Effect of potassium citrate supplementation or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal women: a randomized controlled trial.
Alkali provision may explain why fruit and vegetables benefit bone health. We aimed to determine the effects of alkali-providing potassium citrate (double-blind) and fruit and vegetable intake (single-blind) on bone turnover over 2 y. We conducted a randomized placebo-controlled trial in 276 postmenopausal women (aged 55-65 y). Women were randomly assigned to 4 groups: high-dose potassium citrate (55.5 mEq/d), low-dose potassium citrate (18.5 mEq/d), placebo, and 300 g additional fruit and vegetables/d (equivalent of 18.5 mEq alkali). Serum and fasted urine for bone markers were collected at baseline and at 3, 6, 12, 18, and 24 mo. An additional urine sample was collected at 4-6 wk. Bone mineral density (BMD) was measured at baseline and 2 y. Repeated-measures ANOVA showed no difference between groups for urinary free deoxypyridinoline cross-links relative to creatinine (fDPD/Cr), serum N-terminal propeptide of type 1 collagen, or beta C-terminal telopeptide, although, at 4-6 wk, fDPD/Cr was lower in the high-dose potassium citrate group (P = 0.04). Mean +/- SD spine BMD loss in the placebo group (1.8 +/- 3.9%) did not differ significantly from that in the treatment groups (2.1 +/- 3.2%; P = 0.88). Hip BMD loss in the placebo and low-dose potassium citrate groups was 1.3 +/- 2.3% and 2.2 +/- 2.3%, respectively (P = 0.14). Two-year potassium citrate supplementation does not reduce bone turnover or increase BMD in healthy postmenopausal women, which suggests that alkali provision does not explain any long-term benefit of fruit and vegetable intake on bone.


Free Fatty Acids Modulate Thrombin Mediated Fibrin Generation Resulting in Less Stable Clots.
Upon platelet activation, free fatty acids are released at the stage of thrombus formation, but their effects on fibrin formation are largely unexplored. Our objective was to characterize the kinetic effects of fatty acids on thrombin activity, as well as the structural and mechanical properties of the resultant fibrin clots. Thrombin activity on fibrinogen was followed by turbidimetry and detailed kinetic characterization was performed using a fluorogenic short peptide substrate. The viscoelastic properties of fibrin were measured with rotatory oscillation rheometer, whereas its structure was analyzed with scanning electron microscopy (SEM). In turbidimetric assays of fibrin generation, oleate and stearate at physiologically relevant concentrations (60-600 μM) produced a bell-shaped inhibitory dose response, increasing 10- to 30-fold the time to half-maximal clotting. Oleate inhibited thrombin activity on a short peptide substrate according to a mixed-type inhibitor pattern (a 9-fold increase of the Michaelis constant, Km and a 20% decrease of the catalytic constant), whereas stearate resulted in only a minor (15%) drop in the catalytic constant without any change in the Km. Morphometric analysis of SEM images showed a 73% increase in the median fiber diameter in the presence of stearate and a 20% decrease in the presence of oleate. Concerning the viscoelastic parameters of the clots, storage and loss moduli, maximal viscosity and critical shear stress decreased by 32-65% in the presence of oleate or stearate, but loss tangent did not change indicating decreased rigidity, higher deformability and decreased internal resistance to shear stress. Our study provides evidence that free fatty acids (at concentrations comparable to those reported in thrombi) reduce the mechanical stability of fibrin through modulation of thrombin activity and the pattern of fibrin assembly.


Structurally nanocrystalline-electrically single crystalline ZnO-reduced graphene oxide composites.
ZnO, a wide bandgap semiconductor, has attracted much attention due to its multifunctionality, such as transparent conducting oxide, light-emitting diode, photocatalyst, and so on. To improve its performances in the versatile applications, numerous hybrid strategies of ZnO with graphene have been attempted, and various synergistic effects have been achieved in the ZnO-graphene hybrid nanostructures. Here we report extraordinary charge transport behavior in Al-doped ZnO (AZO)-reduced graphene oxide (RGO) nanocomposites. Although the most challenging issue in semiconductor nanocomposites is their low mobilities, the AZO-RGO nanocomposites exhibit single crystal-like Hall mobility despite the large quantity of nanograin boundaries, which hinder the electron transport by the scattering with trapped charges. Because of the significantly weakened grain boundary barrier and the proper band alignment between the AZO and RGO, freely conducting electrons across the nanograin boundaries can be realized in the nanocomposites. This discovery of the structurally nanocrystalline-electrically single crystalline composite demonstrates a new route for enhancing the electrical properties in nanocomposites based on the hybrid strategy.


The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment.
E2F1 is responsible for the regulation of FOXM1 expression, which plays a key role in epirubicin resistance. Here, we examined the role and regulation of E2F1 in response to epirubicin in cancer cells. We first showed that E2F1 plays a key role in promoting FOXM1 expression, cell survival, and epirubicin resistance as its depletion by siRNA attenuated FOXM1 induction and cell viability in response to epirubicin. We also found that the p38-MAPK activity mirrors the expression patterns of E2F1 and FOXM1 in both epirubicin-sensitive and -resistant MCF-7 breast cancer cells, suggesting that p38 has a role in regulating E2F1 expression and epirubicin resistance. Consistently, studies using pharmacologic inhibitors, siRNA knockdown, and knockout mouse embryonic fibroblasts (MEF) revealed that p38 mediates the E2F1 induction by epirubicin and that the induction of E2F1 by p38 is, in turn, mediated through its downstream kinase MK2 [mitogen-activated protein kinase (MAPK)-activated protein kinase 2; MAPKAPK2]. In agreement, in vitro phosphorylation assays showed that MK2 can directly phosphorylate E2F1 at Ser-364. Transfection assays also showed that E2F1 phosphorylation at Ser-364 participates in its induction by epirubicin but also suggests that other phosphorylation events are also involved. In addition, the p38-MK2 axis can also limit c-jun-NH(2)-kinase (JNK) induction by epirubicin and, notably, JNK represses FOXM1 expression. Collectively, these findings underscore the importance of p38-MK2 signaling in the control of E2F1 and FOXM1 expression as well as epirubicin sensitivity.


Understanding uncertainty and minimizing families' anxiety at the time of transfer from intensive care.
When general ward registered nurses (RN) receive patients from an intensive care unit (ICU) they report that much of their time in the initial phases revolves around meeting family needs (Farvis, 2002). Families experience anxiety when leaving the security of the close monitoring seen in ICU (Leith, 1999) and their anxiety reduces their ability to play a key role in the patient's recovery (McShane, 1991; Leske, 1992) as it can impair their decision-making (Cagan, 1988; Halm et al., 1993). By reducing a family's anxiety, they may be more able to cope with the necessary transition to a general ward and support the patient's recovery. A literature search from 1990 onwards was performed within the CINAHL, Medline and Cochrane databases using the key words: intensive care, family, General System Theory, uncertainty, anxiety and transfer. Further articles were retrieved from citation references from the Web of Science or through the reference lists of retrieved literature. Library catalogues were searched using the same key words for books and book chapters. von Bertalanffy's General System Theory provides a framework for understanding the importance of family in a critical illness situation. Critical illness permits little or no time to adapt, thus reducing the family's ability to cope with the situation. Transfer out of ICU is a significant anxiety-producing event for families. Uncertainty in illness is reported in other illness situations to reduce family's adaptation to illness events, but has not been researched with an ICU cohort of families. Seven out of the top 10 needs of ICU families are information needs, highlighting the importance of communication regarding progress and future plans. Nurses require an increased awareness that transfer anxiety exists for families and to be knowledgeable about ways to reduce its occurrence. Research is required to evaluate the efficacy of interventions to reduce anxiety for families and examine the level of uncertainty in illness in this cohort.


Aurora-C Interactions with Survivin and INCENP Reveal Shared and Distinct Features Compared with Aurora-B Chromosome Passenger Protein Complex.
Aurora-C, a member of the Aurora kinase family that can complement Aurora-B function in mitosis is either moderately expressed or repressed in most adult somatic tissues but is active in early embryonic development and expressed at elevated levels in multiple human cancers. Aurora-C overexpression reportedly plays a role in tumorigenic transformation. We performed detailed characterization of Aurora-C interactions with members of the Chromosome Passenger Complex (CPC), Survivin and Inner Centromere Protein (INCENP) in reference to known Aurora-B interactions to understand the functional significance of Aurora-C overexpression in human cancer cells. The results revealed that silencing of Aurora-C or -B individually does not affect localization of the other kinase and the two kinases exist predominantly in independent complexes in vivo. Presence of Aurora-C and -B in molecular complexes of varying as well as overlapping sizes and co-existence in INCENP overexpressing cells indicated oligomerization of ternary complexes under different physiological conditions in vivo. Furthermore, Aurora-C and -B stabilized INCENP through interaction with and phosphorylation of the IN box domain while Aurora-C was activated following Survivin phosphorylation on Serine 20. Phosphorylation of Survivin residue Serine 20 by Aurora-C and -B appears important for proper chromosome segregation. Taken together, our study suggests that Aurora-C, expressed at low levels in somatic cells, functions as a catalytic component of the CPC together with Aurora-B through mitosis. Elevated expression of Aurora-C in cancer cells alters the structural and functional characteristics of the Aurora-B-CPC leading to chromosomal instability.


Fiber kinematics of small intestinal submucosa under biaxial and uniaxial stretch.
Improving our understanding of the design requirements of biologically derived collagenous scaffolds is necessary for their effective use in tissue reconstruction. In the present study, the collagen fiber kinematics of small intestinal submucosa (SIS) was quantified using small angle light scattering (SALS) while the specimen was subjected to prescribed uniaxial or biaxial strain paths. A modified biaxial stretching device based on Billiar and Sacks (J. Biomech., 30, pp. 753-7, 1997) was used, with a real-time analysis of the fiber kinematics made possible due to the natural translucency of SIS. Results indicated that the angular distribution of collagen fibers in specimens subjected to 10% equibiaxial strain was not significantly different from the initial unloaded condition, regardless of the loading path (p=0.31). Both 10% strip biaxial stretch and uniaxial stretches of greater than 5% in the preferred fiber direction led to an increase in the collagen fiber alignment along the same direction, while 10% strip biaxial stretch in the cross preferred fiber direction led to a broadening of the distribution. While an affine deformation model accurately predicted the experimental findings for a biaxial strain state, uniaxial stretch paths were not accurately predicted. Nonaffine structural models will be necessary to fully predict the fiber kinematics under large uniaxial strains in SIS.


Assessment of the effects of electromagnetic field modification on egg-laying hens in commercial flocks as indicated by production measures.
To assess the effects of electromagnetic (EM) field modification by use of Nufield EM field modification (NEFM) units on egg-laying hens in commercial flocks as indicated by production measures, including hen-day mortality rate (HDMR) and eggs per hen housed (EHH). 16 commercial flocks of egg-laying hens. 5 caged commercial table egg layer flocks (Single Comb White Leghorns) successively housed at the same location during a 6-year period were exposed to NEFM. There were 7 hens/cage (317 cm2 of floor space/bird). At the same site, 11 concurrent non-NEFM-exposed flocks (4 genetically different strains) were sequentially housed. All 16 flocks underwent the same feed and management practices. For each NEFM- and non-NEFM-exposed flock, HDMR and EHH were compared with their respective national breeder goals (BG), defined as the reasonable genetic potential expressed under optimal management and environmental conditions. Furthermore, the HDMRs and EHHs of the NEFM- and non-NEFM-exposed flocks were compared. Mean HDMR and EHH of the NEFM-exposed flocks was 36.9% less and 4.96% greater than the relevant BG, respectively. Mean HDMR and EHH of the non-NEFM-exposed flocks was 12.6% and 0.49% greater than the relevant BG, respectively. Compared with the 11 non-NEFM-exposed flocks, the NEFM-exposed flocks collectively had a 47.6% decrease in HDMR and 1.33% increase in EHH. Results strongly suggest that application of NEFM in commercial egg-layer flocks improves production measures, which has important welfare implications as well as gross economic advantage.


Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution.
Sipuleucel-T, an autologous cellular immunotherapy, is approved for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first personalized treatment for prostate cancer to be manufactured using the immune system of each individual patient. Patient preparation and compliance are critical because patients undergo serial leukapheresis and reinfusion procedures within a relatively short time period, which may result in transient reactions. The study aims to identify patients best suited for sipuleucel-T treatment, provide an overview of treatment, and encourage infusion sites to consider a primary contact model for the efficient coordination of care. Treatment experiences were evaluated from 124 patients with mCRPC who received sipuleucel-T from January 2010 to August 2013 according to current best practices. Feedback was collected from reflective interdisciplinary discussion within the sipuleucel-T delivery team (nurses, advanced practice providers, urologists, and medical oncologists). Early patient identification and education on treatment rationale, delivery, and expectations help ensure a successful sipuleucel-T treatment experience. A multidisciplinary coordinated-care process can facilitate proficient sipuleucel-T delivery, and the selection of a primary contact for care coordination offers benefits, such as clear and efficient education.


N-acetylcysteine slows down ageing and increases the life span of Drosophila melanogaster.
Ageing can be defined as the time-dependent decline of physiological functions of an organism. The molecular causes for the ageing process are multiple, involving both genetic and environmental factors. It has been proposed that antioxidants may positively influence the ageing process, protecting the organism against free radical-induced damage. Here we show that the antioxidant N-acetylcysteine (NAC) has a life-extending effect on Drosophila melanogaster. Dietary uptake of NAC results in a dose-dependent increase in median and maximum life span. Flies fed on 1 mg/ml NAC food live 16.6% longer; at 10 mg/ml, life span increases by 26.6%. We have examined the effect of NAC treatment on protein and RNA levels: we observe an NAC-dependent increase in absolute amounts of total RNA and ribosomal RNA, but no differences in protein levels. The NAC effect on longevity may involve differential expression of specific mRNA genes, as suggested by RNA finger-printing experiments.


The Significance of Demographic Variables on Psychosocial Health from the Early Stage and Nine Months after the COVID-19 Pandemic Outbreak. A Cross-National Study.
This cross-national study explored stability and change in mental health, quality of life, well-being and loneliness during the early stage and nine months after the implementation of COVID-19 pandemic social distancing measures and periodic lockdowns as adjusted by demographic variables. In the USA, the UK, Australia and Norway, 7284 individuals responded to the invitation to take part in two cross-sectional web-based surveys (April and November 2020), including questions about sociodemographic variables and psychosocial outcomes. Independent t-tests and generalized linear models (GLM) and estimated marginal means were used to analyze differences between subgroups and countries, multiple linear regression analyses were conducted on the psychosocial outcome measures by demographic variables and time in each country and mean responses presented by time after adjusting for all demographic variables in the model. Age, gender, civil status, education, employment, place of work and living area were all significant factors for psychosocial health across the countries. Differences in mental health, quality of life, well-being and loneliness were found between the countries in both April and November 2020, while time did not contribute to reducing the toll in any of the four countries over the nine-month period.


A Study of Creatinine Level among Patients with Dyslipidemia and Type 2 Diabetes Mellitus using Multilayer Perceptron and Multiple Linear Regression.
Dyslipidemia is one of the most important risk factors for coronary heart disease with diabetes mellitus. Diabetic dyslipidemia is correlated with reduced concentrations of high-density lipoprotein cholesterol, elevated concentrations of plasma triglycerides, and increased concentrations of dense small particles of low-density lipoprotein cholesterol. Furthermore, dyslipidemia is one of the factors that accelerate renal failure in patients with nephropathy that is observed to be higher in these patients. This paper aims to propose the variable selection using the multilayer perceptron (MLP) neural network methodology before performing the multiple linear regression (MLR) modeling. Dataset consists of patient with Dyslipidemia, and Type 2 Diabetes Mellitus was selected to illustrate the design-build methodology. According to clinical expert's opinion and based on their assessment, these variables were chosen, which comprises the level of creatinine, urea, total cholesterol, uric acid, sodium, and HbA1c. At the first stage, all the selected variables will be a screen for their clinical important point of view, and it was found that creatinine has a significant relationship to the level of urea reading, a total of cholesterol reading, and the level of uric acid reading. By considering the level of significance, α = 0.05, these three variables are being selected and used for the input of the MLP model. Then, the MLR is being applied according to the best variable obtained through MLP process. Through the testing/out-sample mean squared error (MSE), the performance of MLP was assessed. MSE is an indication of the distance from the actual findings from our estimates. The smallest MSE of the MLP shows the best variable selection combination in the model. In this research paper, we also provide the R syntax for MLP better illustration. The key factors associated with creatinine were urea, total cholesterol, and uric acid in patients with dyslipidemia and type 2 diabetes mellitus.


Narrowband tunable photonic notch filter.
We propose a technique for realization of a high-contrast, tunable, low-insertion-loss notch filter using polarization selectivity of whispering-gallery-mode resonators. We demonstrate a 10 MHz filter with 5.5 dB insertion loss and 45.5 dB of in-band rejection. The measured rejection value is limited by the finite (3 kHz) linewidth of our laser. We show that the filter can potentially have tunable bandwidth without significant rejection modification.


Exploration of vertical bias in perceptual completion of illusory contours: Threshold measures and response classification.
We investigated whether the perceptual completion of illusory contours exhibits a vertical bias (J. Pillow & N. Rubin, 2002). Experiments 1-3 measured completion with Pillow and Rubin's shape discrimination procedure, while including novel control conditions to determine if the results were related to perceptual completion per se. These experiments found no evidence for perceptual completion with stimuli used by Pillow and Rubin but did find completion with smaller stimuli that had larger support ratios. However, even when perceptual completion occurred, there was no evidence for a vertical bias in perceptual completion. Experiments 4-5 used the response classification method (B. L. Beard & A. Ahumada, 1998) to determine which local areas were related to illusory contour discrimination in central and peripheral vision. For central stimuli, there was a slight bias favoring completion of vertical contours, although the extent of the bias varied across participants. There was no vertical bias for peripheral stimuli. Overall, although subject to several important caveats, the results obtained with classification images (but not threshold measures) were consistent with the Pillow and Rubin's idea that perceptual completion is more difficult when it requires integrating visual features that are on different sides of the vertical meridian.


Dietary Nitrate and Diet Quality: An Examination of Changing Dietary Intakes within a Representative Sample of Australian Women.
Dietary nitrate is increasingly linked to a variety of beneficial health outcomes. Our purpose was to estimate dietary nitrate consumption and identify key dietary changes which have occurred over time within a representative sample of Australian women. Women from the 1946⁻1951 cohort of the Australian Longitudinal Study on Women's Health with complete food frequency questionnaire data for both 2001 and 2013 were included for analysis. Dietary nitrate intakes were calculated using key published nitrate databases. Diet quality scores including the Australian Recommended Food Score, the Mediterranean Diet Score and the Nutrient Rich Foods Index were calculated along with food group serves as per the Australian Dietary Guidelines. Wilcoxon matched pairs tests were used to test for change in dietary intakes and Spearman's correlations were used to examine associations. In our sample of 8161 Australian women, dietary nitrate intakes were on average 65⁻70 mg/day, and we detected a significant increase in dietary nitrate consumption over time (+6.57 mg/day). Vegetables were the primary source of dietary nitrate (81⁻83%), in particular lettuce (26%), spinach (14⁻20%), beetroot (10⁻11%), and celery (7⁻8%) contributed primarily to vegetable nitrate intakes. Further, increased dietary nitrate intakes were associated with improved diet quality scores (r = 0.3, p < 0.0001). Although there is emerging evidence indicating that higher habitual dietary nitrate intakes are associated with reduced morbidity and mortality, future work in this area should consider how dietary nitrate within the context of overall diet quality can facilitate health to ensure consistent public health messages are conveyed.


Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.
The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3-deficient mice, presynaptic cannabinoid CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins. Finally, the dietary-induced reduction of CB(1)R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets.


Evaluation of immunoassays for the detection and typing of PCR amplified human papillomavirus DNA.
To evaluate different hybridisation techniques to detect and type human papillomavirus (HPV) DNAs amplified by consensus primer polymerase chain reaction (PCR) in biopsy and cytological specimens. A hybrid capture-immunoassay in microtitre wells was performed to detect HPV sequences amplified by PCR and typed by specific oligoprobes. Consensus primers were used to amplify a sequence within the L1 open reading frame, and direct digoxigenin labelling of amplified products was performed during the amplification reaction. The amplified product was separately hybridised with six biotinylated type specific probes (HPV6, 11, 16, 18, 31, and 33); hybrids were then captured into streptavidin coated microtitre wells and detected by a spectrophotometer as an ELISA using antidigoxigenin Fab fragment labelled with peroxidase and a colorimetric substrate. The results were compared with the dot-blot immunoassay used to detect and type PCR amplified HPV DNA sequences. Consensus primers were used to generate the same unlabelled PCR product; digoxigenin labelled type specific probes for HPV6, 11, 16, 18, 31, and 33 were used and hybrids visualised by colorimetric immunoenzymatic reaction. Thirty nine biopsy specimens and 31 cytological samples were tested by the PCR-ELISA and by standard PCR followed by dot-blot hybridisation. The PCR-ELISA proved to be more sensitive than standard PCR with dot-blot hybridisation typing. All samples positive for HPV-DNA in standard PCR with dot-blot hybridisation method were confirmed positive by the PCR-ELISA assay; however, seven samples were positive only by PCR-ELISA. The PCR-ELISA assay, which can be performed in one day, is easily standardised and therefore seems to be a practical, sensitive, and reliable diagnostic tool for the detection and typing of HPV genomes in biopsy and in cytological specimens in the routine diagnostic laboratory.


Cranberry: A Promising Natural Source of Potential Nutraceuticals with Anticancer Activity.
Studies have shown that cranberry and its components may exert anticancer properties. The present study aims to critically summarise the existing experimental studies evaluating the potential effects of cranberry on cancer prevention and treatment. PubMed database was searched to identify relevant studies. Current in vitro studies have indicated that cranberry and/or its components may act as chemopreventive agents, diminishing the risk for cancer by inhibiting cells oxidation and inflammatory-related processes, while they may also exert chemotherapeutic effects by inhibiting cell proliferation and angiogenesis, inducing cell apoptosis and attenuating the ability of tumour cells to invade and metastasis. Limited in vivo studies have further documented potential anticancer activity. Cranberry could be considered as a conglomeration of potential effective anticancer druglike compounds.


The impact of television viewing on brain structures: cross-sectional and longitudinal analyses.
Television (TV) viewing is known to affect children's verbal abilities and other physical, cognitive, and emotional development in psychological studies. However, the brain structural development associated with TV viewing has never been investigated. Here we examined cross-sectional correlations between the duration of TV viewing and regional gray/white matter volume (rGMV/rWMV) among 133 boys and 143 girls as well as correlations between the duration of TV viewing and longitudinal changes that occurred a few years later among 111 boys and 105 girls. After correcting for confounding factors, we found positive effects of TV viewing on rGMV of the frontopolar and medial prefrontal areas in cross-sectional and longitudinal analyses, positive effects of TV viewing on rGMV/rWMV of areas of the visual cortex in cross-sectional analyses, and positive effects of TV viewing on rGMV of the hypothalamus/septum and sensorimotor areas in longitudinal analyses. We also confirmed negative effects of TV viewing on verbal intelligence quotient (IQ) in cross-sectional and longitudinal analyses. These anatomical correlates may be linked to previously known effects of TV viewing on verbal competence, aggression, and physical activity. In particular, the present results showed effects of TV viewing on the frontopolar area of the brain, which has been associated with intellectual abilities.


Phase noise tolerance study in coherent optical circular QAM transmissions with Viterbi-Viterbi carrier phase estimation.
We present a performance evaluation of a non-conventional approach to implement phase noise tolerant optical systems with multilevel modulation formats. The performance of normalized Viterbi-Viterbi carrier phase estimation (V-V CPE) is investigated in detail for circular m-level quadrature amplitude modulation (C-mQAM) signals. The intrinsic property of C-mQAM constellation points with a uniform phase separation allows a straightforward employment of V-V CPE without the need to adapt constellation. Compared with conventional feed-forward CPE for square QAM signals, the simulated results show an enhanced tolerance of linewidth symbol duration product (ΔνTs) at a low sensitivity penalty by using feed-forward CPE structure with C-mQAM. This scheme can be easily upgraded to higher order modulations without inducing considerable complexity.


High-resolution melting technology: a new tool for studying the Wolbachia endosymbiont diversity in the field.
Stable infections by maternally transmitted symbionts are frequently found in field populations, especially in arthropods. Many questions remain regarding their contribution to host biology and ecology, and especially on environmental adaptation of their host. Wolbachia is one of the most common endosymbiont of invertebrates. This cytoplasmically inherited endocellular bacterium induces number of reproductive alterations in its arthropod hosts and various fitness effects that allow it to spread in host populations. To better understand the influence of Wolbachia on host phenotypes and consequences of the manipulation of reproduction on the host genetic differentiation, it is crucial to be able to discriminate Wolbachia strains and determine their prevalence, which requires exhaustive screening. In the present report, we proposed the use of a new tool for the population studies, based on the high resolution melting (HRM) analysis, less expensive and faster than the 'classical' methods for large-scale studies. We investigated the effectiveness of HRM to explore and characterize the diversity of Wolbachia strains. Results obtained showed that HRM is a powerful tool to identify strains and detect polymorphism in singly infected hosts. When individuals harboured a mixture of Wolbachia strains (multiple infections), there is a risk of underestimation of the diversity if the proportions of the strains are highly different. However, the same limitations exist for the other techniques commonly used. Overall, this study demonstrated that HRM analysis is a rapid and reliable technique useful for studying, without a priori, Wolbachia strains diversity in field populations.


A bio-inspired imidazole-functionalised copper cage complex.
An imidazole-functionalised cage is synthesised that can coordinate to Cu(i). X-ray analysis reveals a T-shaped coordination of copper by the imidazole ligands reminiscent of the coordination geometry found in enzymatic active sites. This cage complex can catalyse the oxidation of benzylic alcohols to benzaldehydes utilizing oxygen as the terminal oxidant.


Vibrational Probes: From Small Molecule Solvatochromism Theory and Experiments to Applications in Complex Systems.
The vibrational frequency of a chosen normal mode is one of the most accurately measurable spectroscopic properties of molecules in condensed phases. Accordingly, infrared absorption and Raman scattering spectroscopy have provided valuable information on both distributions and ensemble-average values of molecular vibrational frequencies, and these frequencies are now routinely used to investigate structure, conformation, and even absolute configuration of chemical and biological molecules of interest. Recent advancements in coherent time-domain nonlinear vibrational spectroscopy have allowed the study of heterogeneous distributions of local structures and thermally driven ultrafast fluctuations of vibrational frequencies. To fully utilize IR probe functional groups for quantitative bioassays, a variety of biological and chemical techniques have been developed to site-specifically introduce vibrational probe groups into proteins and nucleic acids. These IR-probe-labeled biomolecules and chemically reactive systems are subject to linear and nonlinear vibrational spectroscopic investigations and provide information on the local electric field, conformational changes, site-site protein contacts, and/or function-defining features of biomolecules. A rapidly expanding library of data from such experiments requires an interpretive method with atom-level chemical accuracy. However, despite prolonged efforts to develop an all-encompassing theory for describing vibrational solvatochromism and electrochromism as well as dynamic fluctuations of instantaneous vibrational frequencies, purely empirical and highly approximate theoretical models have often been used to interpret experimental results. They are, in many cases, based on the simple assumption that the vibrational frequency of an IR reporter is solely dictated by electric potential or field distribution around the vibrational chromophore. Such simplified description of vibrational solvatochromism generally referred to as vibrational Stark effect theory has been considered to be quite appealing and, even in some cases, e.g., carbonyl stretch modes in amide, ester, ketone, and carbonate compounds or proteins, it works quantitatively well, which makes it highly useful in determining the strength of local electric field around the IR chromophore. However, noting that the vibrational frequency shift results from changes of solute-solvent intermolecular interaction potential along its normal coordinate, Pauli exclusion repulsion, polarization, charge transfer, and dispersion interactions, in addition to the electrostatic interaction between distributed charges of both vibrational chromophore and solvent molecules, are to be properly included in the theoretical description of vibrational solvatochromism. Since the electrostatic and nonelectrostatic intermolecular interaction components have distinctively different distance and orientation dependences, they affect the solvatochromic vibrational properties in a completely different manner. Over the past few years, we have developed a systematic approach to simulating vibrational solvatochromic data based on the effective fragment potential approach, one of the most accurate and rigorous theories on intermolecular interactions. We have further elucidated the interplay of local electric field with the general vibrational solvatochromism of small IR probes in either solvents or complicated biological systems, with emphasis on contributions from non-Coulombic intermolecular interactions to vibrational frequency shifts and fluctuations. With its rigorous foundation and close relation to quantitative interpretation of experimental data, this and related theoretical approaches and experiments will be of use in studying and quantifying the structure and dynamics of biomolecules with unprecedented time and spatial resolution when combined with time-resolved vibrational spectroscopy and chemically sensitive vibrational imaging techniques.


Search for Physics Beyond the Standard Model in Events with High-Momentum Higgs Bosons and Missing Transverse Momentum in Proton-Proton Collisions at 13 TeV.
A search for physics beyond the standard model in events with one or more high-momentum Higgs bosons, H, decaying to pairs of b quarks in association with missing transverse momentum is presented. The data, corresponding to an integrated luminosity of 35.9 fb^{-1}, were collected with the CMS detector at the LHC in proton-proton collisions at the center-of-mass energy sqrt[s]=13 TeV. The analysis utilizes a new b quark tagging technique based on jet substructure to identify jets from H→bb[over ¯]. Events are categorized by the multiplicity of H-tagged jets, jet mass, and the missing transverse momentum. No significant deviation from standard model expectations is observed. In the context of supersymmetry (SUSY), limits on the cross sections of pair-produced gluinos are set, assuming that gluinos decay to quark pairs, H (or Z), and the lightest SUSY particle, LSP, through an intermediate next-to-lightest SUSY particle, NLSP. With large mass splitting between the NLSP and LSP, and 100% NLSP branching fraction to H, the lower limit on the gluino mass is found to be 2010 GeV.


Two roles for transforming growth factor beta 1 in colon enterocytic cell differentiation.
The role of transforming growth factor beta 1 (TGF-beta 1) in enterocytic differentiation was examined by treating two undifferentiated HT29 colon carcinoma sublines, U4 and U9, with hexamethylene bisacetamide to up-regulate their level of TGF-beta 1 mRNA expression. Although both lines after treatment secreted approximately equal levels of biologically active TGF-beta 1, only U4H cells were found to undergo enterocytic differentiation when cultured postconfluence on collagen I-coated transwells, forming polarized monolayer cells with an apical brush border, whereas U9H cells remained multilayered and undifferentiated. Enterocytic U4H cells exhibited four times as much cell surface expression of the collagen I-binding protein alpha 2-integrin, twice as much of the accessory collagen-binding protein carcinoembryonic antigen, and almost twice as much binding to collagen I films as undifferentiated U9H cells. TGF-beta 1 treatment doubled U4 cell collagen I binding, increased expression of alpha 2-integrin 4-fold, but increased carcinoembryonic antigen expression only marginally. U4H cells displayed cell cycle regulation by arresting reversibly at a restriction point in G1 when placed in the postconfluent culture conditions which initiated enterocytic differentiation. In contrast, undifferentiated U9H cells exhibited no restriction point but arrested throughout G1. TGF-beta 1 blocked synchronized U4H cells in G1, whereas it stimulated the growth of U9H cells. Thus, TGF-beta 1 has two roles in enterocytic differentiation: to increase levels of collagen I adhesion proteins and to block enterocytic cells in G1 so that they can differentiate.


Implementation of automated reporting of estimated glomerular filtration rate among Veterans Affairs laboratories: a retrospective study.
Automated reporting of estimated glomerular filtration rate (eGFR) is a recent advance in laboratory information technology (IT) that generates a measure of kidney function with chemistry laboratory results to aid early detection of chronic kidney disease (CKD). Because accurate diagnosis of CKD is critical to optimal medical decision-making, several clinical practice guidelines have recommended the use of automated eGFR reporting. Since its introduction, automated eGFR reporting has not been uniformly implemented by U. S. laboratories despite the growing prevalence of CKD. CKD is highly prevalent within the Veterans Health Administration (VHA), and implementation of automated eGFR reporting within this integrated healthcare system has the potential to improve care. In July 2004, the VHA adopted automated eGFR reporting through a system-wide mandate for software implementation by individual VHA laboratories. This study examines the timing of software implementation by individual VHA laboratories and factors associated with implementation. We performed a retrospective observational study of laboratories in VHA facilities from July 2004 to September 2009. Using laboratory data, we identified the status of implementation of automated eGFR reporting for each facility and the time to actual implementation from the date the VHA adopted its policy for automated eGFR reporting. Using survey and administrative data, we assessed facility organizational characteristics associated with implementation of automated eGFR reporting via bivariate analyses. Of 104 VHA laboratories, 88% implemented automated eGFR reporting in existing laboratory IT systems by the end of the study period. Time to initial implementation ranged from 0.2 to 4.0 years with a median of 1.8 years. All VHA facilities with on-site dialysis units implemented the eGFR software (52%, p<0.001). Other organizational characteristics were not statistically significant. The VHA did not have uniform implementation of automated eGFR reporting across its facilities. Facility-level organizational characteristics were not associated with implementation, and this suggests that decisions for implementation of this software are not related to facility-level quality improvement measures. Additional studies on implementation of laboratory IT, such as automated eGFR reporting, could identify factors that are related to more timely implementation and lead to better healthcare delivery.


No associations of Helicobacter pylori infection and gastric atrophy with plasma total homocysteine in Japanese.
Recent studies have suggested that Helicobacter pylori (H. pylori) infection might be a risk factor for atherosclerosis. Since the bacterium has not been isolated from atherosclerotic lesions, a direct role in atherogenesis is not plausible. We examined associations of plasma total homocysteine (tHcy) and serum folate, independent risk factors for atherosclerosis, with H. pylori infection and subsequent gastric atrophy among 174 patients (78 males and 96 females) aged 20 to 73 years, who visited an H. pylori eradication clinic of Nagoya University from July 2004 to October 2005. Polymorphism genotyping was conducted for methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) 28-bp tandem repeats by PCR with confronting two-pair primers and PCR, respectively. H. pylori infection and gastric atrophy were not significantly associated with hyperhomocysteinemia (tHcy > or = 12 nmol/ml), when adjusted by sex, age, smoking, alcohol, and genotypes of MTHFR and TS. The adjusted odds ratio of gastric atrophy for low folate level (< or = 4 mg/ml) was 0.21 (95% confidence interval = 0.05-0.78). The associations of tHcy with serum folate and MTHFR genotype were clearly observed in this dataset. The present study demonstrated that folate and MTHFR genotype were the deterministic factors of plasma tHcy, but not H. pylori infection and subsequent gastric atrophy, indicating that even if H. pylori infection influences the risk of atherosclerosis, the influence may not be through the elevation of homocysteine.


Maxillary Fungal Osteomyelitis: A Review of Literature and Report of a Rare Case.
Fungal osteomyelitis is a life-threatening and seldom seen opportunistic infection. It is commonly an affectation of the nose and paranasal sinuses within the orofacial region. It is an aggressive infection that needs to be addressed promptly to prevent fatal consequences. Here, we present a case of a 62-year-old female who presented with complaints of pain and pus discharge from the extraction socket of the left maxillary 23, 24, 25, 26 teeth. She had a history of uncontrolled diabetes mellitus. On further investigation, using diagnostic and Interventional aids, a final diagnosis of maxillary fungal osteomyelitis was made. The infective fungal agents were a mixture of Mucorales and Aspergillus species. A review of all literatures on the subject in the past 13 years using different search engines showed that craniofacial fungal infections with primary maxillary involvement are a rare phenomenon. The primary aim of reporting this case, therefore, is to highlight its rarity, presentation, management and most importantly the outcome of management.


Optimization of adenoviral vector-mediated transgene expression in the canine brain in vivo, and in canine glioma cells in vitro.
Expression of the immune-stimulatory molecule Fms-like tyrosine kinase 3 ligand (Flt3L) and the conditional cytotoxic enzyme herpes simplex virus type 1 thymidine kinase (HSV1-TK) provides long-term immune-mediated survival of large glioblastoma multiforme (GBM) models in rodents. A limitation for predictive testing of novel antiglioma therapies has been the lack of a glioma model in a large animal. Dogs bearing spontaneous GBM may constitute an attractive large-animal model for GBM, which so far has remained underappreciated. In preparation for a clinical trial in dogs bearing spontaneous GBMs, we tested and optimized adenovirus-mediated transgene expression with negligible toxicity in the dog brain in vivo and in canine J3T glioma cells. Expression of the marker gene beta-galactosidase (beta-Gal) was higher when driven by the murine (m) than the human (h) cytomegalovirus (CMV) promoter in the dog brain in vivo, without enhanced inflammation. In the canine brain, beta-Gal was expressed mostly in astrocytes. beta-Gal activity in J3T cells was also higher with the mCMV than the hCMV promoter driving tetracycline-dependent (TetON) transgene expression within high-capacity adenovirus vectors (HC-Ads). Dog glioma cells were efficiently transduced by HC-Ads expressing mCMV-driven HSV1-TK, which induced 90% reduction in cell viability in the presence of ganciclovir. J3T cells were also effectively transduced with HC-Ads expressing Flt3L under the control of the regulatable TetON promoter system, and as predicted, Flt3L release was stringently inducer dependent. HC-Ads encoding therapeutic transgenes under the control of regulatory sequences driven by the mCMV promoter are excellent vectors for the treatment of spontaneous GBM in dogs, which constitute an ideal preclinical animal model.


Immunolocalization of a neuronal growth-dependent membrane glycoprotein.
Monoclonal antibody (mAb) 5B4 recognizes in the rat a large, developmentally regulated membrane glycoprotein. The larger form of this antigen (185-255 kD) occurs in the developing nervous system and is present in membranes of nerve growth cones, as determined by analysis of a growth cone particle fraction. An immunochemical characterization of this antigen and of a smaller form (140 kD), sparsely present in the mature nervous system, has been described (Ellis, L., I. Wallis, E. Abreu, and K. H. Pfenninger, 1985, J. Cell. Biol., 101:1977-1989). The present paper reports on the localization by immunofluorescence of 5B4 antigen in cultured cortical neurons, developing spinal cord, and the mature olfactory system. In culture, mAb 5B4 stains only neurons; it is sparsely present in neurons at the onset of sprouting while, during sprouting, it appears to be concentrated at the growth cone and in regions of the perikaryon. In the developing spinal cord, 5B4 labeling is faintly detectable on embryonic day 11 but is intense on fetal day 13. At this stage, the fluorescence is observed in regions of the cord where axonal growth is occurring, while areas composed of dividing or migrating neural cells are nonfluorescent. With maturation of the spinal cord, this basic pattern of fluorescence persists initially, but the staining intensity decreases dramatically. In the adult, faint fluorescence is detectable only in gray matter, presumably indicating the presence of the 140 kD rather than the fetal antigen. The only known structure of the adult mammalian nervous system where axonal growth normally occurs is the olfactory nerve. mAb 5B4 intensely stains a variable proportion of olfactory axons in the mucosa as well as in the olfactory bulb. Based on both immunochemical and immunofluorescence data, the 5B4 antigen of 185-255 kD is associated specifically with growing neurons, i.e., neurons that are generating neurites.


Anticipatory representations of reward and threat in perceptual areas from preadolescence to late adolescence.
This study examined whether changes in perceptual processes can partially account for the increase in reward-orientated behaviour during adolescence. This was investigated by examining reinforcement-dependent potentiation to discriminative stimuli (SD) that predicted rewarding or threatening outcomes. To that end, perceptual event-related potentials that are modulated by motivationally salient stimuli, the N170 and Late Positive Potential (LPP), were recorded from 30 preadolescents (9-12 years), 30 adolescents (13-17 years), and 34 late adolescents (18-23 years) while they completed an instrumental task in which they emitted or omitted a motor response to obtain rewards and avoid losses. The LPP, but not the N170, showed age, but not gender, differences in reinforcement-dependent potentiation; preadolescents, adolescents, and late adolescents showed potentiation to SD that predicted a threat, whereas only preadolescents showed potentiation to SD that predicted a reward. Notably, the magnitude of threat-related LPP reinforcement-dependent potentiation decreased during the course of adolescence. In addition, greater sensation seeking was associated with greater LPP amplitudes in preadolescent males, but smaller LPP amplitudes in late adolescent males. Critically, these findings provide initial evidence for developmental differences in value-related coding in perceptual areas, where adolescents show greater perceptual biases to avoidance-related cues than to reward-related cues.


Sedentary Behavior, Physical Activity, and Fitness-The Maastricht Study.
This cross-sectional study examined the mutual independent associations of sedentary behavior, lower intensity physical activity (LPA) and higher intensity physical activity (HPA) (an approximation of moderate to vigorous physical activity with cardiorespiratory fitness (CRF). Two thousand twenty-four participants were included from The Maastricht Study (mean ± SD age, 59.7 ± 8.1 yr; 49.6% men). With the activPAL3 activity monitor, we assessed sedentary time (ST), sedentary pattern variables (number of sedentary breaks, average sedentary bout duration, and number of prolonged sedentary bouts [≥30 min]), LPA, and HPA. CRF was calculated as maximum power output per kilogram body mass (Wmax·kg) estimated from a submaximal cycle ergometer test. Linear regression analyses and isotemporal substitution analyses were used to examine associations of ST, sedentary pattern variables, and HPA with CRF. Analyses were stratified by sex. One hour of ST per day was associated with a lower Wmax·kg: Bmen = -0.03 (95% confidence interval [CI], -0.05 to -0.01) and Bwomen = -0.02 (95% CI, -0.04 to 0.00), independent of HPA. No statistically significant associations between sedentary patterns variables and CRF were observed. LPA was associated with a higher Wmax·kg: Bmen = 0.12 (95% CI, 0.07-0.17) and Bwomen = 0.12 (95% CI, 0.07-0.18). HPA was associated with a higher Wmax·kg: Bmen = 0.48 (95% CI, 0.38-0.58) and Bwomen = 0.27 (95% CI, 0.18-0.36). Replacing ST with LPA (Bmen, 0.08; 95% CI, 0.03-0.14; Bwomen, 0.10; 95% CI, 0.05-0.16) or with HPA (Bmen, 0.49; 95% CI, 0.39-0.59; Bwomen = 0.28; 95% CI, 0.19-0.36), but not with standing was associated with higher CRF. Modest associations between sedentary behavior and CRF were observed. Replacing ST with LPA was associated with higher CRF, which could be of particular importance for individuals who cannot engage in HPA. Nonetheless, replacing ST with HPA was associated with greatest estimated change in CRF.


[Acceptability of the HPV vaccine among Spanish university students in the pre-vaccine era: a cross-sectional study].
Cervical cancer (CC), the second most common cause of cancer deaths in women, is associated with the infection of human papillomavirus (HPV) and is more prevalent in women between the ages of 20 and 24. This research is aimed to determine the background about CC, the human papillomavirus infection and its vaccine, assessing its acceptability in university students. Cross-sectional study over 1,750 students from the University of Alicante (2008) selected at random, proportional associated to gender and studies, by a validated ad-hoc questionnaire. Percentages were computed, confidence intervals, contingency tables according to sex, age and type of studies, calculating adjusted odd ratios (OR). A sample with 58.6 % of women and 6.6% of biohealth students was obtained. 87.3% were willing to have the vaccine to prevent human papillomavirus (HPV), 94.3% would give this vaccine to their daughters, and 48.0% had heard someone talk about the vaccine. 90.6% didn't have a lot of knowledge about the HPV infection and 82.2% didn't know much about the vaccine. 22.4% had knowledge of the association between HPV and CC. Women register higher OR in acknowledging the problem and are more receptive to having the vaccine. The HPV vaccine acceptability is associated to the sex, the confidence of vaccines as a preventive method; the influence of the background is low in relation to the vaccine predisposition. A high acceptability of the vaccine was observed in the period of the study. Raising confidence in people about the vaccines can influence for a better predisposition to be vaccinated.


Robot assisted radical prostatectomy: the new standard?
Over the past decade, the robotic assisted radical prostatectomy (RARP) has grown increasingly popular and quickly equated itself as the most commonly used modality to treat locally-confined prostate cancer. Despite increased utilization, there is limited comparative research demonstrating superiority for RARP over the conventional radical retropubic prostatectomy (RRP). Furthermore, though perioperative and short-term oncologic outcomes are equivalent if not superior for the robotic approach, the optimal utilization of robotic technology remains to be determined with cost serving as a primary driver. In this review, we performed a literature search to identify comparative effectiveness research as it pertains to RARP versus RRP. We performed a PubMed literature search for a review of articles published between 2000 and 2014 using the following keywords to identify pertinent research: "robot or robotic prostatectomy", "open or retropubic prostatectomy", "cost", "resource utilization". Long-term data comparing RARP and RRP remains limited, though short-term positive surgical margins, biochemical recurrence-free survival, and need for adjuvant therapy appear at least equivocal, if not in favor of RARP versus RRP. Functional outcomes including return of continence and potency favor RARP while cost still favors RRP. Nonetheless, the generalization of results remains difficult with surgeon volume playing a large role in improving efficiency and quality. For the foreseeable future, an increasing number of prostatectomies will continue to be performed robotically. Though RARP appears to offer improved functional outcomes with good short-term oncologic outcomes, there is a need for longer-term studies to assess the true value of RARP. Outcomes aside, rigorous, prospective randomized-controlled trials must also be performed on the cost-effectiveness of RARP to determine its overall utility in an era of health care delivery reform.


Even low level of physical activity is associated with reduced mortality among people with metabolic syndrome, a population based study (the HUNT 2 study, Norway).
Low levels of physical activity may increase the risk of developing metabolic syndrome, a cluster of metabolic factors that are associated with the risk of premature death. It has been suggested that physical activity may reduce the impact of factors associated with metabolic syndrome, but it is not known whether physical activity may reduce mortality in people with metabolic syndrome. In a prospective study of 50,339 people, 13,449 had metabolic syndrome at baseline and were followed up for ten years to assess cause-specific mortality. The population was divided into two age groups: those younger than 65 years of age and those older than age 65. Information on their physical activity levels was collected at baseline. Metabolic syndrome was associated with higher mortality from all causes (hazard ratio (HR) 1.35, 95% confidence interval (95% CI) 1.20 to 1.52) and from cardiovascular causes (HR 1.78, 95% CI 1.39 to 2.29) in people younger than 65 years old than among other populations. In older people, there was no overall association of metabolic syndrome with mortality. People with metabolic syndrome who reported high levels of physical activity at baseline were at a reduced risk of death from all causes compared to those who reported no physical activity, both in the younger age group (HR 0.52, 95% CI 0.37 to 0.73) and in the older age group (HR 0.59, 95% CI 0.47 to 0.74). Among people with metabolic syndrome, physical activity was associated with reduced mortality from all causes and from cardiovascular causes. Compared to inactivity, even low levels of physical activity were associated with reduced mortality.


HLA class I antibodies provoke graft arteriosclerosis in human arteries transplanted into SCID/beige mice.
Antibodies toward HLA class I and/or MICA are commonly observed in transplanted patients suffering from allograft arteriosclerosis, also called chronic vascular rejection (CVR). The relative importance of cellular versus humoral alloreactivity for CVR is still disputed. We demonstrate that antibodies toward HLA class I provoke lesions typical for CVR in human arteries in vivo in the absence of cellular immunity. To show this, we grafted segments of human mesenteric arteries from 8 deceased organ donors into 36 immunodeficient SCID/beige mice in the infrarenal aortic position. Three mice died postoperatively. The remaining 33 mice received weekly i.v. injections of either a monoclonal antibody toward HLA class I, toward MICA or an irrelevant monoclonal antibody. At sacrifice after 6 weeks, mice receiving the HLA antibody showed a significant neointimal thickening in the grafted artery due to smooth muscle cell (SMC) proliferation while control mice receiving anti-MICA or irrelevant antibody showed little or no thickening. Whereas antibodies toward HLA class I were mitogenic to SMC in vitro, those directed toward MICA did not have any effect. Humoral alloreactivity toward HLA may thus play a causal role for the development of CVR and this opens new possibilities for the treatment of CVR.


Alloreactive cloned T cell lines. I. Interactions between cloned amplifier and cytolytic T cell lines.
Several T cell clones have been derived by limiting dilution of secondary mixed leukocyte culture cells stimulated by H-2- and M locus (Mls)-disparate spleen cells. When examined for the expression of cytolytic activity and the ability to proliferate, these cell clones can be classified into two major categories. One type of cell is noncytolytic; when cultured with irradiated spleen cells, such clones proliferate in response to Mls determinants. Some, but not all, of these clones express Lyt-1 alloantigens. The other type of cell is cytolytic; these clones do not proliferate when cultured with irradiated allogeneic spleen cells unless supernatant fluid (SF) is added. These cytolytic clones express Lyt-2 alloantigens. Some cytolytic clones are specific for H-2Kd and others for H-2Dd alloantigens. Still other cytolytic cell clones exhibit cross-reactive lysis of different H-2-bearing tumor and Con A blast target cells. Noncytolytic T cell clones, when stimulated by Mls antigens, were examined for their ability to promote proliferation of cytolytic T cell clones. All of the noncytolytic cell clones tested were able to promote proliferation of cytolytic cell clones with the concomitant expression of cytolytic activity directed toward the original stimulating alloantigen (H-2d). Amplification of cytolytic activity was dependent upon stimulation of the noncytolytic amplifier T cell clones by Mls antigens. Specific alloantigen (signal 1), however, was not required for proliferation of the cytolytic cell clones; the amplifying signal (signal 2), delivered by the amplifier cell clones, was sufficient alone to promote proliferation of the cytolytic cell clones. Whereas proliferation of the amplifier cells was radiosensitive, the generation of the soluble amplifying signal was radioresistant. Amplification of cytolytic activity was observed when either amplifier cells were physically separated from responding cytolytic cells in Marbrook cultures or when cytolytic cells were cultured with SF collected from amplifier cell cultures. The amplifying factors were neither antigen specific nor strain specific and could be produced by Lyt-1- cells. The availability of cloned T cell lines that retain specific biologic function offers unique opportunities to characterize cell surface proteins and cell-cell interactions.


Aminoacylase 1 deficiency associated with autistic behavior.
Aminoacylase 1 (ACY1) deficiency is a recently described inborn error of metabolism. Most of the patients reported so far have presented with rather heterogeneous neurologic symptoms. At this moment, it is not clear whether ACY1 deficiency represents a true metabolic disease with a causal relationship between the enzyme defect and the clinical phenotype or merely a biochemical abnormality. Here we present a patient identified in the course of selective screening for inborn errors of metabolism (IEM). The patient was diagnosed with autistic syndrome and admitted to the Children's Memorial Health Institute (CMHI) for metabolic evaluation. Organic acid analysis using gas chromatography-mass spectrometry (GC-MS) revealed increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, glycine, leucine, isoleucine, and valine. In Epstein-Barr virus (EBV)-transformed lymphoblasts, ACY1 activity was deficient. The mutation analysis showed a homozygous c.1057C>T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation and had normal results in the organic acid analysis using GC-MS. This article reports the findings of an ACY1-deficient patient presenting with autistic features.


Michelson wide-field stellar interferometry: principles and experimental verification.
A new interferometric technique for Michelson wide-field interferometry is presented that consists of a Michelson pupil-plane combination scheme in which a wide field of view can be achieved in one shot. This technique uses a stair-shaped mirror in the intermediate image plane of each telescope in the array, allowing for simultaneous correction of the differential delay for the on-axis and off-axis image positions. Experimental results in a laboratory setup show that it is possible to recover the fringes of on-axis and off-axis stars with an angular separation of 1 arc min simultaneously and with a similar contrast. This new technique represents a considerable extension of the field of view of an interferometer without the need for extra observation time.


Effects of brood size manipulation and common origin on phenotype and telomere length in nestling collared flycatchers.
Evidence is accumulating that telomere length is a good predictor of life expectancy, especially early in life, thus calling for determining the factors that affect telomere length at this stage. Here, we investigated the relative influence of early growth conditions and origin (genetics and early maternal effects) on telomere length of collared flycatchers (Ficedula albicollis) at fledging. We experimentally transferred hatchlings among brood triplets to create reduced, control (i.e. unchanged final nestling number) and enlarged broods. Although our treatment significantly affected body mass at fledging, we found no evidence that increased sibling competition affected nestling tarsus length and telomere length. However, mixed models showed that brood triplets explained a significant part of the variance in body mass (18%) and telomere length (19%), but not tarsus length (13%), emphasizing that unmanipulated early environmental factors influenced telomere length. These models also revealed low, but significant, heritability of telomere length (h(2) = 0.09). For comparison, the heritability of nestling body mass and tarsus length was 0.36 and 0.39, respectively, which was in the range of previously published estimates for those two traits in this species. Those findings in a wild bird population demonstrate that telomere length at the end of the growth period is weakly, but significantly, determined by genetic and/or maternal factors taking place before hatching. However, we found no evidence that the brood size manipulation experiment, and by extension the early growth conditions, influenced nestling telomere length. The weak heritability of telomere length suggests a close association with fitness in natural populations.


Moving calls: a vocal mechanism underlying quorum decisions in cohesive groups.
Members of social groups need to coordinate their behaviour when choosing between alternative activities. Consensus decisions enable group members to maintain group cohesion and one way to reach consensus is to rely on quorums. A quorum response is where the probability of an activity change sharply increases with the number of individuals supporting the new activity. Here, we investigated how meerkats (Suricata suricatta) use vocalizations in the context of movement decisions. Moving calls emitted by meerkats increased the speed of the group, with a sharp increase in the probability of changing foraging patch when the number of group members joining the chorus increased from two up to three. These calls had no apparent effect on the group's movement direction. When dominant individuals were involved in the chorus, the group's reaction was not stronger than when only subordinates called. Groups only increased speed in response to playbacks of moving calls from one individual when other group members emitted moving calls as well. The voting mechanism linked to a quorum probably allows meerkat groups to change foraging patches cohesively with increased speed. Such vocal coordination may reflect an aggregation rule linking individual assessment of foraging patch quality to group travel route.


Low-dose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin.
In patients who require warfarin interruption before surgery and have an elevated international normalized ratio (INR) before surgery, low-dose vitamin K may normalize the INR in time for surgery. In a retrospective cohort study, we assessed the efficacy of 1 mg oral vitamin K to normalize the INR for surgery and whether resistance to re-anticoagulation occurs when warfarin is restarted after surgery. We studied a cohort of patients with an INR 1.4-1.9 on the day before surgery who received 1 mg oral vitamin K (vitamin K group), and a comparator group of patients with a normal INR (< or = 1.3) on the day before surgery who did not receive vitamin K (no vitamin K group). In both patient groups, we determined the proportion of patients with a normalized INR on the day of surgery and compared the mean INR after surgery when warfarin was resumed. Of 43 patients in the vitamin K group, the INR was normalized (< or = 1.3) in 33 patients (76.6; 95% confidence interval [CI]: 64.1-89.4), and the INR was normal or near-normal (< or = 1.4) in 39 patients (90.7; 95% CI: 82.0-99.4) on the day of surgery. The mean (standard deviation) INR in the vitamin K and no vitamin K group 4-8 days after surgery was 1.75 (0.34) and 1.59 (0.36), respectively (P = 0.56). In patients requiring interruption of warfarin for surgery, 1 mg oral vitamin K on the day before surgery can normalize the INR by the day of surgery and may not confer resistance to warfarin re-anticoagulation after surgery.


Dermatitis herpetiformis: a comparative assessment of skin and bowel abnormality.
We reviewed 18 patients with a clinical diagnosis of dermatitis herpetiformis who were being treated with dapsone and were on an unrestricted diet. Diagnosis was confirmed by finding IgA deposits in the dermal papillae of unaffected skin. Dapsone was discontinued and biopsy of affected skin was carried out when the typical rash reappeared. The biopsy findings were graded according to the severity of the histological changes. Small bowel tissue from each patient was examined and graded by stereo- and routine microscopy. Thirteen specimens (72%) were stereomicroscopically abnormal; all 18 showed villous atrophy, either partial or subtotal; and in 13 (72%) the interepithelial lymphocyte count was increased. No correlation was found between the histological severity of the skin and the small bowel lesions. Seemingly the severity of the skin rash in dermatitis herpetiformis is no guide to the degree of small bowel abnormality.


National profile of foot orthotic provision in the United Kingdom, part 2: podiatrist, orthotist and physiotherapy practices.
A national survey recently provided the first description of foot orthotic provision in the United Kingdom. This article aims to profile and compare the foot orthoses practice of podiatrists, orthotists and physiotherapists within the current provision. Quantitative data were collected from podiatrists, orthotists and physiotherapists via an online questionnaire. The topics, questions and answers were developed through a series of pilot phases. The professions were targeted through electronic and printed materials advertising the survey. Data were captured over a 10 month period in 2016. Differences between professions were investigated using Chi squared and Fischer's exact tests, and regression analysis was used to predict the likelihood of each aspect of practice in each of the three professions. Responses from 357 podiatrists, 93 orthotists and 49 physiotherapists were included in the analysis. The results reveal statistically significant differences in employment and clinical arrangements, the clinical populations treated, and the nature and volume of foot orthoses caseload. Podiatrists, orthotists and physiotherapists provide foot orthoses to important clinical populations in both a prevention and treatment capacity. Their working context, scope of practice and mix of clinical caseload differs significantly, although there are areas of overlap. Addressing variations in practice could align this collective workforce to national allied health policy.


Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium.
The transition of Candida albicans from a yeast to a hyphal form is controlled by several transcriptional factors, including the key regulators Cph1 and Efg1, and is considered an important virulence attribute. These factors, especially Efg1, regulate the expression of hyphal-associated genes e.g. SAP4-SAP6. In order to investigate the relevance of these transcriptional regulators for hyphal-independent SAP genes, recently constructed cph1 and efg1 single mutants and a cph1/efg1 double mutant lacking these factors were tested during interaction with oral epithelium and polymorphonuclear neutrophils. In contrast to the parental wild-type strain and the cph1 mutant, the efg1 and the cph1/efg1 mutants did not produce hyphal forms in all experiments and were less capable of damaging epithelial cells and neutrophil granulocytes. The attenuated epithelial lesions of these mutants were correlated not only with reduced expression of the hyphal-associated gene SAP4, but also with the lack of SAP1 and SAP3 expression previously shown to be important for oral infections. An efg1 mutant strain carrying a plasmid-borne copy of the EFG1 gene regained hyphal growth, damage of keratinocytes, granulocytes and the expression of SAP1 and SAP3. Although efg1 and cph1/efg1 mutants did not produce germ tubes during infection, expression of the hyphal-associated genes SAP5 and SAP6 was not completely abolished. A reduced capacity to stimulate an epithelial immune response manifested by a delayed onset of IL-1beta, IL-8 and TNF expression was only observed in the cph1/efg1-infected tissue. These results provide further evidence for a combined regulation of different virulence factors, such as dimorphism and expression of SAP genes. Furthermore, it could be demonstrated that the lack of Efg1 also caused reduced expression of hyphal-independent SAP genes. Both the EFG1 and the CPH1 gene products are necessary for adequate induction of an immune response.


Metabolic bone disorders and the promise of marine osteoactive compounds.
Metabolic bone disorders and associated fragility fractures are major causes of disability and mortality worldwide and place an important financial burden on the global health systems. These disorders result from an unbalance between bone anabolic and resorptive processes and are characterized by different pathophysiological mechanisms. Drugs are available to treat bone metabolic pathologies, but they are either poorly effective or associated with undesired side effects that limit their use. The molecular mechanism underlying the most common metabolic bone disorders, and the availability, efficacy, and limitations of therapeutic options currently available are discussed here. A source for the unmet need of novel drugs to treat metabolic bone disorders is marine organisms, which produce natural osteoactive compounds of high pharmaceutical potential. In this review, we have inventoried the marine osteoactive compounds (MOCs) currently identified and spotted the groups of marine organisms with potential for MOC production. Finally, we briefly examine the availability of in vivo screening and validation tools for the study of MOCs.


Biomechanical aspects of segmented arch mechanics combined with power arm for controlled anterior tooth movement: A three-dimensional finite element study.
The porpose of this study was to determine the optimal length of power arms for achieving controlled anterior tooth movement in segmented arch mechanics combined with power arm. A three-dimensional finite element method was applied for the simulation of en masse anterior tooth retraction in segmented power arm mechanics. The type of tooth movement, namely, the location of center of rotation of the maxillary central incisor in association with power arm length, was calculated after the retraction force was applied. When a 0.017 × 0.022-in archwire was inserted into the 0.018-in slot bracket, bodily movement was obtained at 9.1 mm length of power arm, namely, at the level of 1.8 mm above the center of resistance. In case a 0.018 × 0.025-in full-size archwire was used, bodily movement of the tooth was produced at the power arm length of 7.0 mm, namely, at the level of 0.3 mm below the center of resistance. Segmented arch mechanics required shorter length of power arms for achieving any type of controlled anterior tooth movement as compared to sliding mechanics. Therefore, this space closing mechanics could be widely applied even for the patients whose gingivobuccal fold is shallow. The segmented arch mechanics combined with power arm could provide higher amount of moment-to-force ratio sufficient for controlled anterior tooth movement without generating friction, and vertical forces when applying retraction force parallel to the occlusal plane. It is, therefore, considered that the segmented power arm mechanics has a simple appliance design and allows more efficient and controllable tooth movement.


Systemic lupus erythematosus and the economic perspective: a systematic literature review and points to consider.
Systemic lupus erythematosus (SLE) is a chronic, disabling, progressive disease, with many associated comorbidities, affecting patients during prime working years resulting in a high economic burden on society, producing high direct, indirect and intangible costs. In this article, our goals are two-fold. First, we review and discuss studies published in the period 2002-2012 concerning costs of SLE and point out gaps in the published literature. Second, we propose further research studies to advance our understanding of the economic perspective in SLE in the current area of new and emerging therapies. The literature evaluating disease costs in SLE remains limited and to date has only included a small number of countries. Despite these limitations, available studies indicate that SLE has significant socio-economic ramifications. Future studies are needed, especially to assess novel biologic therapies which have been made available or currently under investigation for SLE. An interesting approach in these new economic evaluations in SLE may be represented by the selection of the targets of the treatment to include in the cost-effectiveness and cost-utility analyses. Future treat-to-target strategies will likely include evaluation of their pharmacoeconomic implications.


Improving outcomes for patients with relapsed multiple myeloma: Challenges and considerations of current and emerging treatment options.
Despite the recent introduction of new therapies for multiple myeloma (MM), it remains an incurable disease. As MM progresses, patients experience cycles of relapse and remission, with remission periods becoming increasingly shorter as the disease becomes less treatment-sensitive. The treatment of relapsed refractory MM (RRMM) remains a significant clinical challenge. Patients with RRMM are a highly heterogeneous group and choosing the most appropriate treatment requires careful consideration. Furthermore, the number of treatment options for MM is continually growing with no definitive consensus to guide treating clinicians. The emergence of second-generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory drugs (e.g., pomalidomide) and monoclonal antibodies (e.g., isatuximab) has expanded an already complex treatment landscape. This review provides a clear summary of the available treatments for MM and discusses how to tailor treatments to individual patients' needs. Novel treatments currently under clinical development, including venetoclax, melflufen and CAR T-cell therapies, are also discussed.


Structure and properties of the C-terminal β-helical domain of VgrG protein from Escherichia coli O157.
The bacterial Type 6 secretion system (T6SS) translocates protein toxins (also called effectors) from the cytosol of a T6SS-carrying cell to a target cell by a syringe-like supramolecular complex resembling a contractile tail of bacteriophages. Valine-glycine repeat protein G (VgrG) proteins, which are the homologues of the gp27-gp5 (gene product) cell puncturing complex of bacteriophage T4, are considered to be located at the attacking tip of the bacterial T6SS apparatus. Here, we over-expressed six VgrG proteins from pathogenic Escherichia coli O157 and CFT073 strains. Purified VgrG1 of E. coli O157 and c3393 of E. coli CFT073 form trimer in solution and are rich in β-structure. We also solved the crystal structure of a trypsin-resistant C-terminal fragment of E. coli O157 VgrG1 (VgrG1C(G561)) at 1.95 Å resolution. VgrG1C(G561) forms a three-stranded antiparallel β-helix which is structurally similar to the β-helix domain of the central spike protein (gp138) of phi92 phage, indicating a possible evolutional relationship. Comparison of four different three-stranded β-helix proteins shows how their amino acid composition determines the protein fold.


Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort.
Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population.


Mutational analyses of the BbCRASP-1 protein of Borrelia burgdorferi identify residues relevant for the architecture and binding of host complement regulators FHL-1 and factor H.
Borrelia burgdorferi exploits multiple strategies to evade host immune responses. One central immune escape mechanism is the inactivation of the host complement attack by acquisition host complement regulators FHL-1 and factor H via complement regulator-acquiring surface proteins (BbCRASPs). The BbCRASP-1 protein is the first bacterial factor H/FHL-1-binding protein for which the atomic structure has been solved. Previously, 3 regions including the C terminus were identified as putative contact sites for the two complement regulators by the pepspot analysis. Based on the crystallographic structure an in vitro mutagenesis approach was conducted to identify amino acid residues which are relevant for FHL-1 and factor H binding by exchanging single or multiple residues in region 1 and the C-terminally located region 3. Single changes at 4 positions in region 1 either reduced (Lys136, Lys141, Glu147) or completely eliminated (Leu146) binding of both complement regulators. Substitutions clustered within the C-terminal region decreased (Glu234, Lys238, Tyr239, Lys241, Asp244, Thr245) or abolished binding (Lys240, Asp242, Leu246) of both complement regulators. Mapping the mutations onto the atomic structure of BbCRASP-1 reveals that, in contrast to earlier assumption, the C-terminal mutations act indirectly on FHL-1 and factor H binding, whilst the region 1 mutations map the site of direct complement regulator interaction. The elucidation of BbCRASP-1 structure - function may allow development of novel therapeutic strategies against Lyme disease.


Airborne contamination and surgical site infection: Could a thirty-year-old idea help solve the problem?
Surgical site infection (SSI) is a most serious postoperative complication, associated with increased morbidity and mortality, as well as extended therapy and elevated healthcare costs. In open clean surgery, e.g. orthopedic and cardiothoracic operations, the risk of SSI is strongly correlated with the amount of airborne bacteria being present in the operating room and the surgical field. The source of these bacteria is the surgical team itself, as we all emit thousands of bacteria-carrying skin particles every minute into the air. Although the risk of airborne contamination has decreased over the years, thanks to modern surgical clothing and advanced operating room ventilation, airborne bacteria are still detected and cause SSI. However, during the past thirty years there has been a simple and potentially effective preventive method waiting to be noticed. In 1986 Hall, Mackintosh and Hoffman found in a controlled experimental study that the application of regular unperfumed skin lotion to a person's body reduced the emission of airborne bacteria-carrying particles by approximately 90%. Moreover, the effect lasted at least 4 hours, which corresponds to a major surgical procedure. Thus, in the light of those results the present paper puts forth the hypothesis that this method can decrease the incidence of airborne bacterial contamination and SSI in open clean surgery. The paper also discusses the rationale and advantages of the method, and questions why it has escaped scientific attention for so long. In healthcare, difficult problems rarely have a simple and cheap solution. However, the use of ordinary skin lotion in open surgery may just be one, as it could potentially help prevent surgical site infection, and thereby increase patient safety and reduce healthcare costs.


Laparoscopic radical antegrade modular pancreatosplenectomy.
Although laparoscopic distal pancreatectomy is widely accepted for benign or borderline malignant pancreatic diseases, its application for pancreatic ductal adenocarcinoma (PDAC) remains controversial. Several recent reports have shown that laparoscopic surgery, for the treatment of PDAC, is associated with similar postoperative complications and survival outcomes compared with open surgery, and offers several advantages, particularly shorter hospital stay and less blood loss. However, potential risk of bias cannot be excluded because these results were obtained in retrospective studies. More importantly, it is unclear whether the extent of surgical resection is comparable between laparoscopic and open distal pancreatectomy. The aim of this video article is to show the technical feasibility of laparoscopic surgery to reproduce open radical antegrade modular pancreatosplenectomy (RAMPS) in terms of the extent of surgical resection.


The role of microRNA in metastatic processes of non-small cell lung carcinoma.
MicroRNAs are small non-coding one-stranded RNA molecules that play an important role in the post-transcriptional regulation of genes. Bioinformatic predictions indicate that each miRNA can regulate hundreds of target genes. MicroRNA expression can be associated with various cellular processes leading to the metastasis of malignant tumours including non-small cell lung carcinoma. This review summarizes current knowledge on the role of microRNAs in NSCLC metastasis to the brain and lymph nodes. A search of the NCBI/PubMed database for publications on expression levels and the mechanisms of microRNA action in NSCLC metastasis. Dysregulation of microRNAs in NSCLC can be associated with brain and lymph node metastasis. There are differences in microRNA expression profiling between NSCLC with and without metastases but it is currently not possible to reliably predict the site of metastasis in NSCLC. Based on data from RNAmicroarrays, bioinformatics analysis is able to predict the target genes of highlighted microRNAs, providing us with complex information about cancer cell features such as enhanced proliferation, migration and invasion. Such microRNAs may then be knocked-down using siRNAs or substituted with miRNA mimics. RNA microarray profiling may thus be a useful tool to select up- or down-regulated microRNAs. A number of authors suggest that microRNAs could serve as biomarkers and therapeutic targets in the treatment of NSCLC metastasis.


Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry.
Recent studies indicate that a routine invasive approach for patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) yields improved outcomes compared with a conservative approach, but the optimal timing of this approach remains open to debate. We used day of hospital presentation as an instrumental variable to study the impact of timing of cardiac catheterization and revascularization therapy on acute outcomes (death, reinfarction, stroke, cardiogenic shock, or congestive heart failure) among patients with UA and NSTEMI. Between January 2001 and September 2003, 56,352 patients with UA or NSTEMI were treated at 310 US hospitals participating in the CRUSADE national quality improvement initiative. Weekend patients were defined as those who presented to the hospital between 5 PM on Friday and 7 AM on Sunday. All other patients were classified as weekday. Weekday patients were similar to weekend patients in terms of demographics, clinical characteristics, and the use of medical therapies in the first 24 hours. Although overall rates of cardiac catheterization and revascularization were similar for the 2 groups, median time to catheterization was significantly longer for weekend than for weekday patients (46.3 versus 23.4 hours, P<0.0001). This delay was not associated with increased in-hospital adverse events, including death (weekend 4.4% versus weekday 4.1%, P=0.23), recurrent MI (2.9% versus 3.0%, P=0.36), or their combination (6.6% versus 6.6%, P=0.86). These findings were not affected by risk adjustment or use of alternative definitions of weekend versus weekday presentation. When weekend presentation was used as the basis for an instrumental variable analysis, we found that catheterization within the first 12 hours of presentation was associated with a nonsignificant trend toward reduced in-hospital mortality (absolute risk reduction 1.9%; 95% CI 6.7% lower to 2.9% higher; P=0.43) that decreased with longer treatment delays. Although weekend presentation is associated with a delay in invasive management among patients with UA and NSTEMI, in the context of contemporary medical therapy, this does not increase adverse events. Weekend presentation appears to fulfill accepted criteria as an instrumental variable for studying the optimal timing of invasive management for acute coronary syndrome patients. Using weekend status as an instrumental variable, we found no significant benefit to early catheterization, although we could not exclude an important risk reduction, particularly for catheterization within 12 hours of presentation.


A mathematical formulation of DNA computation.
DNA computation is to use DNA molecules for information storing and processing. The task is accomplished by encoding and interpreting DNA molecules in suspended solutions before and after the complementary binding reactions. DNA computation is attractive, due to its fast parallel information processing, remarkable energy efficiency, and high storing capacity. Challenges currently faced by DNA computation are: 1) lack of theoretical computational models for applications and 2) high error rate for implementation. This paper attempts to address these problems from mathematical modeling and genetic coding aspects. The first part of this paper presents a mathematical formulation of DNA computation. The model may serve as a theoretical framework for DNA computation. In the second part, a genetic code based DNA computation approach is presented to reduce error rate for implementation, which has been a major concern for DNA computation. The method provides a promising alternative to reduce error rate for DNA computation.


The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early-stage breast cancer.
Nonadherence to hormonal therapy is common and is associated with increased copayment amount. We investigated the change in adherence after the introduction of generic aromatase inhibitors (AIs) in 2010. Using deidentified pharmacy and claims data from OptumInsight, we identified women older than 50 years on brand-name AIs (BAIs) and/or generic AIs (GAIs) for early breast cancer between January 1, 2007 and December 31, 2012. Clinical, demographic, and financial variables were evaluated. Adherence was defined as a medication possession ratio (MPR) 80% or greater. We identified 5511 women, 2815 (51.1%) on BAI, 1411 (25.6%) on GAI, and 1285 (23.3%) who switched from BAI to GAI. The median 30-day copayment was higher for BAI ($33.3) than for GAI ($9.04). In a multivariable Cox-proportional hazard analysis, women who took GAI were less likely to discontinue therapy (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.57 to 0.84) compared with BAI. Discontinuation was positively associated with a higher monthly copayment of $15 to $30 (HR = 1.21, 95% CI = 1.01 to 1.44) and more than $30 (HR = 1.49, 95% CI = 1.23 to 1.80) compared with less than $15. In a multivariable logistic regression analysis, adherence (medication possession ratio ≥ 80%) was positively associated with GAI use (odds ratio = 1.53, 95% CI = 1.22 to 1.91) compared with BAI and inversely associated with increased monthly copayment. In addition, adherence was associated with a high annual income of more than $100k/year (odds ratio = 1.58, 95% CI = 1.17 to 2.11). Higher prescription copayment amount was associated with nonadherence and discontinuation of AIs. After controlling for copayment, discontinuation was higher and adherence was lower with Brand AIs. Because nonadherence is associated with worse survival, efforts should be directed towards reducing out-of-pocket costs for these life-saving medications.


Lower-extremity amputations in NIDDM. 12-yr follow-up study in Pima Indians.
The incidence of lower-extremity amputations was estimated in the Pima Indians of the Gila River Indian Community in Arizona, a population with a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). Between 1972 and 1984, from a study population of 4399 subjects, lower-extremity amputations were performed on 84 patients, 80 (95%) of whom had NIDDM. Among diabetic subjects, the incidence rate of first lower-extremity amputations was higher in men than in women. Rates increased significantly with increasing duration of diabetes. Presence of medial arterial calcification, retinopathy, or nephropathy; absence of patellar tendon reflexes; impaired great toe vibration-perception threshold; and degree of fasting and 2-h postload hyperglycemia were significant risk factors for amputations. Serum cholesterol concentration, blood pressure, age, and absence of Achilles tendon reflexes were not predictive of amputations. The death rate was greater in diabetic amputees than in diabetic nonamputees of similar age, sex, and duration of diabetes, and a significant increase in cardiovascular deaths was observed in diabetic subjects with amputations. The incidence rate of lower-extremity amputations in diabetic Pima Indians is higher than that reported in other diabetic populations. This may reflect differences in risk or a more complete case ascertainment than was possible in previous studies. If the latter is true, the rate of amputations in diabetic individuals may be higher than has been previously appreciated.


Experimental evidence for a role of dopamine in avian personality traits.
There is increasing interest in the genetic and physiological bases of behavioural differences among individuals, namely animal personality. One particular dopamine (DA) receptor gene (the dopamine receptor D4 gene) has been used as candidate gene to explain personality differences, but with mixed results. Here, we used an alternative approach, exogenously manipulating the dopaminergic system and testing for effects on personality assays in a social bird species, the common waxbill (Estrilda astrild). We treated birds with agonists and antagonists for DA receptors of both D1 and D2 receptor pathways (the latter includes the D4 receptor) and found that short-term manipulation of DA signalling had an immediate effect on personality-related behaviours. In an assay of social responses (mirror test), manipulation of D2 receptor pathways reduced time spent looking at the social stimulus (mirror image). Blocking D2 receptors reduced motor activity in this social assay, while treatment with a D2 receptor agonist augmented activity in this social assay but reduced activity in a non-social behavioural assay. Also, in the non-social assay, treatment with the D1 receptor antagonist markedly increased time spent at the feeder. These results show distinct and context-specific effects of the dopaminergic pathways on waxbill personality traits. Our results also suggest that experimental manipulation of DA signalling can disrupt a behavioural correlation (more active individuals being less attentive to mirror image) that is habitually observed as part of a behavioural syndrome in waxbills. We discuss our results in the context of animal personality, and the role of the DA system in reward and social behaviour.