, provided additional treatment of some asymptomatic urethral pathogens. Additional antibiotics would be required to treat asymptomatic trichomoniasis and gonorrhea.

When modeling the cardiovascular system, the use of boundary conditions that closely represent the interaction between the region of interest and the surrounding vessels and organs will result in more accurate predictions. An often overlooked feature of outlet boundary conditions is the dynamics associated with regulation of the distribution of pressure and flow. This study implements a dynamic impedance outlet boundary condition in a one-dimensional fluid dynamics model using the pulmonary vasculature and respiration (feedback mechanism) as an example of a dynamic system. The dynamic boundary condition was successfully implemented and the pressure and flow were predicted for an entire respiration cycle. The cardiac cycles at maximal expiration and inspiration were predicted with a root mean square error of $0.61$ and $0.59$ mm Hg, respectively.

Cellular responses to mechanical perturbation are vital to cell physiology. In particular, migrating cells have been shown to sense substrate stiffness and alter cell morphology and speed. Zyxin is a focal adhesion protein that responds to external mechanical forces; however, the mechanisms of zyxin recruitment at force-bearing sites are unknown. Using force-sensing microfabricated substrates, we simultaneously measured traction force and zyxin recruitment at force-bearing sites. GFP-tagged zyxin accumulates at force-bearing sites at the leading edge, but not at the trailing edge, of migrating epithelial cells. Zyxin recruitment at force-bearing sites depends on Rho-kinase and myosin II activation, suggesting that zyxin responds not only to the externally applied force, as previously shown, but also to the internally generated actin-myosin force. Zyxin in turn recruits vasodilator-stimulated phosphoprotein, a regulator of actin assembly, to force-bearing sites. To dissect the domains of zyxin that are essential for this unique force-dependent accumulation, we generated two zyxin truncation mutants: one lacking the LIM domain (ΔLIM) and one containing only the LIM domain with all three LIM motifs (LIM). GFP-tagged ΔLIM does not localize to the force-bearing sites, but GFP-tagged zyxin LIM-domain is sufficient for the recruitment to and dynamics at force-bearing focal adhesions. Furthermore, one or two LIM motifs are not sufficient for force-dependent accumulation, suggesting that all three LIM motifs are required. Therefore, the LIM domain of zyxin recruits zyxin to force-bearing sites at the leading edge of migrating cells.

Recent observations suggest that Type IIn supernovae (SNe IIn) may exhibit late-time (>100 days) infrared (IR) emission from warm dust more than other types of core-collapse SNe. Mid-IR observations, which span the peak of the thermal spectral energy distribution, provide useful constraints on the properties of the dust and, ultimately, the circumstellar environment, explosion mechanism, and progenitor system. Due to the low SN IIn rate (, Accepted for publication to ApJ, 17 pages, 10 figures, 10 tables

The primary objective of this sub-study, undertaken as an extension to the previously reported phase-I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary pharmacodynamic (PD) studies were also performed to enable comparison of the biological effects of the oral and intravenous formulations.Oral belinostat was administered in a range of doses and schedules (once, twice or thrice daily), on either day 1 or days 1-5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase-I trial of intravenous belinostat. Serial blood samples were collected for PK and PD (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration.A total mean daily AUC of 2,767 ± 1,453 ng h/ml (8.7 ± 4.6 μM h) resulted from a dose of 1,000 mg/m(2) once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid); however, a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half-life (T½) of a single dose of 1,000 mg/m(2) was 1.5 h (± 0.3 h) and peak levels were reached in an average of 1.9 h (± 0.3 h). The half-life was found to be independent of dose, but a trend towards increasing half-life following multiple dosing was observed. Histone H4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration.High doses of oral belinostat, up to 1,000 mg/m(2) bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat.