Ligand sensitized strong luminescence from Eu3+-doped LiYF4 nanocrystals: a photon down-shifting strategy to increase solar-to-current conversion efficiency.
Lanthanide (Ln)-doped nanocrystals generally display low luminescence quantum efficiency due to forbidden nature of the 4f-4f transition besides possessing low absorption cross sections (∼10 M-1 cm-1). Considering the demand for these materials, particularly for light emission and bioimaging applications, it is very important to improve their quantum efficiency. This work demonstrates a strategy to enhance Si solar cell efficiency via sensitization of Eu3+ ions luminescence from colloidal nanocrystals. We have for the first time developed a simple ligand exchange approach to attach 4,4,4-trifluoro-1-phenyl-1,3 butanedione (TPB) to the surface of Eu3+-doped LiYF4 nanocrystals (NCs). Owing to the good overlap between the emission of the TPB ligands and the energy levels of Eu3+ ions, an efficient energy transfer takes place from the ligand to Eu3+ ions upon ultraviolet (UV) excitation of the ligand, leading to intense red emission. The sensitization of Eu3+ ions greatly enhanced the quantum yield of Eu3+ ions (∼31%) compared to the ∼5% obtained via direct excitation of Eu3+ ions (λexi = 394 nm) in Eu3+-doped LiYF4 NCs. A device was fabricated by embedding the nanocrystals on a Si solar cell to capture the UV photons and convert them into visible ones, which subsequently creates charge carriers inside the cell. Upon exposure to UV light, the nanocrystal embedded Si solar cell shows overall enhancement in the photocurrent upon excitation under UV radiation.


Inverse relationship between the expression of the human papillomavirus type 16 transcription factor E2 and virus DNA copy number during the progression of cervical intraepithelial neoplasia.
The human papillomavirus type 16 (HPV-16) status of 43 cervical biopsies, which had been characterized histologically as normal, various grades of cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma, was examined by using (i) a novel antibody against the HPV-16 E2 protein, (ii) sensitive HPV-16 DNA in situ hybridization and (iii) microdissection/PCR for the E2 ORF. The data indicate that E2 protein expression is highest in koilocytes in lower-grade CIN (I), but decreases with increasing grade, whereas the detection of HPV DNA is delayed until CIN I/II, rising to the highest levels in carcinoma cells. Co-localization of E2 with HPV-16 DNA-positive cells was most commonly observed in koilocytes in CIN II lesions. PCR analyses of microdissected epithelium from the same or serial sections indicated that E2 ORFs were retained in an intact form in a number of higher-grade CIN lesions and invasive carcinomas.


Intradermal delivery of a synthetic DNA vaccine protects macaques from Middle East respiratory syndrome coronavirus.
Emerging coronaviruses from zoonotic reservoirs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been associated with human-to-human transmission and significant morbidity and mortality. Here, we study both intradermal and intramuscular 2-dose delivery regimens of an advanced synthetic DNA vaccine candidate encoding a full-length MERS-CoV spike (S) protein, which induced potent binding and neutralizing antibodies as well as cellular immune responses in rhesus macaques. In a MERS-CoV challenge, all immunized rhesus macaques exhibited reduced clinical symptoms, lowered viral lung load, and decreased severity of pathological signs of disease compared with controls. Intradermal vaccination was dose sparing and more effective in this model at protecting animals from disease. The data support the further study of this vaccine for preventing MERS-CoV infection and transmission, including investigation of such vaccines and simplified delivery routes against emerging coronaviruses.


[The morning report - an important item in the training of psychiatrists in residence at psychiatric hospitals].
In this article we focus on the role, function and composition of the morning report in the training of psychiatrists in residence at psychiatric hospitals. We also pay attention to the way in which the case should be presented in the morning report. To make some proposals regarding ways in which the efficiency of the morning report and the case presented in that report can be improved. We studied currently available literature and publications about the morning report and we also drew on our own experience with the morning report. We found very few publications that dealt specifically with morning report in the psychiatric teaching hospital. However, our studies have shown that the morning report should not be regarded purely as an instrument for passing on care details about the patient; it should also be seen as an essential link in the chain of instruction required by trainee psychiatrist. On the basis of rhetoric, constructivism and social-constructionism, we present a model for case presentation. Making improvements in the quality of the morning report is an important way of contributing to the learning process of trainee psychiatrists and staff members and should therefore enhance the status of the psychiatric hospital as a teaching community.


Endogenous endothelial cell signaling systems maintain vascular stability.
The function of the endothelium is to provide a network to allow delivery of oxygen and nutrients to tissues throughout the body. This network comprises adjacent endothelial cells that utilize adherens junction proteins such as vascular endothelial cadherin (VE-cadherin) to maintain the appropriate level of vascular permeability. The disruption of VE-cadherin interactions during pathologic settings can lead to excessive vascular leak with adverse effects. Endogenous cell signaling systems have been defined, which help to maintain the proper level of vascular stability. Perhaps the best described system is Angiopoietin-1 (Ang-1). Ang-1 acting through its receptor Tie2 generates a well-described set of signaling events ultimately leading to enhanced vascular stability. In this review, we will focus on what is known about additional endogenous cell signaling systems that stabilize the vasculature, and using Ang-1/Tie2 as a model, we will address where our understanding of these additional systems is lacking.


Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.
The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation.


Kinematic risky driving behavior among younger and older drivers: Differences over time by age group and sex.
Objective: This research examined the incidence rates of elevated gravitational force events (kinematic risky driving, KRD) among 16- to 17-year-old drivers compared to those of 18- to 20-year-old, 21- to 25-year-old, and 35- to 55-year-old drivers over a 12-month period. Methods: Data were sampled from the Strategic Highway Research Program 2 (SHRP2) naturalistic driving study that recruited a U.S. national sample of study participants. General linear mixed models (GLIMMIX) for recurrent events were used to estimate KRD incident rates for age cohorts in 3-month periods. Results: KRD incidence rates for 16- to 17-year-old drivers were higher than the rates for older drivers at each 3-month period. Analyses of individual differences for the 12-month period indicated that incidence rates for the 16- to 17-year-old group were 1.84 times higher than the rates for 18- to 20-year-old drivers, 2.86 higher than those for 21- to 25-year-old drivers, and 4.92 times higher than those for 35- to 55-year-old drivers. The incident rate for 16- to 17-year-old males was 1.9 times higher than that for same-aged females in the first 3 months and 2.3 times higher over 12 months. Over the study period, KRD rates of 16- to 17-year-old participants declined 24.5% among females and 18.0% among males. Conclusions: KRD rates were higher among younger relative to older, more experienced drivers and did not decline over time, consistent with a protracted period of risky driving behavior. The persistently higher KRD rate among young drivers suggests the need to enhance crash prevention approaches, such as feedback about abrupt maneuvering, to young drivers and their parents.


The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients.
To determine the nature of unexplained chronic serum aspartate aminotransferase elevations of a mild to moderate degree in asymptomatic patients, we performed systematic clinical, biochemical and histologic examinations in 47 individuals who had been screened for virus-, alcohol- or drug-related disease. Serum aspartate aminotransferase levels ranged from 3- to 8-fold normal (mean: 156 +/- 7 units per liter) for at least 6 months (mean: 30 +/- 6 months). Serum alanine aminotransferase levels were also increased but to a lesser degree in most patients. Thirty-four patients (72%) had histologic features of chronic active hepatitis, including 16 with cirrhosis. Ten patients (21%) had steatohepatitis and three (6%) had miscellaneous disorders. Patients with chronic active hepatitis and cirrhosis could not be distinguished from counterparts without cirrhosis by individual clinical or laboratory findings. Antinuclear or smooth muscle antibodies were detected in 18 of the patients with chronic active hepatitis (53%). All patients with steatohepatitis were women, and they had laboratory changes at presentation, including seropositivity for antinuclear antibodies, that overlapped with those of patients with chronic active hepatitis. We conclude that asymptomatic patients with unexplained chronic aspartate aminotransferase elevations of a mild to moderate degree frequently have chronic active hepatitis and that many have cirrhosis. Immunoserologic findings compatible with autoimmune hepatitis are commonly present. Steatohepatitis is the most frequent alternative diagnosis, especially in women, and it is not excluded by the presence of antinuclear antibodies. Differentiation of the disorders is possible only by histologic examination.


Microplastics and other anthropogenic particles in Antarctica: Using penguins as biological samplers.
Microplastics (< 5 mm in size) are known to be widespread in the marine environment but are still poorly studied in Polar Regions, particularly in the Antarctic. As penguins have a wide distribution around Antarctica, three congeneric species: Adélie (Pygoscelis adeliae), chinstrap (Pygoscelis antarcticus) and gentoo penguins (Pygoscelis papua) were selected to evaluate the occurrence of microplastics across the Antarctic Peninsula and Scotia Sea. Scat samples (used as a proxy of ingestion), were collected from breeding colonies over seven seasons between 2006 and 2016. Antarctic krill (Euphausia superba), present in scat samples, contributed 85%, 66% and 54% of the diet in terms of frequency of occurrence to the diet of Adélie, gentoo and chinstrap penguins, respectively. Microplastics were found in 15%, 28% and 29% scats of Adélie, chinstrap and gentoo penguin respectively. A total of 92 particles were extracted from the scats (n = 317) and 32% (n = 29) were chemically identified via micro-Fourier Transform Infrared Spectroscopy (μ-FTIR). From all the particles extracted, 35% were identified as microplastics, particularly polyethylene (80%) and polyester (10%). It was not possible to ascertain the identification of the remaining 10% of samples. Other anthropogenic particles were identified in 55% of samples, identified as cellulose fibres. The results show a similar frequency of occurrence of particles across all colonies, suggesting there is no particular point source for microplastic pollution in the Scotia Sea. Additionally, no clear temporal variation in the number of microplastics in penguins was observed. Overall, this study reveals the presence of microplastics across Antarctica, in three penguin species and offers evidence of other anthropogenic particles in high numbers. Further research is needed to better understand the spatio-temporal dynamics, fate and effect of microplastics on these ecosystems, and improve plastic pollution policies in Antarctica.


High vacuum distillation of ionic liquids and separation of ionic liquid mixtures.
The vaporisation of ionic liquids has been investigated using temperature programmed desorption (TPD) and ultra-high vacuum (UHV) distillation. 1-Alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids, [C(n)C(1)Im][Tf(2)N] (n = 2, 8), have been distilled at UHV and T > 500 K in a specially designed still. The distillation process yielded spectroscopically pure ionic liquid distillates with complete removal of volatile impurities such as water, argon and 1-methylimidazole. Such UHV distillation offers a method of obtaining high purity ionic liquids for analytical applications. The vapour phase of the ionic liquid mixtures [C(2)C(1)Im](0.05)[C(8)C(1)Im](0.95)[Tf(2)N] and [C(2)C(1)Im][C(8)C(1)Im][Tf(2)N][EtSO(4)] has been analysed by TPD using line-of-sight mass spectrometry (LOSMS). The vapour phase consisted of all possible combinations of neutral ion pairs (NIPs) from the liquid mixture. Neither mixture showed evidence of decomposition during TPD, and the [C(2)C(1)Im](0.05)[C(8)C(1)Im](0.95)[Tf(2)N] mixture was shown to obey Raoult's law. Based on the TPD results, fractional distillations were attempted for [C(2)C(1)Im][C(8)C(1)Im][Tf(2)N](2) and [C(2)C(1)Im][C(8)C(1)Im][Tf(2)N][EtSO(4)] mixtures. The distillate from [C(2)C(1)Im][C(8)C(1)Im][Tf(2)N](2) was enhanced in the more volatile [C(2)C(1)Im][Tf(2)N] components, but the [C(2)C(1)Im][C(8)C(1)Im][Tf(2)N][EtSO(4)] mixture underwent significant decomposition. The similarities and differences between UHV TPD, and high vacuum distillation, of ionic liquids, are discussed. Design parameters are outlined for a high vacuum ionic liquid still that will minimise decomposition and maximise separation of ILs of differing volatility.


Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells. The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNF-alpha in the incubated cells. The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.


Recognition, perceptions and treatment practices for severe malaria in rural Tanzania: implications for accessing rectal artesunate as a pre-referral.
Preparatory to a community trial investigating how best to deliver rectal artesunate as pre-referral treatment for severe malaria; local understanding, perceptions of signs/symptoms of severe malaria and treatment-seeking patterns for and barriers to seeking biomedical treatment were investigated. 19 key informant interviews, 12 in-depth interviews and 14 focus group discussions targeting care-givers, opinion leaders, and formal and informal health care providers were conducted. Monthly fever episodes and danger signs or symptoms associated with severe malaria among under-fives were recorded. Respondents recognized convulsions, altered consciousness and coma, and were aware of their risks if not treated. But, these symptoms were perceived to be caused by supernatural forces, and traditional healers were identified as primary care providers. With some delay, mothers eventually visited a health facility when convulsions were part of the illness, despite pressures against this. Although vomiting and failure to eat/suck/drink were associated with malaria, they were not considered as indicators of danger signs unless combined with another more severe symptom. Study communities were familiar with rectal application of medicines. Communities' recognition and awareness of major symptoms of severe malaria could encourage action, but perceptions of their causes and poor discrimination of other danger signs - vomiting and failure to feed - might impede early treatment. An effective health education targeting parents/guardians, decision-makers/advisors, and formal and informal care providers might be a prerequisite for successful introduction of rectal artemisinins as an emergency treatment. Role of traditional healers in delivering such medication to the community should be explored.


Obesity and cancer risk: recent review and evidence.
The prevalence of overweight and obesity is increasing worldwide, and the evidence base for a link between obesity and cancer is growing. In the United States, approximately 85,000 new cancer cases per year are related to obesity. Recent research has found that as the body mass index increases by 5 kg/m2, cancer mortality increases by 10%. Additionally, studies of patients who have had bariatric surgery for weight loss report reductions in cancer incidence and mortality, particularly for women. The goal of this review is to provide an update of recent research, with a focus on epidemiologic studies on the link between obesity and cancer. In addition, we will briefly review hypothesized mechanisms underlying the relationship between obesity and cancer. High priorities for future research involve additional work on the underlying mechanisms, and trials to examine the effect of lifestyle behavior change and weight loss interventions on cancer and intermediate biomarkers.


Toward whole-brain in vivo optoacoustic angiography of rodents: modeling and experimental observations.
Cerebrovascular imaging of rodents is one of the trending applications of optoacoustics aimed at studying brain activity and pathology. Imaging of deep brain structures is often hindered by sub-optimal arrangement of the light delivery and acoustic detection systems. In our work we revisit the physics behind opto-acoustic signal generation for theoretical evaluation of optimal laser wavelengths to perform cerebrovascular optoacoustic angiography of rodents beyond the penetration barriers imposed by light diffusion in highly scattering and absorbing brain tissues. A comprehensive model based on diffusion approximation was developed to simulate optoacoustic signal generation using optical and acoustic parameters closely mimicking a typical murine brain. The model revealed three characteristic wavelength ranges in the visible and near-infrared spectra optimally suited for imaging cerebral vasculature of different size and depth. The theoretical conclusions are confirmed by numerical simulations while in vivo imaging experiments further validated the ability to accurately resolve brain vasculature at depths ranging between 0.7 and 7 mm.


Evolving concepts in biofilm infections.
Several pathogens associated with chronic infections, including Pseudomonas aeruginosa in cystic fibrosis pneumonia, Haemophilus influenzae and Streptococcus pneumoniae in chronic otitis media, Staphylococcus aureus in chronic rhinosinusitis and enteropathogenic Escherichia coli in recurrent urinary tract infections, are linked to biofilm formation. Biofilms are usually defined as surface-associated microbial communities, surrounded by an extracellular polymeric substance (EPS) matrix. Biofilm formation has been demonstrated for numerous pathogens and is clearly an important microbial survival strategy. However, outside of dental plaques, fewer reports have investigated biofilm development in clinical samples. Typically biofilms are found in chronic diseases that resist host immune responses and antibiotic treatment and these characteristics are often cited for the ability of bacteria to persist in vivo. This review examines some recent attempts to examine the biofilm phenotype in vivo and discusses the challenges and implications for defining a biofilm phenotype.


Simultaneous Scanning Ion Conductance Microscopy and Atomic Force Microscopy with Microchanneled Cantilevers.
We combined scanning ion conductance microscopy (SICM) and atomic force microscopy (AFM) into a single tool using AFM cantilevers with an embedded microchannel flowing into the nanosized aperture at the apex of the hollow pyramid. An electrode was positioned in the AFM fluidic circuit connected to a second electrode in the bath. We could thus simultaneously measure the ionic current and the cantilever bending (in optical beam deflection mode). First, we quantitatively compared the SICM and AFM contact points on the approach curves. Second, we estimated where the probe in SICM mode touches the sample during scanning on a calibration grid and applied the finding to image a network of neurites on a Petri dish. Finally, we assessed the feasibility of a double controller using both the ionic current and the deflection as input signals of the piezofeedback. The experimental data were rationalized in the framework of finite elements simulations.


Roguing with replacement in perennial crops: conditions for successful disease management.
Replacement of diseased plants with healthy plants is commonly used to manage spread of plant pathogens in perennial cropping systems. This strategy has two potential benefits. First, removing infected plants may slow pathogen spread by eliminating inoculum sources. Second, replacing infected plants with uninfected plants may offset yield losses due to disease. The extent to which these benefits are realized depends on multiple factors. In this study, sensitivity analyses of two spatially explicit simulation models were used to evaluate how assumptions concerning implementation of a plant replacement program and pathogen spread interact to affect disease suppression. In conjunction, effects of assumptions concerning yield loss associated with disease and rates of plant maturity on yields were simultaneously evaluated. The first model was used to evaluate effects of plant replacement on pathogen spread and yield on a single farm, consisting of a perennial crop monoculture. The second model evaluated effects of plant replacement on pathogen spread and yield in a 100 farm crop growing region, with all farms maintaining a monoculture of the same perennial crop. Results indicated that efficient replacement of infected plants combined with a high degree of compliance among farms effectively slowed pathogen spread, resulting in replacement of few plants and high yields. In contrast, inefficient replacement of infected plants or limited compliance among farms failed to slow pathogen spread, resulting in replacement of large numbers of plants (on farms practicing replacement) with little yield benefit. Replacement of infected plants always increased yields relative to simulations without plant replacement provided that infected plants produced no useable yield. However, if infected plants produced useable yields, inefficient removal of infected plants resulted in lower yields relative to simulations without plant replacement for perennial crops with long maturation periods in some cases.


Mixed modelling to characterize genotype-phenotype associations.
We propose using mixed effects models to characterize the association between multiple gene polymorphisms, environmental factors and measures of disease progression. Characterizing high-order gene-gene and gene-environment interactions presents an analytic challenge due to the large number of candidate genes and the complex, undescribed interactions among them. Several approaches have been proposed recently to reduce the number of candidate genes and post hoc approaches to identify gene-gene interactions are described. However, these approaches may be inadequate for identifying high-order interactions in the absence of main effects and generally do not permit us to control for potential confounders. We describe how mixed effects models and related testing procedures overcome these limitations and apply this approach to data from a cohort of subjects at risk for cardiovascular disease. Four (4) genetic polymorphisms in three genes of the same gene family are considered. The proposed modelling approach allows us first to test whether there is a significant genetic contribution to the variability observed in our disease outcome. This contribution may be through main effects of multi-locus genotypes or through an interaction between genotype and environmental factors. This approach also enables us to identify specific multi-locus genotypes that interact with environmental factors in predicting the outcome. Mixed effects models provide a flexible statistical framework for controlling for potential confounders and identifying interactions among multiple genes and environmental factors that explain the variability in measures of disease progression.


Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.
OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.


Morphology control in self-assembled monolayers written by dip pen nanolithography.
Here, we describe the effect of writing speed in dip pen nanolithography on the morphology (height and density) of self-assembled monolayers of alkanethiols on gold surfaces. The analysis of atomic force microscopy images of written monolayers shows that molecules assemble according to a nucleation and growth mechanism. Slow writing speeds lead to dense monolayers that can be used either to direct the self-assembly of metal nanoparticles or as masks for selective etching of conductive gold nanowires.


Chemokine gene expression during allograft rejection: comparison of two quantitative PCR techniques.
The ability to analyse expression of genes rapidly in small samples of tissue is essential for the clinical assessment of many conditions, including the onset of rejection after transplantation. Chemokines have been shown to play a critical role in leukocyte recruitment to transplanted organs and in leukocyte localisation within tissues and antagonism of certain chemokines or chemokine receptors, identified as being up-regulated during allograft rejection, it has been shown to delay leukocyte infiltration into the graft and to prolong graft survival. The analysis of chemokine and chemokine receptor expression in allografts after transplantation may therefore be a useful early indicator of the onset of rejection. RT-PCR techniques are the most sensitive for the detection of low abundance mRNA when the amount of tissue sample is limited. Here we compared competitive-quantitative RT-PCR (CQ-PCR) with real-time PCR for the sequential quantification of chemokine transcripts after transplantation of a fully MHC mismatched mouse cardiac allograft. Although CQ-PCR was found to be an accurate and sensitive technique, real-time PCR was more sensitive and reproducible. Despite the reproducibility, differences in sensitivity between the two techniques were high. Real-time PCR avoids hazardous post-PCR manipulations thereby decreasing the potential risk of sample contamination, and offers the advantage that several genes can be analysed from small tissue samples in a shorter period of time, a key parameter for graft biopsy samples. Real-time PCR was therefore used to extend the analysis of intragraft mRNA chemokine expression levels. Expression of CXCL5 and CCL2 was found to be independent of T cell infiltration while intragraft expression of CCL3, CCL4, CCL5, CXCL9, CXCL10, XCL1 and CCL1 was clearly T cell dependent and increased significantly with time after transplantation. Overall, real-time PCR analysis showed that chemokine gene expression during rejection is clearly distinct from that in non-rejecting syngeneic grafts and is altered by the onset of infiltration of alloantigen-reactive T cells into the graft.


Fast Pathogen Identification Using Single-Cell Matrix-Assisted Laser Desorption/Ionization-Aerosol Time-of-Flight Mass Spectrometry Data and Deep Learning Methods.
In diagnostics of infectious diseases, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) can be applied for the identification of pathogenic microorganisms. However, to achieve a trustworthy identification from MALDI-TOF MS data, a significant amount of biomass should be considered. The bacterial load that potentially occurs in a sample is therefore routinely amplified by culturing, which is a time-consuming procedure. In this paper, we show that culturing can be avoided by conducting MALDI-TOF MS on individual bacterial cells. This results in a more rapid identification of species with an acceptable accuracy. We propose a deep learning architecture to analyze the data and compare its performance with traditional supervised machine learning algorithms. We illustrate our workflow on a large data set that contains bacterial species related to urinary tract infections. Overall we obtain accuracies up to 85% in discriminating five different species.


Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease.
Coronary-artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are alternative methods of revascularization in patients with coronary artery disease. We tested the hypothesis that in selected patients with multivessel disease suitable for treatment with either procedure, an initial strategy of PTCA does not result in a poorer five-year clinical outcome than CABG. Patients with multivessel disease were randomly assigned to an initial treatment strategy of CABG (n = 914) or PTCA (n = 915) and were followed for an average of 5.4 years. Analysis of outcome events was performed according to the intention to treat. The respective in-hospital event rates for CABG and PTCA were 1.3 percent and 1.1 percent for mortality, 4.6 percent and 2.1 percent for Q-wave myocardial infarction (P < 0.01), and 0.8 percent and 0.2 percent for stroke. The five-year survival rate was 89.3 percent for those assigned to CABG and 86.3 percent for those assigned to PTCA (P = 0.19; 95 percent confidence interval of the difference in survival, -0.2 percent to 6.0 percent). The respective five-year survival rates free from Q-wave myocardial infarction were 80.4 percent and 78.7 percent. By five years after study entry, 8 percent of the patients assigned to CABG had undergone additional revascularization procedures, as compared with 54 percent of those assigned to PTCA; 69 percent of those assigned to PTCA did not subsequently undergo CABG. Among diabetic patients who were being treated with insulin or oral hypoglycemic agents at base line, a subgroup not specified by the protocol, five-year survival was 80.6 percent for the CABG group as compared with 65.5 percent for the PTCA group (P = 0.003). As compared with CABG, an initial strategy of PTCA did not significantly compromise five-year survival in patients with multivessel disease, although subsequent revascularization was required more often with this strategy. For treated diabetics, five-year survival was significantly better after CABG than after PTCA.


Pharmacokinetics after subcutaneous administration of a single dose of cefovecin sodium in African lions (Panthera leo).
OBJECTIVE To determine the pharmacokinetics of cefovecin sodium after SC administration of a single dose to African lions (Panthera leo). ANIMALS 3 adult (9 to 10 years old; 1 male and 2 females) and 3 juvenile (2 years old; 1 male and 2 females) African lions. PROCEDURES A crossover study was conducted. A single dose of cefovecin was administered SC at 4 mg/kg (half dose) and 8 mg/kg (full dose) to African lions. Blood samples were collected daily for 14 days after cefovecin injection. Plasma drug concentrations were determined by use of high-performance liquid chromatography with UV detection. RESULTS Cefovecin had first-order elimination kinetics for doses of 4 and 8 mg/kg. Mean ± SD maximum plasma concentration was 9.73 ± 1.01 μg/mL and 18.35 ± 0.94 μg/mL after doses of 4 and 8 mg/kg, respectively. Time to maximum plasma concentration was approximately 4 hours for both doses. Mean elimination half-life was approximately 111 and 115 hours after doses of 4 and 8 mg/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Cefovecin was detected in lion plasma for 336 hours after administration at both 4 and 8 mg/kg at concentrations greater than the reported minimum inhibitory concentration (0.06 μg/mL) for common bacterial organisms in domestic cats. These results indicated that cefovecin administered at 4 mg/kg SC reached therapeutic concentrations for an extended period in African lions.


Cancer incidence in eighteen cities of the State of São Paulo, Brazil.
As in Brazil cancer registries are mostly based on large cities, there are no estimates per state or per region and information on the disease incidence in the vast in-land areas is very scarce. An incidence survey was conducted in 18 major cities of the state of São Paulo, excluding the capital, aiming to collect information about cancer incidence in the state of São Paulo. Of the 18 cities in state of São Paulo included in the survey, all had available resources for cancer management. Data from the year of 1991 were collected by the personnel of the Instituto Brasileiro de Geografia e Estatística (Brazilian Institute of Statistics), who were especially trained by the study coordinators at the Fundação Oncocentro de São Paulo (Cancer Center of São Paulo). The collected data were processed and analyzed at the Oncocentro. Data collection, processing, and analyses were performed according to the recommendations of the International Agency for Research on Cancer. Although some discrepancies were observed in cancer incidence rates between the cities, results obtained for all 18 cities combined were remarkably close to those recently found for the city of São Paulo in the year 1993. One remarkable finding was the relatively high cancer incidence rates in both sexes in the city of Santos. The very similar all-sites cancer incidence rates found in the year 1991, when compared to those for the city of São Paulo in the year 1993, are suggestive that all regions have common cancer-related factors. Nevertheless, other explanations, such as the inclusion in the study of prevalent cases, as well as of non-residents, may have occurred in both studies, biasing the results. There is a need of further studies to confirm the high cancer incidence in Santos.


Organogenesis of Ileal Peyer's Patches Is Initiated Prenatally and Accelerated Postnatally With Comprehensive Proliferation of B Cells in Pigs.
Morphogenesis and differentiation of organs is required for subsequent functional maturation. The morphological features of Peyer's patches vary among species. In pigs, they develop extensively in the ileum as ileal Peyer's patches (IPPs). However, the role of IPPs in the porcine immune system remains to be elucidated because of a lack of complete understanding of IPP organogenesis. Results of the present study revealed that development of porcine IPPs is initiated prenatally between embryonic days 76 and 91. The process of IPP organogenesis is concomitant with increased transcriptional patterns of CXCL13 and CCL19. IPPs undergo further development postnatally by forming central, marginal, and subepithelial zones. Importantly, a large number of proliferating B cells and apoptotic cells are found in porcine IPPs postnatally, but not prenatally. The expression level of IgM in proliferating B cells depends on the zone in which distinct B cells are separately localized after birth. Specifically, IgM+ cells are predominantly found in the central zone, whereas IgM-/low cells are abundant in the marginal zone. Importantly, the cellular feature of IPPs differs from that of mesenteric lymph nodes (MLNs) where such distinct zones are not formed both prenatally and postnatally. Our findings suggest that IPPs (not MLNs) in postnatal pigs are involved in complementing functions of the primary lymphoid tissue that promotes the differentiation and maturation of B cells.


West Nile virus cluster analysis and vertical transmission in Culex pipiens complex mosquitoes in Sacramento and Yolo Counties, California, 2011.
West Nile virus (WNV) is now endemic in California, with annual transmission documented by the statewide surveillance system. Although much is known about the horizontal avian-mosquito transmission cycle, less is known about vertical transmission under field conditions, which may supplement virus amplification during summer and provide a mechanism to infect overwintering female mosquitoes during fall. The current study identified clusters of WNV-infected mosquitoes in Sacramento and Yolo Counties, CA, during late summer 2011 and tested field-captured ovipositing female mosquitoes and their progeny for WNV RNA to estimate the frequency of vertical transmission. Space-time clustering of WNV-positive Culex pipiens complex pools was detected in the northern Elk Grove area of Sacramento County between July 18 and September 18, 2011 (5.22 km radius; p<0.001 and RR=7.80). Vertical transmission by WNV-infected females to egg rafts was 50% and to larvae was 40%. The estimated minimal filial infection rate from WNV-positive, ovipositing females was 2.0 infected females/1,000. The potential contribution of vertical transmission to WNV maintenance and amplification are discussed.


Evaluation of Listeria monocytogenes survival in ice cream mixes flavored with herbal tea using Taguchi method.
In this study, the effects of the incorporation of some herbal teas at different concentrations into the ice cream mix on the population of Listeria monocytogenes were studied using Taguchi method. The ice cream mix samples flavored with herbal teas were prepared using green tea and sage at different concentrations. Afterward, fresh culture of L. monocytogenes was inoculated into the samples and the L. monocytogenes was counted at different storage periods. Taguchi method was used for experimental design and analysis. In addition, some physicochemical properties of samples were examined. Results suggested that there was some effect, although little, on the population of L. monocytogenes when herbal tea was incorporated into the ice cream mix. Additionally, the use of herbal tea caused a decrease in the pH values of the samples and significant changes in the color values.


Kidney disease trials for the 21st century: innovations in design and conduct.
Compared to other specialties, nephrology has reported relatively few clinical trials, and most of these are too small to detect moderate treatment effects. Consequently, interventions that are commonly used by nephrologists have not been adequately tested and some may be ineffective or harmful. More randomized trials are urgently needed to address important clinical questions in patients with kidney disease. The use of robust surrogate markers may accelerate early-phase drug development. However, scientific innovations in trial conduct developed by other specialties should also be adopted to improve trial quality and enable more, larger trials in kidney disease to be completed in the current era of burdensome regulation and escalating research costs. Examples of such innovations include utilizing routinely collected health-care data and disease-specific registries to identify and invite potential trial participants, and for long-term follow-up; use of prescreening to facilitate rapid recruitment of participants; use of pre-randomization run-in periods to improve participant adherence and assess responses to study interventions prior to randomization; and appropriate use of statistics to monitor studies and analyse their results. Nephrology is well positioned to harness such innovations due to its advanced use of electronic health-care records and the development of disease-specific registries. Adopting a population approach and efficient trial conduct along with challenging unscientific regulation may increase the number of definitive clinical trials in nephrology and improve the care of current and future patients.


Effect of acidic environment on the push-out bond strength of calcium-enriched mixture cement.
This laboratory study was performed to evaluate the effect of different acidic pH values on the push-out bond strength of calcium-enriched mixture (CEM) cement. Forty-eight root dentin slices were obtained from freshly extracted single rooted human teeth and their lumen were instrumented to achieve a diameter of 1.3 mm. Then, CEM cement was mixed according to manufacturers' instruction and placed in the lumens with minimal pressure. The specimens were randomly divided into four groups (n=12) which were wrapped in pieces of gauze soaked in either synthetic tissue fluid (STF) (pH=7.4) or butyric acid which was buffered at pH values of 4.4, 5.4 and 6.4. They were then incubated for 4 days at 37°C. The push-out test was performed by means of the universal testing machine. Specimens were then examined under a digital light microscope at 20× magnification to determine the nature of the bond failure. The data were analyzed using the Kruskal-Wallis test followed by Dunn's test for pairwise comparisons. The highest push-out bond strength (10.19±4.39) was seen in the pH level of 6.4, which was significantly different from the other groups (P<0.05). The values decreased to 2.42±2.25 MPa after exposure to pH value of 4.4. Lower pH value of highly acidic environments (pH=4.4), adversely affects the force needed for displacement of CEM cement; while in higher pH values (pH=6.4) the bond-strength was not affected. CEM cement is recommended in clinical situations where exposure to acidic environment is unavoidable.


Performance and diagnostic usefulness of commercially available enzyme linked immunosorbent assay and rapid kits for detection of HIV, HBV and HCV in India.
HIV, HBV and HCV pose a major public health problem throughout the world. Detection of infection markers for these agents is a major challenge for testing laboratories in a resource poor setting. As blood transfusion is an important activity saving millions of live every year, it also carries a risk of transfusion transmissible infections caused by these fatal blood borne pathogens if the quality of testing is compromised. Conventional ELISA is regarded as the mostly used screening technique but due to limitations like high cost, unavailability in many blood banks and testing sites, involvement of costly instruments, time taking nature and requirement of highly skilled personnel for interpretation, rapid tests are gaining more importance and warrants comparison of performance. A comparative study between these two techniques has been performed using commercially available diagnostic kits to assess their efficacy for detection of HIV, HBV and HCV infections. Rapid kits were more efficient in specificity with synthetic antigens along with high PPV than ELISA in most cases. Comparison between different ELISA kits revealed that Microlisa HIV and Hepalisa (J. Mitra & Co. Pvt. Ltd.); ERBA LISA HIV1 + 2, ERBA LISA Hepatitis B and ERBA LISA HCV (Transasia Bio-medicals Ltd.) gives uniform result with good performance in terms of sensitivity, specificity, PPV, NPV and efficiency, whereas, Microlisa HCV (J. Mitra & Co. Pvt. Ltd.), Microscreen HBsAg ELISA and INNOVA HCV (Span Diagnostics Ltd.) did not perform well. Rapid kits were also having high degree of sensitivity and specificity (100%) except in HIV Comb and HCV Comb (J. Mitra & Co. Pvt. Ltd.). The kit efficiency didn't vary significantly among different companies and lots in all the cases except for HCV ELISA showing statistically significant variation (p < 0.01) among three kit types. ELISA is a good screening assay for markers of HIV, HBV and HCV infections. Rapid tests are useful for further detection of false positive samples. ELISA seems the appropriate assay in blood bank. For availability of quality commercial diagnostic assays, evaluation of kit may be helpful.


Gradiate: A radial sweep approach to measuring detailed contrast sensitivity functions from eye movements.
The contrast sensitivity function (CSF) is an informative measure of visual health, but the practical difficulty of measuring it has impeded detailed analyses of its relationship to different visual disorders. Furthermore, most existing tasks cannot be used in populations with cognitive impairment. We analyzed detailed CSFs measured with a nonverbal procedure called "Gradiate," which efficiently infers visibility from eye movements and manipulates stimulus appearance in real time. Sixty observers of varying age (38 with refractive error) were presented with moving stimuli. Stimulus spatial frequency and contrast advanced along 15 radial sweeps through CSF space in response to stimulus-congruent eye movements. A point on the CSF was recorded when tracking ceased. Gradiate CSFs were reliable and in high agreement with independent low-contrast acuity thresholds. Overall CSF variation was largely captured by two orthogonal factors ("radius" and "slope") or two orthogonal shape factors when size was normalized ("aspect ratio" and "curvature"). CSF radius was highly predictive of LogMAR acuity, as were aspect ratio and curvature together, but only radius was predictive of observer age. Our findings suggest that Gradiate holds promise for assessing spatial vision in both verbal and nonverbal populations and indicate that variation between detailed CSFs can reveal useful information about visual health.


Oncolytic Viruses: Treatment and Implications for Patients With Gliomas .
Oncolytic viral therapies are increasingly being explored for the treatment of diverse cancer types, most notably melanoma. However, advances in the treatment of high-grade gliomas, and specifically glioblastoma multiforme (GBM), are the result of novel oncolytic viral therapies. Delta-24-RGD is one such therapy that has demonstrated promising results in phase 1 trials. . The objective of this article is to provide an overview of Delta-24-RGD, highlighting considerations for nurses in diverse clinical, research, and advanced practice roles. . A high-level overview of the pathophysiology of the Delta-24-RGD virus as it relates to GBM is presented. A case study is used to illustrate the course of care for a patient receiving this therapy. . Delta-24-RGD has demonstrated remarkable clinical efficacy in the near to complete regression of GBM activity. Nurses may increasingly be caring for patients who are undergoing such therapy or have received it in the past. Understanding the mechanism of action, safe-handling implications, and expected patient care needs and treatment sequelae is important.


The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program.
The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc), aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of Cancer™ in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D.C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational cancer immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website.


Could Hyperbaric Oxygen Be a Solution in the Treatment of Spinal Infections?
Background and Objective: Pyogenic spinal infections are rare and potentially devastating, requiring prompt recognition and management. Parallel to the ever-increasing number of invasive spinal procedures, its incidence is on a steady rise, particularly in an expanding elderly population. The aim of this study was to evaluate the efficacy of hyperbaric oxygen (HBO2) therapy in the treatment of this heterogeneous group of disorders. Materials and Methods: Nineteen patients who were referred to our center for HBO2 with a clinical diagnosis of spinal infections (vertebral osteomyelitis, pyogenic spondylitis, spondylodiscitis, surgical site infection following spine surgery, epidural abscess) were retrospectively reviewed. Results: Infection resolution was adequately achieved in 12 of 13 patients (92.3%) on magnetic resonance imaging at the end of HBO2 treatment or during the first month of follow-up. The mean follow-up period was 11 months (range 1 month to 3 years). Conclusions: This study suggests that HBO2 therapy is efficacious in patients with pyogenic spinal infections complicated by primary therapy failure or by medical comorbidities that may impede the eradication of microbial infection and delay wound healing. HBO2 therapy may be useful for reducing long hospital stays, repeated surgeries, and morbidities.


Mental retardation and prenatal methylmercury toxicity.
Methylmercury (MeHg) is a developmental neurotoxicant; exposure results principally from consumption of seafood contaminated by mercury (Hg). In this analysis, the burden of mental retardation (MR) associated with methylmercury exposure in the 2000 U.S. birth cohort is estimated, and the portion of this burden attributable to mercury (Hg) emissions from coal-fired power plants is identified. The aggregate loss in cognition associated with MeHg exposure in the 2000 U.S. birth cohort was estimated using two previously published dose-response models that relate increases in cord blood Hg concentrations with decrements in IQ. MeHg exposure was assumed not to be correlated with native cognitive ability. Previously published estimates were used to estimate economic costs of MR caused by MeHg. Downward shifts in IQ resulting from prenatal exposure to MeHg of anthropogenic origin are associated with 1,566 excess cases of MR annually (range: 376-14,293). This represents 3.2% of MR cases in the US (range: 0.8%-29.2%). The MR costs associated with decreases in IQ in these children amount to $2.0 billion/year (range: $0.5-17.9 billion). Hg from American power plants accounts for 231 of the excess MR cases/year (range: 28-2,109), or 0.5% (range: 0.06%-4.3%) of all MR. These cases cost $289 million (range: $35 million-2.6 billion). Toxic injury to the fetal brain caused by Hg emitted from coal-fired power plants exacts a significant human and economic toll on American children.


Skin Preparation and Electrode Replacement to Reduce Alarm Fatigue in a Community Hospital Intensive Care Unit.
Nurses in intensive care units are exposed to hundreds of alarms during a shift, and research shows that most alarms are not clinically relevant. Alarm fatigue can occur when a nurse becomes desensitized to alarms. Alarm fatigue can jeopardize patient safety, and adverse alarm events can lead to patients dying. To evaluate how a process intervention affects the number of alarms during an 8-hour shift in an intensive care unit. A total of 62 patients from an intensive care unit were included in the study; 32 of these patients received the intervention, which included washing the patient's chest with soap and water and applying new electrocardiography electrodes at the start of a shift. The number of alarms, clinical diagnoses, and demographic variables were collected for each patient. A Poisson regression model was used to evaluate the impact of the intervention on the overall number of clinical alarms during the shift, with no adjustments to the alarm settings or other interventions. After relevant covariates are controlled for, the results suggest that patients in the intervention group presented significantly fewer alarms than did patients in the control group. Managing clinical alarms is a main issue in terms of both patient safety and staff workload management. The results of this study demonstrate that a relatively simple process-oriented strategy can decrease the number of alarms.


Effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females.
Cranberries have been shown to produce urinary metabolites that influence uropathogen adhesion and prevent urinary tract infections. This study was designed to determine if consuming reconstituted, unsweetened cranberry drink from extract retained its bioactive properties by reducing uropathogen adhesion without adversely affecting urinary calcium, magnesium and the vaginal microflora. A randomized crossover study was undertaken in 12 healthy women consuming reconstituted unsweetened cranberry drink, CranActin or water. The urine was collected at 4 hours and 1 week of consumption and evaluated for antiadhesive properties and urinary pH, calcium and magnesium. Vaginal swabs were collected after 1 week of treatment to assess the vaginal microbiota by DGGE. The resultant urine produced by subjects who consumed 500 ml reconstituted cranberry extract twice per day, significantly reduced the adherence to epithelial cells of P-fimbriated uropathogenic Escherichia coli and showed a tendency towards significance for two E. coli strains expressing fimbriae and an Enterococcus faecalis isolate. The cranberry drink treatment did not alter urinary pH, but reduced calcium and magnesium concentrations compared to water, although not to statistical significance. The reconstituted cranberry drink had no apparent detrimental effect on the vaginal microbiota. However, consuming twice daily resulted in an apparent loss of a potential pathogen from the vagina in 42% subjects. The present findings suggest that reconstituted cranberry drink may retain the ability to reduce the risk of UTI by inhibiting pathogen adhesion while not detrimentally affecting urinary pH or vaginal microbiota, or the risk of calculi.


Engineering of high yield production of L-serine in Escherichia coli.
L-serine is a widely used amino acid that has been proposed as a potential building block biochemical. The high theoretical yield from glucose makes a fermentation based production attractive. In order to achieve this goal, serine degradation to pyruvate and glycine in E. coli MG1655 was prevented by deletion of three L-serine deaminases sdaA, sdaB, and tdcG, as well as serine hydroxyl methyl transferase (SHMT) encoded by glyA. Upon overexpression of the serine production pathway, consisting of a feedback resistant version of serA along with serB and serC, this quadruple deletion strain showed a very high serine production yield (0.45 g/g glucose) during small-scale batch fermentation in minimal medium. Serine, however, was found to be highly toxic even at low concentrations to this strain, which lead to slow growth and production during fed batch fermentation, resulting in a serine production of 8.3 g/L. The production strain was therefore evolved by random mutagenesis to achieve increased tolerance towards serine. Additionally, overexpression of eamA, a cysteine/homoserine transporter was demonstrated to increase serine tolerance from 1.6 g/L to 25 g/L. During fed batch fermentation, the resulting strain lead to the serine production titer of 11.7 g/L with yield of 0.43 g/g glucose, which is the highest yield reported so far for any organism.


Bacterial and viral infections and related inflammatory responses in chronic obstructive pulmonary disease.
In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline. KEY MESSAGE Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients. The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung. The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.


Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome.
Laryngeal mask airway (LMA) administration is one way of delivering surfactant to the infant lung, with the potential benefit of avoiding endotracheal intubation and ventilation, ventilator induced lung injury and bronchopulmonary dysplasia (BPD). To determine the effect of LMA surfactant administration either as prophylaxis or treatment compared to placebo, no treatment, or intratracheal surfactant administration on morbidity and mortality in preterm infants with, or at risk of, respiratory distress syndrome (RDS). We searched CENTRAL (The Cochrane Library, October 2010), MEDLINE and PREMEDLINE (1950 to October 2010), EMBASE (1980 to October 2010) and CINAHL (1982 to October 2010). We also searched proceedings of scientific meetings, clinical trial registries, Google Scholar and reference lists of identified studies, as well as contacting expert informants and surfactant manufacturers. Randomised, cluster-randomised or quasi-randomised controlled trials of laryngeal mask surfactant administration compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. Two review authors independently assessed studies for eligibility and quality, and extracted data. We found no studies of prophylactic or early LMA surfactant administration. A single small study of late rescue LMA surfactant was identified as eligible for inclusion. The study enrolled 26 preterm infants born ≥ 1200 g with RDS on continuous positive airway pressure (nCPAP). LMA surfactant administration compared to no treatment resulted in a reduction in mean FiO(2) required to maintain oxygen saturation between 88% and 92% for 12 hours after the intervention. No significant difference was reported in subsequent mechanical ventilation and endotracheal surfactant, pneumothorax, days on intermittent positive airway pressure (IPPV), and days on IPPV or oxygen. There is evidence from a single small trial that LMA surfactant administration in preterm infants ≥ 1200 g with established RDS may have a short term effect in reducing oxygen requirements although the study is underpowered to detect important clinical effects. Adequately powered trials are required to determine the effect of LMA surfactant administration for prevention or treatment of RDS in preterm infants. LMA surfactant administration should be limited to clinical trials.


Clonality and recombination in genetically differentiated subgroups of Cryptococcus gattii.
Cryptococcus gattii is a pathogenic yeast that together with Cryptococcus neoformans causes cryptococcosis in humans and animals. High numbers of viable C. gattii propagules can be obtained from certain species of Australian Eucalyptus camaldulensis trees, and an epidemiological link between Eucalyptus colonization and human exposure has been proposed. However, the highest prevalence of C. gattii cryptococcosis occurs in Papua New Guinea and in regions of Australia where the eucalypt species implicated to date are not endemic. This study investigated the population structure of three geographically distinct clinical and veterinary populations of C. gattii from Australia and Papua New Guinea. All populations that consisted of a genotype found frequently in Australia (VGI) were strongly clonal and were highly differentiated from one another. Two populations of the less common VGII genotype from Sydney and the Northern Territory had population structures inferring recombination. In addition, there was some evidence of reduced genetic differentiation between these geographically remote regions. In a companion study presented in this issue, VGII isolates were overwhelmingly more fertile than those of the VGI genotype, giving biological support to the indirect assessment of sexual exchange. It appears that the VGI genotype propagates clonally on eucalypts in Australia and on an unknown substrate in Papua New Guinea, with infection initiated by an unidentified infectious propagule. VGII isolates are completing their life cycles and may be dispersed via sexually produced basidiospores, which are also likely to initiate respiratory infection.


Preventing child mental health problems in southeastern Europe: Feasibility study (phase 1 of MOST framework).
The prevalence of child emotional and behavioral problems is an international problem but is higher in low- and middle-income countries (LMIC) where there are often less mental health supports for families. Parenting programs can be an effective means of prevention, but must be low-cost, scalable, and suitable for the local context. The RISE project aims to systematically adapt, implement, and evaluate a low-cost parenting program for preventing/reducing child mental health problems in three middle-income countries in Southeastern Europe. This small pre-post pilot study is informed by the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework and tested the feasibility of the intervention, the implementation, and evaluation procedures: Phase 1 of the three-phase Multiphase Optimization Strategy (MOST) for program adaptation. Local facilitators delivered the Parenting for Lifelong Health (PLH) for Young Children program to parents of children aged 2-9 in North Macedonia, the Republic of Moldova and Romania in 2018. Parents completed assessments pre- and post-program. Results demonstrated positive pre-post change for participating families (N = 140) on various outcomes including child externalizing and internalizing symptoms and parenting behavior, in all three countries, all in the expected direction. Program participation was associated with positive outcomes in participating families. Based on the experiences of this pilot study, we outline the practical implications for the successful implementation of parenting programs in the three countries that will inform our next study phases, factorial experiment, and RCT.


Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population.
We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR.


Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function.
Physiological role of creatine (Cr) became first evident in the experiments of Belitzer and Tsybakova in 1939, who showed that oxygen consumption in a well-washed skeletal muscle homogenate increases strongly in the presence of creatine and with this results in phosphocreatine (PCr) production with PCr/O(2) ratio of about 5-6. This was the beginning of quantitative analysis in bioenergetics. It was also observed in many physiological experiments that the contractile force changes in parallel with the alteration in the PCr content. On the other hand, it was shown that when heart function is governed by Frank-Starling law, work performance and oxygen consumption rate increase in parallel without any changes in PCr and ATP tissue contents (metabolic homeostasis). Studies of cellular mechanisms of all these important phenomena helped in shaping new approach to bioenergetics, Molecular System Bioenergetics, a part of Systems Biology. This approach takes into consideration intracellular interactions that lead to novel mechanisms of regulation of energy fluxes. In particular, interactions between mitochondria and cytoskeleton resulting in selective restriction of permeability of outer mitochondrial membrane anion channel (VDAC) for adenine nucleotides and thus their recycling in mitochondria coupled to effective synthesis of PCr by mitochondrial creatine kinase, MtCK. Therefore, Cr concentration and the PCr/Cr ratio became important kinetic parameters in the regulation of respiration and energy fluxes in muscle cells. Decrease in the intracellular contents of Cr and PCr results in a hypodynamic state of muscle and muscle pathology. Many experimental studies have revealed that PCr may play two important roles in the regulation of muscle energetics: first by maintaining local ATP pools via compartmentalized creatine kinase reactions, and secondly by stabilizing cellular membranes due to electrostatic interactions with phospholipids. The second mechanism decreases the production of lysophosphoglycerides in hypoxic heart, protects the cardiac cells sarcolemma against ischemic damage, decreases the frequency of arrhythmias and increases the post-ischemic recovery of contractile function. PCr is used as a pharmacological product Neoton in cardiac surgery as one of the components of cardioplegic solutions for protection of the heart against intraoperational injury and injected intravenously in acute myocardial ischemic conditions for improving the hemodynamic response and clinical conditions of patients with heart failure.


The correlation between ultrasonographic findings and pathologic features in breast disorders.
Breast ultrasonography has gained widespread acceptance as a diagnostic tool for the evaluation of human breast disorders. It is important to evaluate the correlation of ultrasonography findings with the corresponding histopathological features. We retrospectively reviewed the 154 cases of breast disorders. We evaluated the correlation the ultrasonography findings and carcinoma cells extension with their corresponding histopathological findings. In addition, we also studied the information on estimation of histological types and cancer extension used by the other modalities such as computed tomography and magnetic resonance imaging. The concordance rate for margins between ultrasonography findings and histopathological features was 91.6% (P < 0.001) and that for boundary zone was 87.0% (P < 0.001). Histopathological correlation of internal and posterior echoes demonstrated that internal low echo masses were composed of fibroblastic cells with marked collagenization in the stroma, or the cases in which carcinoma cells proliferated in a monotonous, solid and/or expanding manners. Attenuation of posterior echo was detected in the cases associated with hyperplasia of collagenized fibroblastic stroma. An increased cellularity in the mass with prominent large tumor nests and little fibrous stroma demonstrated the accentuation or no alterations of the posterior echo. The concordance rate of borders was 84.4% (P < 0.001). The correlation between estimated histological type by ultrasonography diagnosis and actual histological types was 87.0%. An overall detection rate of carcinoma extension by ultrasonography was 86.4%. In addition, an overall detection rate of carcinoma extension by ultrasonography, magnetic resonance imaging and computed tomography was 93.8%. These results demonstrated correlation between histopathological and ultrasonographic findings of the breast lesions is cardinal for quality control or improving the quality of ultrasonography.


Estrogen-dependent variations in 18F-fluorodeoxyglucose uptake in uterine leiomyomas.
Positron emission tomography/computed tomography (PET/CT) is an important tool in oncology for assessment of disease extent and recurrence. Recognition of benign fluorodeoxyglucose (FDG) uptake promotes correct interpretation of imaging data. This study assesses the appearance of benign uterine leiomyomas (ULs) on PET/CT and evaluates possible hormonal influences. This was a retrospective study performed in a tertiary referral cancer center in Israel. One hundred fifty-two women with nongynecologic malignancies were referred for PET/CT scans, with incidental UL on imaging. Information on menopausal status and menstrual phase and on the use of oral contraceptives, hormone replacement therapy, and selective estrogen receptor modulators (SERM) was collected. Fluorodeoxyglucose uptake measured as standard uptake value (SUV) was obtained for UL, normal myometrium, and gluteus muscle. Changes associated with menopausal status, menstrual cycle phase, and the use of oral contraceptives, hormone replacement therapy, and SERM were assessed. The mean ± SD SUV in UL for the entire cohort was 1.39 ± 0.65 and was higher than in myometrium (1.24 ± 0.33) and gluteus muscle (0.48 ± 0.36). Fluorodeoxyglucose uptake was similar in UL and in myometrium during the preovulatory (1.42 ± 0.31 vs. 1.23 ± 0.34) and postovulatory (1.23 ± 0.34 vs. 1.38 ± 0. 4) periods. During ovulation, SUV was significantly higher in UL (1.62 ± 0.39) than in normal myometrium (1.12 ± 0.15; P = 0.01). Uterine leiomyoma FDG uptake in premenopausal women (1.47 ± 0.32) was higher than in postmenopausal women (1.29 ± 0.41; P < 0.02). The UL/gluteus SUV ratio in patients on hormone replacement therapy (2.53 ± 0.23) was significantly higher than in untreated patients (1.27 ± 0.92; P = 0.05). Lower uptake was recorded in patients on SERM (SUV, 1.1 ± 0.24) than in untreated patients (SUV, 1.41 ± 0.36; P < 0.01). Fluorine 18 FDG uptake in UL may be estrogen dependent. Endogenous estrogen and hormone replacement therapy increase FDG uptake, whereas withdrawal of estrogen by menopause or SERM decreases uptake.


Electrophoresis microchip with integrated waveguides for simultaneous native UV fluorescence and absorbance detection.
Simultaneous label-free detection of UV absorbance and native UV-excited fluorescence in an electrophoresis microchip is presented. UV transparent integrated waveguides launch light at a wavelength of 254 nm from a mercury lamp along the length of a 1-mm long detection cell. Transmitted UV light is collected by another waveguide in the opposite end of the detection cell, while visible fluorescence is collected vertically through the lid of the chip. The background of scattered excitation light is suppressed by detection perpendicular to the excitation, the limited UV transparency of the borosilicate lid and by choosing a PMT insensitive to the excitation light. This way, the need for a fluorescence filter is eliminated. Calibration curves were measured for serotonin, tryptophan, propranolol and acetaminophen, and separations of the four compounds were demonstrated by electrophoresis and MEKC. All compounds could be detected in the micromolar range by absorbance detection, but fluorescence detection improved detection limits for compounds displaying native UV fluorescence up to ten times. The simultaneous detection also proved useful for the identification of compounds with similar retention times and even enables accurate quantification of co-eluting compounds.


Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer.
New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0·0149 and 0·0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0·001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.


Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation.
To clarify the mechanisms involved in the critical endoplasmic reticulum (ER) stress initiating unfolded protein response pathway modified by melatonin. Hepatoma cells, HepG2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure HepG2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes' expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis. In the present study, we first identified that melatonin selectively blocked activating transcription factor 6 (ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 siRNA contributed the enhanced HepG2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed. These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis.


Gas confinement in compartmentalized coordination polymers for highly selective sorption.
Discrimination between different gases is an essential aspect for industrial and environmental applications involving sensing and separation. Several classes of porous materials have been used in this context, including zeolites and more recently MOFs. However, to reach high selectivities for the separation of gas mixtures is a challenging task that often requires the understanding of the specific interactions established between the porous framework and the gases. Here we propose an approach to obtain an enhanced selectivity based on the use of compartmentalized coordination polymers, named CCP-1 and CCP-2, which are crystalline materials comprising isolated discrete cavities. These compartmentalized materials are excellent candidates for the selective separation of CO2 from methane and nitrogen. A complete understanding of the sorption process is accomplished with the use of complementary experimental techniques including X-ray diffraction, adsorption studies, inelastic- and quasi-elastic neutron scattering, magnetic measurements and molecular dynamics calculations.


Action of endotoxin on lymphoid cells.
Endotoxin (lipopolysaccharide, LPS) has been found to act on all three cell types of the immune system, thymus-derived (T-) cells, bone marrow-derived (B-) cells, and macrophages. LPS is mitogenic for B-lymphocytes and activates them to release a chemotactic lymphokine. Macrophage activation appears to be mediated by macrophage-activating factor, another lymphokine released from B-cells. In addition, LPS acts synergistically with phytohemagglutinin to initiate division of purified T-lymphocytes. All these phenomena are mediated by the lipid A moiety of LPS. The role of lymphoid cells in mediating the lethal effects of LPS have also been investigated. The adoptive transfer of spleen cells from LPS-responsive mice (C3H/HeN) to LPS-resistant but histocompatible mice (C3H/HeJ) rendered the LPS-resistant mice significantly more susceptible to LPS-induced lethality. These findings suggest that spleen cells play an essential role in mediating the lethal effects of LPS in vivo.


Use of pallidal deep brain stimulation in postinfarct hemidystonia.
Reports of outcomes in treating dystonia secondary to stroke with deep brain stimulation (DBS) are limited. We report our experience with 3 patients, all with infarcts involving the striatum, who developed hemidystonia and were treated with unilateral globus pallidus interna DBS. Case series describing characteristics and outcomes based on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after DBS at 3, 6 and at least 12 months. All patients reported subjective improvements after surgery. At 1 year or more after surgery, none of the 3 patients displayed a measureable improvement in the BFMDRS movement score. Our findings are consistent with previous reports of limited benefits from pallidal DBS in secondary dystonia. Future work should focus on predictive factors for DBS outcomes and the development of more sensitive assessment tools specifically for secondary dystonias as well as the exploration of alternative brain targets for stimulation.


Ibuprofen worsens Streptococcus pyogenes soft tissue infections in mice.
Group A streptococcus (GAS) is a common cause of soft tissue infection. Nonsteroidal anti-inflammatory drugs have been reported to worsen GAS soft tissue infections. A mouse model of GAS soft tissue infection was developed. The extent of cutaneous lesions, tissue damage, release of inflammatory cytokines, and survival rates were compared between mice with and without ibuprofen administration after GAS soft tissue infection. All twelve mice without ibuprofen administration survived for at least 10 days. In contrast, mortality rate of 14 mice with ibuprofen therapy was 72.5%. Ibuprofen-treated mice exhibited more evident macrophage infiltration and tissue damage in the GAS-infected soft tissues. In GAS-infected mice, tissue levels of interleukin 6 and tumor necrosis factor alpha were significantly higher in ibuprofen-treated mice than those in the control group. The results supported the concept that ibuprofen use in GAS soft tissue infections might induce the development of severe necrotizing infections and increase mortality rate.


Chromosomal polymorphism of Rattus rattus (Linnaeus, 1758) (rodentia: muridae) in Central Anatolia.
In this study, conventionally stained, C- and Ag-NOR banded karyotypes of Rattus rattus from Central Anatolia are presented. The karyotype of the specimens from Ankara and (Cankiri provinces consist of 2n = 38, NF = 60 and NFa = 58 while the karyotype of Kirikkale specimens consist of 2n = 38 and NFa = 59 due to a heteromorphic autosome pair. The X is a large to medium sized acrocentric and the Y chromosome is a small acrocentric in all examined specimens. Constitutive heterochromatin is located in the centromeric regions of all pairs of autosomes and the X chromosome. Nucleolar organizer regions (NORs) are located only in 3 autosome pairs.


Feature-oriented multiple description wavelet-based image coding.
We address the problem of resilient image coding over error-prone networks where packet losses occur. Recent literature highlights the multiple description coding (MDC) as a promising approach to solve this problem. In this paper, we introduce a novel wavelet-based multiple description image coder, referred to as the feature-oriented MDC (FO-MDC). The proposed multiple description (MD) coder exploits the statistics of the wavelet coefficients and identifies the subsets of samples that are sensitive to packet loss. A joint optimization between tree-pruning and quantizer selection in the rate-distortion sense is used in order to allocate more bits to these sensitive coefficients. When compared with the state-of-the-art MD scalar quantization coder, the proposed FO-MDC yields a more efficient central-side distortion tradeoff control mechanism. Furthermore, it proves to be more robust for image transmission even with high packet loss ratios, which makes it suitable for protecting multimedia streams over packet-erasure channels.


Sex-specific associations of lipoprotein(a) with presence and quantity of coronary artery calcification in an asymptomatic population.
Lipoprotein(a) (Lp(a)) is a potential risk factor for coronary artery disease (CAD). The relationship between serum Lp(a) and coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, has not been extensively explored. Electron beam computed tomography was performed on 616 asymptomatic, white individuals (285 men) from a community-based study. Mean age was 57.2 years. Serum Lp(a) levels were measured by an immunoturbidimetric assay. Tobit regression was used to determine the sex-specific association of Lp(a) levels with presence and quantity of CAC. In women, Lp(a) was a significant predictor (P=0.0426) of presence and quantity of CAC after adjustment for age, hypertension status, waist circumference, presence of high low-density lipoprotein cholesterol (LDL-C), and history of smoking. In men, after adjusting for age, hypertension status, body mass index, presence of high LDL-C, and history of smoking, a positive interaction between Lp(a) and history of smoking (P=0.0387) was significantly associated with presence and quantity of CAC. Sex-specific relationships between Lp(a) and CAC provide evidence supporting sex-specific risk factor profiling for CAD. In women, Lp(a) alone may be an independent risk factor for coronary atherosclerosis, while in men, Lp(a) may confer higher risk conditional on the presence and level of other risk factors. The role of Lp(a) in the prediction and pathogenesis of subclinical coronary atherosclerosis needs to be further elucidated.


Discovery of a sensory organ that coordinates lunge feeding in rorqual whales.
Top ocean predators have evolved multiple solutions to the challenges of feeding in the water. At the largest scale, rorqual whales (Balaenopteridae) engulf and filter prey-laden water by lunge feeding, a strategy that is unique among vertebrates. Lunge feeding is facilitated by several morphological specializations, including bilaterally separate jaws that loosely articulate with the skull, hyper-expandable throat pleats, or ventral groove blubber, and a rigid y-shaped fibrocartilage structure branching from the chin into the ventral groove blubber. The linkages and functional coordination among these features, however, remain poorly understood. Here we report the discovery of a sensory organ embedded within the fibrous symphysis between the unfused jaws that is present in several rorqual species, at both fetal and adult stages. Vascular and nervous tissue derived from the ancestral, anterior-most tooth socket insert into this organ, which contains connective tissue and papillae suspended in a gel-like matrix. These papillae show the hallmarks of a mechanoreceptor, containing nerves and encapsulated nerve termini. Histological, anatomical and kinematic evidence indicate that this sensory organ responds to both the dynamic rotation of the jaws during mouth opening and closure, and ventral groove blubber expansion through direct mechanical linkage with the y-shaped fibrocartilage structure. Along with vibrissae on the chin, providing tactile prey sensation, this organ provides the necessary input to the brain for coordinating the initiation, modulation and end stages of engulfment, a paradigm that is consistent with unsteady hydrodynamic models and tag data from lunge-feeding rorquals. Despite the antiquity of unfused jaws in baleen whales since the late Oligocene (∼23-28 million years ago), this organ represents an evolutionary novelty for rorquals, based on its absence in all other lineages of extant baleen whales. This innovation has a fundamental role in one of the most extreme feeding methods in aquatic vertebrates, which facilitated the evolution of the largest vertebrates ever.


Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.
Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known. We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age. The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age. In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth.


Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies.
Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.