Omnidirectional diffraction control with rotational topological defects.
We present a new scheme for the directional diffraction management of light with incompatible transformation optics. By introducing the concept of disclinations into transformation optics, we demonstrate that the rotational incompatible mapping violates the integrability condition of the coordinate transformation and gives rise to the non-vanishing Frank vector. It is revealed that such special coordinate transformations can produce rotational topological defects in physical space, which magnifies or compresses the diffraction of light beams propagating in arbitrary directions. We verify our theoretical analysis by numerical simulations of the light scattering from a cylinder of a generic disclination medium.


Pore-Scale Geochemical Reactivity Associated with CO2 Storage: New Frontiers at the Fluid-Solid Interface.
The reactivity of carbonate and silicate minerals is at the heart of porosity and pore geometry changes in rocks injected with CO2, which ultimately control the evolution of flow and transport properties of fluids in porous and/or fractured geological reservoirs. Modeling the dynamics of CO2-water-rock interactions is challenging because of the resulting large geochemical disequilibrium, the reservoir heterogeneities, and the large space and time scales involved in the processes. In particular, there is a lack of information about how the macroscopic properties of a reservoir, e.g., the permeability, will evolve as a result of geochemical reactions at the molecular scale. Addressing this point requires a fundamental understanding of how the microstructures influence the macroscopic properties of rocks. The pore scale, which ranges from a few nanometers to centimeters, has stood out as an essential scale of observation of geochemical processes in rocks. Transport or surface reactivity limitations due to the pore space architecture, for instance, are best described at the pore scale itself. It can be also considered as a mesoscale for aggregating and increasing the gain of fundamental understanding of microscopic interfacial processes. Here we focus on the potential application of a combination of physicochemical measurements coupled with nanoscale and microscale imaging techniques during laboratory experiments to improve our understanding of the physicochemical mechanisms that occur at the fluid-solid interface and the dynamics of the coupling between the geochemical reactions and flow and transport modifications at the pore scale. Imaging techniques such as atomic force microscopy, vertical scanning interferometry, focused ion beam transmission electron microscopy, and X-ray microtomography, are ideal for investigating the reactivity dynamics of these complex materials. Minerals and mineral assemblages, i.e., rocks, exhibit heterogeneous and anisotropic reactivity, which challenges the continuum description of porous media and assumptions required for reactive transport modeling at larger scales. The conventional approach, which consists of developing dissolution rate laws normalized to the surface area, should be revisited to account for both the anisotropic crystallographic structure of minerals and the transport of chemical species near the interface, which are responsible for the intrinsic evolution of the mineral dissolution rate as the reaction progresses. In addition, the crystal morphology and the mineral assemblage composition, texture, and structural heterogeneities are crucial in determining whether the permeability and transport properties of the reservoir will be altered drastically or maintain the sealing properties required to ensure the safe sequestration of CO2 for hundreds of years. Investigating the transport properties in nanometer- to micrometer-thick amorphous Si-rich surface layers (ASSLs), which develop at the fluid-mineral interface in silicates, provides future direction, as ASSLs may prevent contact between the dissolving solids and the pore fluid, potentially inhibiting the dissolution/carbonation process. Equally, at a larger scale, the growth of micrometer- to millimeter-thick alteration layers, which result from the difference in reactivity between silicates and carbonates, slows the transport in the vicinity of the fluid-solid interface in polymineralic rocks, thus limiting the global reactivity of the carbonate matrix. In contrast, in pure limestone, the global reactivity of the monomineralic rock decreases because the flow localization promotes the local reactivity within the forming channels, thus enhancing permeability changes compared with more homogeneous dissolution of the rock matrix. These results indicate that the transformation of the rock matrix should control the evolution of the transport properties in reservoirs injected with CO2 to the same extent as the intrinsic chemical reactivity of the minerals and the reservoir hydrodynamics. This process, which is currently not captured by large-scale modeling of reactive transport, should benefit from the increasing capabilities of noninvasive and nondestructive characterization tools for pore-scale processes, ultimately constraining reactive transport modeling and improving the reliability of predictions.


Does aminoglycoside therapy cause significant acute kidney injury in febrile neutropenia?
Owing to concern about aminoglycoside-related acute kidney injury (AKI) in therapy for febrile neutropenia, the aim of this study was to ascertain the incidence, severity and persistence of AKI secondary to aminoglycoside use for febrile neutropenia at an adult tertiary referral hospital. All admitted adults with neutropenia in a 27-month period were reviewed. Cases of febrile neutropenia due to chemotherapy who received an aminoglycoside were identified and renal function was assessed up to Day 30 after aminoglycoside administration. Transient renal impairment (TRI) was defined as any temporary rise in serum creatinine of >44 μmol/L within 30 days; and persistent, significant renal impairment (PSRI) was defined as an elevation of serum creatinine of >44 μmol/L at Day 30, or death from renal failure or need for dialysis. The Acute Kidney Injury Network (AKIN) stage for all episodes was also determined. Amongst 554 episodes of neutropenia, 148 episodes of chemotherapy-related febrile neutropenia with aminoglycoside treatment were identified. PSRI occurred in six episodes [4.1%; 95% confidence interval (CI) 1.9-8.6%] and TRI occurred in seven episodes (4.7%; 95% CI 2.3-9.4%). No PSRI was attributable to aminoglycoside therapy alone (0%; 95% CI 0-3.2%). Severe sepsis was the main cause of PSRI. Aminoglycoside therapy was the main contributing cause of TRI in two episodes (1.4%; 95% CI 0.2-5.3%). In conclusion, PSRI is a rare complication of aminoglycoside therapy for febrile neutropenia at this institution. AKIN stage 1 AKI is a common complication of febrile neutropenia episodes in which aminoglycosides are administered.


Early results and operative considerations of endoventricular circular patch plasty for ischemic cardiomyopathy.
Seven patients with ischemic cardiomyopathy who underwent elective endoventricular circular patch plasty (EVCPP) were included in this study. The mean age of the patients at the time of surgery was 63 years old. All seven patients had anterior left ventricular aneurysms following old myocardial infarction. Two patients were graded NYHA class II, 4 patients class III, and one patient class IV. EVCPP was performed under cardiac arrest with moderate hypothermia in five patients. The two most recent patients underwent EVCPP under on-pump beating and normothermia. Coronary artery bypass grafting was conducted in all cases and the mean number of grafts was 1.8, ranging from one to three. The mitral valve was replaced in one patient. One patient died of myonephrotic metabolic syndrome caused by ischemia of the lower limb. In the follow-up of six patients, the left ventricular end-diastolic volume index (LVEDI) decreased significantly from 128 +/- 31 mL/ m2 to 108 +/- 37 mL/m2. Left ventricular end-systolic volume index (LVESI) decreased in five patients. Left ventricular end-diastolic and end-systolic diameter remained unchanged after surgery. The left ventricular ejection fraction (LVEF) increased from 0.28 +/- 0.08 to 0.321 +/- 0.1. LVESI and LVEF did not improve in one patient with a large residual dyskinetic area at the distal LV septum. A residual dyskinetic area at the distal LV septum was observed in two of four patients who underwent EVCPP under cardiac arrest. This condition, however, was not detected in two patients who underwent EVCPP under on-pump beating conditions. In the follow-up study, the grade of NYHA functional classification improved in all six patients. In conclusion, EVCPP under on-pump beating is a realistic and effective procedure with which to complete ideal LV geometry and promote good results in patients with ischemic cardiomyopathy.


A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing.
Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. As a preliminary demonstration to mitigate all these challenges, at MIT we have developed active pharmaceutical ingredients manufacturing in a miniature platform. However, manufacturing of final oral solid dosage as tablets from drug substances had not been demonstrated. In this study, a compact, portable, re-configurable, and automated tablet manufacturing system, roughly the size of a North American household oven, [72.4 cm (length) × 53.3 cm (width) × 134.6 cm (height)] was designed, built and demonstrated. This miniature system is able to manufacture on-demand tablets from drug crystals on a scale of hundreds to thousands per day. Ibuprofen and Diazepam, each having different drug loading, were manufactured using this miniature system and meet U.S. Pharmacopeia standards. We foresee this flexible, miniature, plug-and-play pharmaceutical solids dosage manufacturing system advancing on-demand ready-to-use pharmaceuticals enabling future treatment of human diseases at the point-of-care.


Arbitrary precision composite pulses for NMR quantum computing.
We discuss the implementation of arbitrary precision composite pulses developed using the methods of Brown et al. [K.R. Brown, A.W. Harrow, I.L. Chuang, Arbitrarily accurate composite pulse sequences, Phys. Rev. A 70 (2004) 052318]. We give explicit results for pulse sequences designed to tackle both the simple case of pulse length errors and the more complex case of off-resonance errors. The results are developed in the context of NMR quantum computation, but could be applied more widely.


Salt restriction in hypertensive patients. Comparison of advice, education, and group management.
The purpose of this study was to identify the best of three methods of treating hypertensive outpatients in order to minimize dietary sodium levels and thereby decrease the need for antihypertensive drugs. Forty-eight outpatients with hypertension were randomly assigned to three treatment programs: (1) advice; (2) an intensive educational program; and (3) small-group management plus feedback. This last program had a problem-solving format in which patients shared ideas and provided mutual support for dietary change. Only these group management patients were told the results of their sodium determinations. In a one-year study, group management plus the feedback to patients of information on the sodium content of their urine was more effective in decreasing dietary sodium intake than advice or an intensive educational effort.


Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms.
Bacterial infection promotes the infiltration of inflammatory leukocytes mediated in part by receptors for formyl-methionine-terminated peptides. In this study, we show that LPS can markedly enhance the expression of the formyl peptide receptor gene (FPR1) in mouse macrophages and neutrophils by enhancing transcription and by stabilization of the mRNA. In untreated cells, FPR1 mRNA exhibits a half-life of approximately 90 min and this is markedly increased (to >6 h) following stimulation with LPS. Although FPR1 mRNA levels remained elevated over baseline for >20 h after stimulation, the half-life of the message is prolonged only transiently. LPS-induced FPR1 mRNA expression is mediated in part by the intermediate production of secreted factors. First, the response to LPS is partially blocked by the translational inhibitor cycloheximide. Second, a heat-labile but polymyxin B-insensitive factor present in supernatants from LPS-treated cells stimulates enhanced expression of FPR1 mRNA and, like LPS, promotes stabilization of FPR1 mRNA. Furthermore, supernatants from LPS-treated wild-type macrophages can stimulate FPR1 mRNA expression in LPS-insensitive macrophages from TLR4-mutant mice. Elevated FPR1 mRNA expression is also induced in response to ligands for TLR2 and TLR3. TNF-alpha but not IL-1, IL-6, IFN-beta, and IFN-gamma can mimic the effects of LPS although other factors apparently also contribute. Collectively, these findings define a distinct molecular pattern of response to TLR stimulation in inflammatory phagocytes and demonstrate that regulation of FPR1 expression is achieved through both transcriptional and posttranscriptional mechanisms.


Quality indicators for diabetes prevention programs in health care targeted at people at high risk.
Type 2 diabetes can be efficiently prevented by lifestyle intervention provided for people at high diabetes risk. The aim of this paper was to conduct a literature search on existing quality indicators for type 2 diabetes prevention and to collate and present a set of indicators that could be applied in European countries with different health care systems and cultures. Scientific and grey literature was searched for relevant studies using electronic databases. We also hand searched previous systematic reviews and reference lists of relevant articles. The only publication identified was the report presenting the results from the IMAGE project. The IMAGE indicators were used as the basis for the proposed indicators. Publications on quality indicators of diabetes prevention programmes are scarce. The quality indicators presented here are a first step toward the definition of a core set of European indicators to monitor and improve the quality of diabetes prevention.


Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.
Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely noncoding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent antiviral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate crosstalk with BrCa cells by utilizing exosomes to instigate antiviral signaling. This expands BrCa subpopulations adept at resisting therapy and reinitiating tumor growth.


Contraception and adolescent pregnancy.
To identify reasons for increasing numbers of pregnant adolescents, questionnaires were distributed to teenagers with unplanned pregnancies to determine the level of their knowledge of contraception. Findings revealed that 94% of the subjects had an adequate knowledge of availability, while only 43% had an adequate overall knowledge of contraception. Subjects reported many misconceptions about contraceptives and a general lack of motivation concerning contraceptive use.


[Pay attention to the mental disorders related dry eye].
The number of patients suffering from both dry eye and mental disorders (especially anxiety and depression) has risen rapidly in ophthalmic clinics. However, the mental disorders related dry eye has not received enough attention. At present, it lacks related information of basic data, and there is no standard for the clinical diagnosis and treatment. To this end, this article aims to determine the role of mental factors in the pathogenesis of dry eye, to strengthen the relevant basic and clinical research, to standardize its clinical diagnosis and treatment, and thus to promote the prevention and treatment of the mental disorder related dry eye in China.


SOCIAL PSYCHOLOGICAL DYNAMICS OF ENHANCED HIV RISK REDUCTION AMONG PEER INTERVENTIONISTS.
The authors present a model of interactive social psychological and relational feedback processes leading to human immunodeficiency virus (HIV) risk reduction behavior change among active drug users trained as Peer Health Advocates (PHAs). The model is supported by data from qualitative interviews with PHAs and members of their drug-using networks in the Risk Avoidance Partnership (RAP) project. Results suggest three mutually reinforcing social psychological processes that motivate PHAs to provide HIV prevention intervention to their peers and to reduce their own risk behaviors: development of a prosocial identity, positive social reinforcement from drug users and community members, and cognitive dissonance associated with continued risk behavior while engaging in health advocacy. These processes directly influence peer interventionists' motivation and efficacy to continue giving intervention to their peers, and to reduce their HIV risk behaviors. The authors discuss implications of the model for continued research on effective HIV prevention in high-risk groups.


A Proof of Concept to Bridge the Gap between Mass Spectrometry Imaging, Protein Identification and Relative Quantitation: MSI~LC-MS/MS-LF.
Mass spectrometry imaging (MSI) is a powerful tool to visualize the spatial distribution of molecules on a tissue section. The main limitation of MALDI-MSI of proteins is the lack of direct identification. Therefore, this study focuses on a MSI~LC-MS/MS-LF workflow to link the results from MALDI-MSI with potential peak identification and label-free quantitation, using only one tissue section. At first, we studied the impact of matrix deposition and laser ablation on protein extraction from the tissue section. Then, we did a back-correlation of the m/z of the proteins detected by MALDI-MSI to those identified by label-free quantitation. This allowed us to compare the label-free quantitation of proteins obtained in LC-MS/MS with the peak intensities observed in MALDI-MSI. We managed to link identification to nine peaks observed by MALDI-MSI. The results showed that the MSI~LC-MS/MS-LF workflow (i) allowed us to study a representative muscle proteome compared to a classical bottom-up workflow; and (ii) was sparsely impacted by matrix deposition and laser ablation. This workflow, performed as a proof-of-concept, suggests that a single tissue section can be used to perform MALDI-MSI and protein extraction, identification, and relative quantitation.


Structured mRNAs regulate translation initiation by binding to the platform of the ribosome.
Gene expression can be regulated at the level of initiation of protein biosynthesis via structural elements present at the 5' untranslated region of mRNAs. These folded mRNA segments may bind to the ribosome, thus blocking translation until the mRNA unfolds. Here, we report a series of cryo-electron microscopy snapshots of ribosomal complexes directly visualizing either the mRNA structure blocked by repressor protein S15 or the unfolded, active mRNA. In the stalled state, the folded mRNA prevents the start codon from reaching the peptidyl-tRNA (P) site inside the ribosome. Upon repressor release, the mRNA unfolds and moves into the mRNA channel allowing translation initiation. A comparative structure and sequence analysis suggests the existence of a universal stand-by site on the ribosome (the 30S platform) dedicated for binding regulatory 5' mRNA elements. Different types of mRNA structures may be accommodated during translation preinitiation and regulate gene expression by transiently stalling the ribosome.


Coping with childhood maltreatment: Avoidance and eating disorder symptoms.
Childhood maltreatment is associated with eating disorder symptoms; however, the nature of this association is unclear. We found those who experienced childhood maltreatment had higher avoidant coping and eating disorder symptoms. We also found an additive effect for maltreatment, such that with more types of maltreatment experienced, avoidant coping and eating disorder symptoms were greater. We also found evidence of an indirect effect such that childhood maltreatment was related to eating disorder symptoms through avoidant coping. Future research is needed to better understand factors that may promote development of adaptive coping patterns and prevention of eating disorder symptoms.


[Changes of Serum Gonadal Hormones Levels During Musk-secreting Period and Estrus of Moschus berezovskii].
To detect concentrations of serum gonadal hormones (testosterone, estradiol and progesterone) in musk-secreting period and estrus of Moschus berezovskii, and to study the association of serum gonadal hormones concentrations and musk-secreting. The concentrations of serum gonadal hormones were detected with magnetic particle separation ELISA. During musk-secreting period, concentration changes of three serum gonadal hormones showed clear regularity, three crests occurred synchronously. Before musk-secreting period, testosterone, estradiol and progesterone concentrations were at its lower level, in prime musk-secreting period, they increased rapidly to respective highest peak; at later musk-secreting period, they quickly dropped to close to its previous levels before musk-secreting period. During estrus, serum testosterone concentration increased to lower peaks than that at later musk-secreting period. Estradiol remained at a low level and progesterone level was closed to zero. Serum testosterone concentrations in prime musk-secreting period were 114.4 ~ 190.5 times of estrus. During musk-secreting period, there were significant positive correlation among three serum gonadal hormone levels, a positive correlation between musk yield and serum testosterone levels, and negative correlation of musk yield with serum estradiol and progesterone levels as well as musk deer ages. Serum testosterone concentrations in prime musk-secreting period increase to the highest levels,which can provide reference in musk secretion induced by artificial means.


Anemia with spur cells: a red cell defect acquired in serum and modified in the circulation.
The sera and red cells of three patients with severe liver disease and "spur cells" were studied. In each case the per cent of serum cholesterol which was free (unesterified) was elevated, and the serum lecithin: cholesterol acyltransferase activity was depressed. Lipoproteins with beta mobility were increased, but exhibited immune reactivity with antisera to both alpha- and beta-lipoproteins. Serum bile salt concentrations were markedly elevated and consisted primarily of chenodeoxycholic acid, with small amounts of lithocholic acid present as well.SPUR CELLS MANIFESTED A STRIKING INCREASE IN CHOLESTEROL CONTENT AND IN THE CHOLESTEROL: phospholipid ratio, but a normal osmotic fragility. When incubated in heated normal serum, spur cells lost their excess cholesterol and became spherocytic and osmotically fragile. Conversely, sera from patients with spur cells readily transferred up to one-third of their free cholesterol to normal red cells, causing normal cells to become resistant to osmotic lysis. In addition, these sera caused normal red cells to acquire thorny membrane projections. Cholesterol transfer to normal cells also occurred from normal serum which had previously been incubated with spur cells. Changes in cell cholesterol were induced by all of the lipoprotein fractions of spur serum. When transfused into a patient with spur cells, normal red cells became more resistant to osmotic lysis over the course of 24 hr. However, over the subsequent 7 days they underwent a progressive increase in osmotic fragility. These normal cells, as well as the patient's own cells, had a shortened survival. Correlating with the moderate decrease in the filterability of red cells spurred in vitro, red cell destruction occurred predominently in the spleen. Red cells in this disorder appear to serve as repositories for free cholesterol loosely bound to serum lipoproteins. Cholesterol acquisition by the red cell membrane increases its surface area and causes the red cell to be resistant to osmotic lysis. The associated alteration in red cell shape leads to further changes in the cell membrane during circulation in vivo resulting in the loss of membrane surface area and culminating in the cell's premature destruction in the spleen.


Four-dimensional imaging of transvacuolar strand dynamics in tobacco BY-2 cells.
The vacuole is a characteristic organelle of plant cells and fulfills several important functions related to metabolism and growth of the cell. To shed light on the details of vacuolar structural changes in plant cells, we explored the three-dimensional organization and dynamics of living Nicotiana tabacum L. cv. Bright Yellow 2 cell vacuoles by real-time confocal time-lapse imaging. For imaging, the cells were pulse-labeled with the amphipathic styryl dye FM1-43 (N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl)pyridinium dibromide), which is delivered to the plant vacuole by endocytic uptake and then incubated overnight. Imaging of the membrane-labeled vacuole revealed a complex vacuole morphology underlaid by constant remodeling. The vacuole is traversed by multiple transvacuolar strands which move along each other and fuse in multiple manners. New strands were created by fission of large membrane sheets. Endocytic vesicle trafficking was followed within the dynamic transvacuolar strands. The movement occurred in a stop-and-go fashion with an average vesicle velocity of 0.46 microm/s and a peak velocity of 0.82 microm/s. Transvacuolar-strand reduction and creation is a characteristic event observed during mitosis. Here we propose a mechanistic model for the alteration of the number of transvacuolar strands, on the basis of their fusion and fission.


Sexual activity and chronic heart failure.
Little has been published about sexual function in chronic heart failure (CHF) and knowledge among clinicians in this regard is sparse. To review data regarding sexual function and dysfunction in patients with CHF, 2 of the authors (S.A.M. and P.A.U.) independently conducted a literature search using the MEDLINE database. English-language articles and cited bibliographies published between January 1996 and November 2006 were reviewed. Search terms included heart failure or CHF or ventricular dysfunction or heart disease in conjunction with sexual activity, erectile dysfunction, impotence, or sex. Articles were selected for inclusion if they had a primary focus on CHF and sexual function or dysfunction. Critical reviews of the literature, observational studies using self-reported patient surveys, and prospective, blinded, randomized, placebo-controlled trials were included. Articles were not excluded on the basis of patient sample size but were excluded if the article concerned a broad aspect of cardiovascular disease rather than CHF. When properly screened and treated, most patients with CHF can safely engage in sexual activity and be treated for erectile dysfunction with sildenafil, provided that they do not have active ischemia and do not require treatment with nitrates. Clinicians should know the physiological requirements of sexual activity and the impact CHF has on sexual performance. Fear of a cardiac event during intercourse can interfere with patients' ability to perform and enjoy sex, and so it is important that the physician be able to counsel patients with CHF about sexual activity.


Design of a new multi-turn ion optical system 'IRIS' for a time-of-flight mass spectrometer.
A new multi-turn ion optical system 'IRIS' has been designed for use with a high-performance time-of-flight (TOF) mass spectrometer, which satisfies the new design concepts of time focusing and phase space stability. It has an elliptical flight path composed of four toroidal electric sectors, with a flight path length for one lap of 0.974 m. Dimensions and voltages of sector electrodes have been optimized to satisfy theoretical requirements by simulations using surface charge method. Generally, multi-turn instruments require an injection and ejection system to inject and eject ions. On the basis of this ion optical study, we have designed an injection and ejection ion optical system, which achieves time focusing for the total system. Furthermore, we have designed novel field-adjusting electrodes (FAEs) for the perforated sectors in the injection and ejection systems, which accurately correct the electric potential around the perforated sector's hole. We have also used simulations to evaluate mass resolving power and ion transmissions for various lap numbers or flight path lengths. Through these we have confirmed that mass resolving powers of over 100,000 can be achieved with reasonable ion transmissions for a given set of initial conditions. Usually a multi-turn TOF mass spectrometer with a closed optic axis has mass range limitations from overtaking ions. To solve this problem, a TOF segmentation method is proposed that identifies all peaks in a TOF spectrum, including those from overtaking ions.


Allotype-Specific Glycosylation and Cellular Localization of Human Leukocyte Antigen Class I Proteins.
Presentation of antigens by human leukocyte antigen (HLA) complexes at the cell surface is a key process in the immune response. The α-chain, containing the peptide-binding groove, is one of the most polymorphic proteins in the proteome. All HLA class I α-chains carry a conserved N-glycosylation site, but little is known about its nature and function. Here, we report an in-depth characterization of N-glycosylation features of HLA class I molecules. We observe that different HLA-A α-chains carry similar glycosylation, distinctly different from the HLA-B, HLA-C, and HLA-F α-chains. Although HLA-A displays the broadest variety of glycan characteristics, HLA-B α-chains carry mostly mature glycans, and HLA-C and HLA-F α-chains carry predominantly high-mannose glycans. We expected these glycosylation features to be directly linked to cellular localization of the HLA complexes. Indeed, analyzing HLA class I complexes from crude plasma and inner membrane-enriched fractions confirmed that most HLA-B complexes can be found at the plasma membrane, while most HLA-C and HLA-F molecules reside in the endoplasmic reticulum and Golgi membrane, and HLA-A molecules are more equally distributed over these cellular compartments. This allotype-specific cellular distribution of HLA molecules should be taken into account when analyzing peptide antigen presentation by immunopeptidomics.


Augmentation of ethanol-induced enhancement of dimethylnitrosamine and diethylnitrosamine metabolism by lowered carbohydrate intake.
Hepatic metabolism in vitro of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), 3,4-benzopyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA) was assayed using the liver of rats maintained for 3 weeks on liquid diets containing three levels of carbohydrate (CHO) with or without supplementation of ethanol (5 g/100 ml). Ethanol consumption increased the metabolism of DMN and DEN to different degrees depending on the diet consumed simultaneously. Lowered CHO intake, which by itself increased the metabolism, dose-dependently augmented the increase due to ethanol: the lower the CHO intake, the more remarkable was the enhancement caused by ethanol. Ethanol increased microsomal cytochrome P-450 content only when combined with low-CHO diets. It was confirmed by a Salmonella mutagenicity test that the enhancement of DMN and DEN metabolism was accompanied by increased capacity of the liver to activate these nitrosamines to mutagens. On the other hand, neither lowered CHO intake, nor ethanol consumption, nor their combination affected the metabolism of BP and DMBA. Ethanol combined with a diet deficient in CHO even suppressed the metabolism of BP.


Silage preparation and fermentation quality of kudzu, sugarcane top and their mixture treated with lactic acid bacteria, molasses and cellulase.
We studied silage fermentation of kudzu (KZ), sugarcane top (ST) and their mixtures treated with additives to be able to effectively use available local feed resources. The silages were prepared using KZ, ST, KZ 90% + ST 10%, KZ 80% + ST 20%, KZ 70% + ST 30% and KZ 60% + ST 40%, based on fresh matter (FM). These silages were treated with 108 colony-forming units/g epiphytic lactic acid bacteria (LAB), 5% molasses and 0.02% cellulase of FM. The KZ contained higher crude protein (CP; 14.52%) content and lower levels of neutral detergent fiber (NDF; 62.15%) than those of ST (6.84% CP and 64.93% NDF) based on dry matter (DM). The KZ 60% + ST 40% silage fermented well with a higher (P < 0.05) lactic acid content and lower (P < 0.05) pH than those of the other mixed silages. Silages treated with molasses had lower (P < 0.05) ammonia-N, NDF, acid detergent fiber, and hemi-cellulose contents as well as pH, but higher (P < 0.05) DM, water-soluble carbohydrate, and lactic acid contents, than those of the control, LAB and cellulase treatments. The results confirmed that KZ 60% + ST 40% was the best mixing ratio to prepare silage, and molasses improved silage fermentation and fiber degradation.


A Value-Based Steering Model for Healthcare.
This article aims to answer how a commissioning body can steer health services based on value in an environment where the commissioner is responsible for the health services of a population with varying health service needs. In this design science study, we constructed a value-based steering model consisting of three parts: (1) the principles of steering; (2) the steering process; and (3) Value Steering Canvas, a concrete tool for steering. The study is based on Finland, a tax-funded healthcare system, where healthcare is a public service. The results can be applied in any system where there is a commissioner and a service provider, whether they are two separate organizations or not. We conclude that steering can be done based on value. The commissioning body can start using value-based steering without changes in legislation or in the present service system. Further research is needed to test the model in practice.


In vitro antimicrobial susceptibility of Salmonellae from animals in Louisiana.
A total of 56 Salmonella isolates from animals were tested for susceptibility to 12 antimicrobial agents by the standard disk diffusion and mirodilution methods. All isolates were susceptible to gentamicin, tobramycin, amikacin, chloramphenicol, crimethoprim and sulfonamide, colistin, and nitrofurantoin. Isolates were most frequently resistant to tetracycline (50%) and kanamycin (36%). A low prevalence of resistance to ampicillin (16%), carbenicillin (16%), and cephalothin (4%) was found. The differences in susceptibility results between the two methods were minor.


Epidemiology of Bleeding in Critically Ill Children.
Objective: Bleeding can be a severe complication of critical illness, but its true epidemiologic impact on children has seldom been studied. Our objective is to describe the epidemiology of bleeding in critically ill children, using a validated clinical tool, as well as the hemostatic interventions and clinical outcomes associated with bleeding. Design: Prospective observational cohort study. Setting: Tertiary pediatric critical care unit Patients: All consecutive patients (1 month to 18 years of age) admitted to a tertiary pediatric critical care unit Measurements and Main Results: Bleeding events were categorized as minimal, moderate, severe, or fatal, according to the Bleeding Assessment Scale in Critically Ill Children. We collected demographics and severity at admission, as evaluated by the Pediatric Index of Mortality. We used regression models to compare the severity of bleeding with outcomes adjusting for age, surgery, and severity. Over 12 months, 902 critically ill patients were enrolled. The median age was 64 months (IQR 17; 159), the median admission predicted risk of mortality was 0.5% (IQR 0.2; 1.4), and 24% were post-surgical. Eighteen percent of patients experienced at least one bleeding event. The highest severity of bleeding was minimal for 7.9% of patients, moderate for 5.8%, severe for 3.8%, and fatal for 0.1%. Adjusting for age, severity at admission, medical diagnosis, type of surgery, and duration of surgery, bleeding severity was independently associated with fewer ventilator-free days (p < 0.001) and fewer PICU-free days (p < 0.001). Adjusting for the same variables, bleeding severity was independently associated with an increased risk of mortality (adjusted odds ratio for each bleeding category 2.4, 95% CI 1.5; 3.7, p < 0.001). Conclusion: Our data indicate bleeding occurs in nearly one-fifth of all critically ill children, and that higher severity of bleeding was independently associated with worse clinical outcome. Further multicenter studies are required to better understand the impact of bleeding in critically ill children.


Anti-Idiotypic Antibodies Specific to prM Monoantibody Prevent Antibody Dependent Enhancement of Dengue Virus Infection.
Dengue virus (DENV) co-circulates as four serotypes (DENV1-4). Primary infection only leads to self-limited dengue fever. But secondary infection with another serotype carries a higher risk of increased disease severity, causing life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Serotype cross-reactive antibodies facilitate DENV infection in Fc-receptor-bearing cells by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody dependent enhancement (ADE). Most studies suggested that enhancing antibodies were mainly specific to the structural premembrane protein (prM) of DENV. However, there is still no effective drugs or vaccines to prevent ADE. In this study, we firstly confirmed that both DENV-2 infected human sera (anti-DENV-2) and DENV-2 prM monoclonal antibody (prM mAb) could significantly enhance DENV-1 infection in K562 cells. Then we developed anti-idiotypic antibodies (prM-AIDs) specific to prM mAb by immunizing of Balb/c mice. Results showed that these polyclonal antibodies can dramatically reduce ADE phenomenon of DENV-1 infection in K562 cells. To further confirm the anti-ADE effect of prM-AIDs in vivo, interferon-α and γ receptor-deficient mice (AG6) were used as the mouse model for DENV infection. We found that administration of DENV-2 prM mAb indeed caused a higher DENV-1 titer as well as interleukin-10 (IL-10) and alaninea minotransferase (ALT) in mice infected with DENV-1, similar to clinical ADE symptoms. But when we supplemented prM-AIDs to DENV-1 challenged AG6 mice, the viral titer, IL-10 and ALT were obviously decreased to the negative control level. Of note, the number of platelets in peripheral blood of prM-AIDs group were significantly increased at day 3 post infection with DENV-1 compared that of prM-mAb group. These results confirmed that our prM-AIDs could prevent ADE not only in vitro but also in vivo, suggested that anti-idiotypic antibodies might be a new choice to be considered to treat DENV infection.


Selection and use of SNP markers for animal identification and paternity analysis in U.S. beef cattle.
DNA marker technology represents a promising means for determining the genetic identity and kinship of an animal. Compared with other types of DNA markers, single nucleotide polymorphisms (SNPs) are attractive because they are abundant, genetically stable, and amenable to high-throughput automated analysis. In cattle, the challenge has been to identify a minimal set of SNPs with sufficient power for use in a variety of popular breeds and crossbred populations. This report describes a set of 32 highly informative SNP markers distributed among 18 autosomes and both sex chromosomes. Informativity of these SNPs in U.S. beef cattle populations was estimated from the distribution of allele and genotype frequencies in two panels: one consisting of 96 purebred sires representing 17 popular breeds, and another with 154 purebred American Angus from six herds in four Midwestern states. Based on frequency data from these panels, the estimated probability that two randomly selected, unrelated individuals will possess identical genotypes for all 32 loci was 2.0 x 10(-13) for multi-breed composite populations and 1.9 x 10(-10) for purebred Angus populations. The probability that a randomly chosen candidate sire will be excluded from paternity was estimated to be 99.9% and 99.4% for the same respective populations. The DNA immediately surrounding the 32 target SNPs was sequenced in the 96 sires of the multi-breed panel and found to contain an additional 183 polymorphic sites. Knowledge of these additional sites, together with the 32 target SNPs, allows the design of robust, accurate genotype assays on a variety of high-throughput SNP genotyping platforms.


Dietary B vitamins and glioma: A case-control study based on Chinese population.
Dietary antioxidants have long been thought to be likely to prevent the development of gliomas. Previous studies have reported vitamin A, C, and E protective effects against gliomas. B vitamins, one of the main vitamins in the diet, are closely related to human health, but the association with gliomas has rarely been reported. This study aimed to evaluate the relationship between five B vitamins and glioma. In this Chinese population-based case-control study, 506 glioma cases and 506 matched (age and sex) controls were included. The dietary intake of study participants was assessed using a valid 111-item food frequency questionnaire. The intake of five B vitamins was calculated based on participants' dietary information from the food frequency questionnaire. The logistic regression model was used to examine the association between B vitamins and glioma, and the restriction cubic spline evaluated the dose-response relationship between the two. After adjusting for confounding factors, thiamine (OR = 0.09, 95%CI: 0.05-0.20), riboflavin (OR = 0.12, 95%CI: 0.06-0.25), nicotinic acid (OR = 0.24, 95%CI: 0.12-0.47), folate (OR = 0.07, 95%CI: 0.03-0.15) and biotin (OR = 0.14, 95%CI: 0.07-0.30) in the highest tertile were associated with a significantly decreased risk of glioma compared with the lowest tertile. The results of thiamine and biotin in glioma with different pathological types and grades were different. The restricted cubic spline function showed significant dose-response relationships between the intake of five B vitamins and the risk of glioma. When B vitamins exceeded a specific intake, the risk of glioma did not change. Our study suggests that higher dietary intake of thiamine, riboflavin, nicotinic acid, and folate are associated with a decreased risk of glioma, but the results of biotin are not consistent among different populations. In the future, prospective studies should be conducted better to validate the effects of B vitamins on gliomas.


Anxiety Disorders in Family Caregivers of Breast Cancer Patients Receiving Oncologic Treatment in Malaysia
Background: Anxiety is recognized as a normal psychological reaction of those caring for cancer patients. However, anxiety disorders in caregivers may interfere with their care-giving role and require further clinical attention. Objectives: To determine the prevalence and associated factors of anxiety disorders among caregivers of breast cancer patients receiving oncologic treatment in Kuala Lumpur Hospital. Methodology: A cross-sectional study was conducted on 130 caregiver-patient dyads, recruited by non-random sampling at Kuala Lumpur Hospital. Data were collected in 2 stages: 1) the caregivers were screened for psychological distress using the Depression, Anxiety, Stress, Scale (DASS-21) while other related factors for the patients and their caregivers were obtained; 2) the identified distressed caregivers (n=64) were then administered the Mini International Neuropsychiatric Interview (MINI) to diagnose anxiety disorders. Results: A total of 11.5% (n=15) of the caregivers reported suffering from anxiety disorders. Bivariate analysis found duration of caregiving (OR=3.31; CI=2.21-11.93), shared caregiving (OR=4.07; CI=1.34-12.36), and patients' treatment type (OR=3.42; CI=1.92-12.76) were significantly associated with anxiety disorders (p value <0.05), with shared caregiving and patient's treatment type remaining significant using logistic regression (p value < 0.05, R2 = 0.255). Conclusions: Every one in ten of the caregivers in this study had a diagnosable anxiety disorder, associated with certain care-giving factors and patients' treatment. This should alert clinicians to such risk and indicates psychological support needs for family caregivers.


The influence of comorbid personality disorder and neuroticism on treatment outcome in first episode depression.
It has never been investigated whether comorbid personality disorder or neuroticism predicts a poor treatment outcome in first episode depression. Medically treated patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. The patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and a detailed assessment of medical treatment history using standardised procedures (Treatment Response to Antidepressants Questionnaire, TRAQ). Remission was defined as a score of < or =7 on the Hamilton Depression Rating Scale, 17 items, and a score of > or =4 on the TRAQ following (1) a first adequate trial of antidepressant treatment, and (2) 2 trials of antidepressant treatment. Further personality traits were assessed by means of the Eysenck Personality Questionnaire. Among a total of 301 patients with a single depressive episode, 31.9% fulfilled diagnostic criteria for at least 1 personality disorder of any kind. Comorbid personality disorder was associated with a 2.2-times (95% CI: 1.1-4.2) increased risk of non-remission following the first antidepressant trial, whereas no effect was found following the second antidepressant trial (OR: 1.6; 95% CI: 0.8-3.4). A high level of neuroticism was associated with non-remission in first as well as second trials. Comorbid personality disorder and high levels of neuroticism in first episode depression predict an increased risk of non-remission from depression.


Water-soluble coenzyme Q10 formulation in presbycusis: long-term effects.
These findings provide the basis for understanding the duration of the effect after the last use of the drug and encourage a larger clinical trial to collect additional evidence on the effect of coenzyme Q10 (CoQ10) in preventing the development of hearing loss in subjects with presbycusis. The aim of this study was to evaluate the long-term effects of a water-soluble formulation of CoQ10 (Q-TER) in subjects with presbycusis. Sixty patients with presbycusis were included and divided at random into three numerically equal groups. For 30 days, group A underwent therapy with Q-TER, group B underwent therapy with vitamin E, and group C received placebo. Before, at the end, and 6 months after the end of the treatment, all patients underwent evaluation of pure tone audiometry, transient evoked otoacoustic emissions and otoacoustic products of distortion, auditory brainstem response, and speech audiometry. Compared with group B, at the end of the treatment in group A the pure tone audiometry showed a significant (p < 0.05) improvement of the audiometric thresholds at 1000, 2000, 4000, and 8000 Hz. This improvement was confirmed by the speech audiometry and last check. We found no significant differences in the other parameters and in group C.


Can subcellular organization be explained only by physical principles?
In a recent forum article, Dan Needleman and Jan Brugues argue that, despite the astonishing advances in cell biology, a fundamental understanding of even the most well-studied subcellular biological processes is lacking.(1) This lack of understanding is evidenced by our inability to make precise predictions of subcellular and cellular behaviors. They suggest that to achieve such an understanding, we need to apply a combination of quantitative experiments with new theoretical concepts and determine the physical principles of subcellular biological organization.(1) We discuss these issues and suggest that, besides biophysics, we need strong theoretical inputs from biocommunication theory in order to understand all the core agents of the cellular life and subcellular organization.


N-terminal B-type natriuretic peptide urinary concentrations and retinopathy of prematurity.
BackgroundTo validate the findings of a single-center pilot study showing elevated urinary N-terminal B-type natriuretic peptide (NTproBNP) concentrations in preterm infants subsequently developing severe retinopathy of prematurity (ROP) in a multicenter setting across eight European and Middle East countries.MethodsProspective observational study in 967 preterm infants <30 weeks' gestational age assessing the capacity of urinary NTproBNP on days of life (DOLs) 14 and 28 to predict ROP requiring treatment.ResultsUrinary NTproBNP concentrations were markedly elevated in infants who developed ROP requiring treatment (n=94) compared with survivors without ROP treatment (n=837), at both time points (median (interquartile range) DOL14: 8,950 (1,925-23,783) vs. 3,083 (1,193-17,393) vs. 816 (290-3,078) pg/ml, P<0.001) and DOL28 (2,203 (611-4,063) vs. 1,671 (254-11,340) vs. 408 (162-1,126) pg/ml, P<0.001). C-statistic of NTproBNP for treated ROP or death was 0.731 (95% confidence interval 0.654-0.774) for DOL14 and 0.683 (0.622-0.745) for DOL28 (P<0.001). Threshold scores were calculated, potentially enabling around 20% of infants with low NTproBNP scores never to be screened with ophthalmoscopy.ConclusionThere is a strong association between early urinary NTproBNP and subsequent ROP development, which can be used to further refine subgroups of patients with high or low risk of severe ROP.


Real-time observation of reactive spreading of gold on silicon.
The spreading of a bilayer gold film propagating outward from gold clusters, which are pinned to clean Si(111), is imaged in real time by low-energy electron microscopy. By monitoring the evolution of the boundary of the gold film at fixed temperature, a linear dependence of the spreading radius on time is found. The measured spreading velocities in the temperature range of 800 < T < 930 K varied from below 100 pm/s to 50 nm/s. We show that the spreading rate is limited by the reaction to form Au silicide, and the spreading velocity is likely regulated by the reconstruction of the gold silicide that occurs at the interface.


Antithrombotic therapy in end-stage renal disease.
The delicate balance of risk vs. benefit of using antiplatelet and antithrombotic agents in the general population is well established. The decision to use these agents in the end stage renal disease (ESRD) population remains complex and difficult. The concomitant association of a prothombotic state with high risk of bleeding in the ESRD population requires individualization and careful clinical judgment before implementing such therapy. There remains a paucity of clinical trials and lack of substantial evidence in literature for safe and effective use of antithrombotic drugs in patients with advanced chronic kidney disease. The current review summarizes the pros and cons of using antiplatelet and antithrombotic agents in primary and secondary prevention of cardiovascular events, evaluate the risks with routine use of anticoagulation for cerebrovascular stroke prevention with nonvalvular atrial fibrillation and role of newer oral anticoagulants as alternate agents in the dialysis population.


Attitudes about Mechanical Restraint Use in Mental Health Hospitalization Services: A Spanish Survey.
The aim of this study was to analyze the attitudes of professionals in Mental Health Services throughout Spain who are directly or indirectly involved in the use of mechanical restraint and the barriers perceived to reduce its use. The study involved an online anonymous survey using Google Forms completed by Spanish mental health professionals working with service users; the survey assessed their involvement in and general attitudes and beliefs towards mechanical restraint. The survey was completed by 225 participants. Only 13.30% of the participants considered that mechanical restraint use was never necessary to guarantee the safety of users/staff in dangerous situations. Poor staff training (38.0%) and a lack of resources/staff (34.7%) were the most frequent barriers identified for the reduction of mechanical restraint. In the multivariate analysis, participation in learning programs to prevent the use of mechanical restraint was associated with lower acceptance of the use of mechanical restraint, but the result was barely significant (p = 0.050). A high percentage of mental health staff still consider mechanical restraint use necessary for safety reasons. According to the results, the participants perceived that more staff and resources and better training could reduce the use of mechanical restraint in Mental Health Hospitalization Services.


Oxygen-Vacancy-Introduced BaSnO3- δ Photoanodes with Tunable Band Structures for Efficient Solar-Driven Water Splitting.
To achieve excellent photoelectrochemical water-splitting activity, photoanode materials with high light absorption and good charge-separation efficiency are essential. One effective strategy for the production of materials satisfying these requirements is to adjust their band structure and corresponding bandgap energy by introducing oxygen vacancies. A simple chemical reduction method that can systematically generate oxygen vacancies in barium stannate (BaSnO3 (BSO)) crystal is introduced, which thus allows for precise control of the bandgap energy. A BSO photoanode with optimum oxygen-vacancy concentration (8.7%) exhibits high light-absorption and good charge-separation capabilities. After deposition of FeOOH/NiOOH oxygen evolution cocatalysts on its surface, this photoanode shows a remarkable photocurrent density of 7.32 mA cm-2 at a potential of 1.23 V versus a reversible hydrogen electrode under AM1.5G simulated sunlight. Moreover, a tandem device constructed with a perovskite solar cell exhibits an operating photocurrent density of 6.84 mA cm-2 and stable gas production with an average solar-to-hydrogen conversion efficiency of 7.92% for 100 h, thus functioning as an outstanding unbiased water-splitting system.


Radiomics Analysis Based on Automatic Image Segmentation of DCE-MRI for Predicting Triple-Negative and Nontriple-Negative Breast Cancer.
To investigate whether quantitative radiomics features extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could be used to differentiate triple-negative breast cancer (TNBC) and nontriple-negative breast cancer (non-TNBC). This retrospective study included DCE-MRI images of 81 breast cancer patients (44 TNBC and 37 non-TNBC) from August 2018 to October 2019. The MR scans were achieved at a 1.5 T MR scanner. For each patient, the largest tumor mass was selected to analyze. Three-dimensional (3D) images of the regions of interest (ROIs) were automatically segmented on the third DCE phase by a deep learning segmentation model; then, the ROIs were checked and revised by 2 radiologists. DCE-MRI radiomics features were extracted from the 3D tumor volume. The patients were randomly divided into training (N = 57) and test (N = 24) cohorts. The machine learning classifier was built in the training dataset, and 5-fold cross-validation was performed on the training cohort to train and validate. The data of the test cohort were used to investigate the predictive power of the radiomics model in predicting TNBC and non-TNBC. The performance of the model was evaluated by the area under receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. The radiomics model based on 15 features got the best performance. The AUC achieved 0.741 for the cross-validation, and 0.867 for the independent testing cohort. The radiomics model based on automatic image segmentation of DCE-MRI can be used to distinguish TNBC and non-TNBC.


Neglected losses and key costs: tracking the energetics of walking and running.
As one of the most energetically demanding daily activities, locomotion has attracted substantial investigative attention. Although legged locomotion has been well described, it is currently not well understood. Looking at energy accounting might be a good pathway with which to solve this problem. One relatively simple way of analyzing energy management is to look directly at the flow of mechanical energy into and out of the system, in terms of costs and losses (with some attention to the mechanisms responsible for this flow). In this commentary we argue that a key source of energetic loss has largely been neglected: the redirection of body motion from downward to upward at each step. We discuss the role of this loss and the compensating energetic costs, identifying some of the general features of the trade-offs that determine gait optimization strategies. We find that even at a conceptual level, a focus on the main mechanism of loss and the strategies available to the organism to effectively compensate for losses can yield substantial insight into observations as diverse as the functional limits of a playground swing through to the strikingly different effect of reduced gravity on human walking and running. Such insight changes the interpretation of fundamental features of leg function, such as push-off timing and the role of elastic deflection during stance.


Kinetic Analysis Reveals the Role of Secondary Nucleation in Regenerated Silk Fibroin Self-Assembly.
Silk proteins obtained from the Bombyx mori silkworm have been extensively studied due to their remarkable mechanical properties. One of the major structural components of this complex material is silk fibroin, which can be isolated and processed further in vitro to form artificial functional materials. Due to the excellent biocompatibility and rich self-assembly behavior, there has been sustained interest in such materials formed through the assembly of regenerated silk fibroin feedstocks. The molecular mechanisms by which the soluble regenerated fibroin molecules self-assemble into protein nanofibrils remain, however, largely unknown. Here, we use the framework of chemical kinetics to connect macroscopic measurements of regenerated silk fibroin self-assembly to the underlying microscopic mechanisms. Our results reveal that the aggregation of regenerated silk fibroin is dominated by a nonclassical secondary nucleation processes, where the formation of new fibrils is catalyzed by the existing aggregates in an autocatalytic manner. Such secondary nucleation pathways were originally discovered in the context of polymerization of disease-associated proteins, but the present results demonstrate that this pathway can also occur in functional assembly. Furthermore, our results show that shear flow induces the formation of nuclei, which subsequently accelerate the process of aggregation through an autocatalytic amplification driven by the secondary nucleation pathway. Taken together, these results allow us to identify the parameters governing the kinetics of regenerated silk fibroin self-assembly and expand our current understanding of the spinning of bioinspired protein-based fibers, which have a wide range of applications in materials science.


The heart in neurofibromatosis type 1: an echocardiographic study.
Comprehensive data are unavailable for cardiac abnormalities in patients with neurofibromatosis type 1 (NF1). The goal of this study was to evaluate the prevalence of cardiovascular abnormalities with echocardiography with color Doppler scan (ECHO) in a large, consecutive series of patients with NF1. We studied 48 patients with NF1 (mean age, 10 years). Thirty healthy subjects comparable for age and sex served as the control group. All ECHO studies were performed by the same cardiologist and reviewed by a second cardiologist blinded to the physical findings of the subjects. Cardiac abnormalities were found in 13 of the 48 young patients (27%). A secundum atrial septal defect with a left to right shunt was found in 2 children. ECHO evidence of mild left pulmonary artery stenosis was found in 1 participant. A moderate coarctation of the thoracic aorta was found in 1 patient. ECHO criteria for mitral valve prolapse and evidence of trivial mitral regurgitation with myxomatous mitral valve was present in 1 case. Mild mitral regurgitation was found in 2 patients. A regurgitant mild flow signal was detected from the aortic valve in 2 subjects. Atrial septal aneurysm was found in 2 patients without patent foramen ovale. Two patients had septal to posterior left ventricular free wall ratio greater than 1.5, suggesting hypertrophic cardiomyopathy. This is the first attempt to evaluate the prevalence of cardiovascular abnormalities in patients with NF1 with ECHO. The study's most striking finding is the high prevalence of cardiovascular abnormalities. Congenital lesions have potential long-term hemodynamic consequences that justify an early diagnosis. Thus, a cardiologic assessment at regular intervals, including ECHO study, is mandatory for patients with NF1.


Screening and Molecular Docking of Novel Benzothiazole Derivatives as Potential Antimicrobial Agents.
The burden of antibiotic resistance necessitates a continued search for new antimicrobials. We evaluated the antimicrobial activities of novel benzothiazoles synthesized by our group. Antibacterial activity was evaluated in vitro in Staphylococcus aureus, Bacillus subtilis, and Escherichia coli, while the antifungal activity was tested in Candida albicans and Aspergillus niger, and expressed as the minimum inhibitory concentration (MIC; µg/mL). MIC values of benzothiazole compounds ranged from 25 to 200 µg/mL. Compounds 3 and 4 gave high antibacterial and moderate antifungal activities, while 10 and 12 showed moderate activity against all tested organisms. In addition, some benzothiazole compounds significantly suppressed the activity of Escherichia coli dihydroorotase and inhibited the dimorphic transition of Candida albicans. Moreover, the active benzothiazole compounds induced DNA and protein leakage in Aspergillus niger spores. Molecular interactions of benzothiazole derivatives with dihydroorotase revealed the formation of hydrogen bonds with the active site residues LEU222 or ASN44. Strong hydrophobic interactions of the bulky thiazole and naphthalene rings at the entrance to the active site might interfere with the access of substrates to their binding sites, which results in dihydroorotase inhibition. Thus, inhibition of dihydroorotase might contribute to the observed antimicrobial actions of these compounds.


miR-33a-5p inhibits the progression of esophageal cancer through the DKK1-mediated Wnt/β-catenin pathway.
Esophageal cancer (EC) is one of the most lethal malignancies in humans, and multiple miRNAs have been identified to modulate EC progression by targeting different targets. However, the effect and related mechanism of microRNA-33a-5p (miR-33a-5p) on EC development remain elusive. In this study, we explored the clinical value, function, and possible mechanism of miR-33a-5p in EC. We uncovered that miR-33a-5p and DKK1 are involved in the progression of EC. Significantly, the expression levels of miR-33a-5p were reduced and DKK1 levels were elevated in serum and tissues of clinical EC samples and in EC cell lines. The downregulation of miR-33a-5p and DKK1 upregulation were related to high TNM staging and poor differentiation of patients. The area under the curves (AUCs) of miR-33a-5p and DKK1 for the occurrence of EC were 0.914 and 0.900, respectively. Down-regulation of miR-33a-5p or overexpression of DKK1 indicated a worse prognosis. The miR-33a-5p overexpression or DKK1 depletion induced apoptosis and repressed proliferation, migration, and invasion of EC cells. The repression of miR-33a-5p by inhibitor or DKK1 overexpression presented the conversed effects on EC cells. Mechanically, miR-33a-5p suppressed DKK1 expression, and miR-33a-5p targeted DKK1 to affect the biological behavior of EC through the Wnt/β-catenin pathway. Meanwhile, miR-33a-5p inhibited the tumor growth of EC in vivo. Thus, we concluded that miR-33a-5p inhibited the progression of EC through the DKK1-mediated Wnt/β-catenin pathway. MiR-33a-5p and DKK1 can be used as potential therapeutic targets of EC.


Human brucellosis in Kuwait: a prospective study of 400 cases.
The clinical pattern of 400 cases of brucellosis in Kuwait is presented. The disease was acute in 77 per cent, sub-acute in 12.5 per cent and chronic in 10.5 per cent of cases. Raw milk was the major source of infection. The major features on presentation, irrespective of the course of the disease, were fever, sweating, headache, rigors, arthralgia, myalgia, and low back pain. Hepatosplenomegaly was present in 41 per cent of cases and in 32 per cent neither liver nor spleen were palpable. The haematologic findings were not specific and hepatic dysfunction (shown by liver enzyme abnormalities) was common. Skeletal (26 per cent) and genital (8.5 per cent) changes and neurobrucellosis (7 per cent) were the major complications. The ELISA was the most sensitive and reliable diagnostic test especially in relation to chronic brucellosis and neurobrucellosis. ELISA allowed the determination of brucella-specific immunoglobulins (Ig)G, IgM and IgA in the CSF, and provided profiles of Ig, in sera, which were different in patients with chronic (elevated IgG and IgA) from those with acute (elevated IgM alone or IgG, IgM and IgA) brucellosis. Treatment with tetracycline, doxycycline or rifampicin gave a cure rate of over 91 per cent in acute and subacute brucellosis. Co-trimoxazole was associated with a relapse rate of 50 per cent. Two drug combinations of streptomycin and tetracycline, streptomycin and rifampicin or streptomycin and doxycycline were effective, but one of five patients with chronic brucellosis relapsed. A combination of streptomycin, tetracycline and rifampicin with or without steroids was used successfully in neurobrucellosis, septicaemic shock and subacute bacterial endocarditis.


Transient Fatigue is Not Influenced by Ball-In-Play Time During Elite Rugby League Matches.
Waldron, M, Thomson, E, Highton, J, and Twist, C. Transient fatigue is not influenced by ball-in-play time during elite rugby league matches. J Strength Cond Res 33(1): 146-151, 2019-The capacity to sustain high-speed running is important for rugby league players. Transient fatigue, described as a reduction in high-speed running in the 5 minutes after a peak 5-minute period, is a phenomenon observed during rugby league matches. This concept has recently been questioned based on the proposed confounding influence of ball-in-play time during these periods. Therefore, this study examined the changes in high-speed running (>14 km·h) of elite rugby league players, and ball-in-play time, during the peak, subsequent, and mean 5-minute periods of 5 competitive matches using 5-Hz Global Positioning System devices. The suitability of ball-in-play time as a covariate was also evaluated. The high-speed running and ball-in-play time was different between peak (26.7 ± 5.5 m·min and 177 ± 37 seconds) and subsequent (12.1 ± 6.2 m·min and 147 ± 37 seconds) 5-minute periods (p ≤ 0.05; most likely ↓). However, there was no relationship (r = 0.01 to -0.13; p > 0.05) between ball-in-play time and high-speed running, and ball-in-play time was not independent of the match period. This study has reaffirmed the presence of transient fatigue during elite rugby league matches but questioned the influence of ball-in-play time as a confounding factor. These observations have implications for the design of appropriate training practices and informing tactical strategies used by coaches. Most importantly, any practitioner wishing to measure transient fatigue could follow a similar statistical approach taken herein and based on the current findings would not need to account for ball-in-play time as a confounding variable.


Help for 'mini A&Es'.
Mike Paynter, a nurse consultant in urgent care at a Somerset trust, set up a telemedicine service in 2008 that gives clinicians at major injuries units access to fast, expert interpretation of ECG results. The service prevents an estimated 900 acute admissions a year.


The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission.
It has been reported that fluoride exposure may cause serious public health problems, particularly neurotoxicity. However, the underlying mechanisms remain unclear. This study used Neuro-2A cells to investigate the effects of fluoride on the cytoskeleton. The Neuro-2A cells were exposed to 0, 1, 2, 4 and 6 mM sodium fluoride (NaF) for 24 h. Cell viability and lactate dehydrogenase (LDH) release were examined. It was observed that exposure to NaF reduced cell viability, disrupted cellular membrane integrity, and high levels of LDH were released. The observed changes occurred in a dose response manner. Morphologic observations showed that cell became rounded and were loosely adherent following exposure to NaF. Axon spines and normal features disappeared with high dose NaF treatment. The expression of MAP2 and synaptophysin decreased, particularly at 4 mM and 6 mM (P < 0.05) for MAP2. These results corroborate the morphologic observations. The content of glutamate and NMDAR (glutamate receptor) protein were assessed to help understand the relationship between synapses and neurotransmitter release using ELISA and Western-blot. Compared with the control, glutamate and NMDAR expression declined significantly at 4 mM and 6 mM (P < 0.05) group. Finally, the ultrastructural changes observed with increasing doses of NaF were: disappearance of synapses, mitochondrial agglutination, vacuole formation, and cellular edema. Taken together, NaF exposure disrupted cellular integrity and suppressed the release of neurotransmitters, thus effecting neuronal function. These findings provide deeper insights into roles of NaF in neuron damage, which could contribute to a better understanding of fluoride-induced neurotoxicity.


Outcomes, readmissions, and costs in transfemoral and alterative access transcatheter aortic valve replacement in the US Medicare population.
To comprehensively evaluate and compare utilization, outcomes, and especially costs of transfemoral (TF), transapical (TA), and transaortic (TAO) transcatheter aortic valve replacement (TAVR). All Medicare fee-for-service patients undergoing TF (n = 4065), TA (n = 691), or TAO (n = 274) TAVR between January 1, 2011, and November 30, 2012, were identified using Health Care Procedure Classification Codes present on Medicare claims. Hospital charges from Medicare claims were converted to costs using hospital-specific Medicare cost-to-charge ratios. TA and TAO patients were similar in age, race, and common comorbidities. Compared with TF patients, TA and TAO patients were more likely to be female and to have peripheral vascular disease, chronic lung disease, and renal failure. Thirty-day mortality rates were higher among TA and TAO patients than among TF patients (TA, 9.6%; TAO, 8.0%; TF, 5.0%; P < .001). Adjusted mortality beyond 1 year did not differ by access. TA patients were more likely to require cardiopulmonary bypass (CPB). Increased adjusted mortality was associated with CPB (hazard ratio, 2.13; P < .01) and increased 30-day cost ($62,000 [interquartile range (IQR)], $45,100-$86,400 versus $48,800 [IQR, $38,100-$62,900]; P < .01). Cost at 30 days was lowest for TF ($48,600) compared with TA ($49,800; P < .01) and TAO ($53,200; P = .03). For patients ineligible to receive TF TAVR, TAO and TA approaches offer similar clinical outcomes at similar cost with acceptable operative and 1-year survival, except for higher rates of CPB use in TA patients. CPB was associated with worse survival and increased costs.


[Platelets and arterial thrombosis].
The pathological mechanisms involved in arterial thrombus formation are similar to the mechanisms involved in physiological hemostasis. Arterial thrombosis is initiated following lesion of the vessel wall, either through rupture of an atherosclerotic plaque containing lipids, adhesive proteins and tissue factor or after angioplasty exposing the thrombogenic subendothelial matrix. Platelets play a major role in arterial thrombus formation through ADP secretion and thrombin generation on their activated surface. Arterial thrombosis is a frequent complication of atherosclerotic lesions and leads to acute ischemic events. These events are therapeutic emergencies which require administration of antithrombotic drugs inhibiting platelet functions and thrombin.


The mechanosensory lateral line is used to assess opponents and mediate aggressive behaviors during territorial interactions in an African cichlid fish.
Fish must integrate information from multiple sensory systems to mediate adaptive behaviors. Visual, acoustic and chemosensory cues provide contextual information during social interactions, but the role of mechanosensory signals detected by the lateral line system during aggressive behaviors is unknown. The aim of this study was first to characterize the lateral line system of the African cichlid fish Astatotilapia burtoni and second to determine the role of mechanoreception during agonistic interactions. The A. burtoni lateral line system is similar to that of many other cichlid fishes, containing lines of superficial neuromasts on the head, trunk and caudal fin, and narrow canals. Astatotilapia burtoni males defend their territories from other males using aggressive behaviors that we classified as non-contact or contact. By chemically and physically ablating the lateral line system prior to forced territorial interactions, we showed that the lateral line system is necessary for mutual assessment of opponents and the use of non-contact fight behaviors. Our data suggest that the lateral line system facilitates the use of non-contact assessment and fight behaviors as a protective mechanism against physical damage. In addition to a role in prey detection, the diversity of lateral line morphology in cichlids may have also enabled the expansion of their social behavioral repertoire. To our knowledge, this is the first study to implicate the lateral line system as a mode of social communication necessary for assessment during agonistic interactions.


Effect of molecular targeted agents in chemotherapy for treating platinum-resistant recurrent ovarian cancer: A systematic review and meta-analysis.
This study aimed to investigate the effect of molecular targeted agents (MTAs) in chemo on platinum-resistant recurrent ovarian cancer (ROC). We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements. Randomized controlled trials reporting data about platinum-resistant ovarian cancer treated by MTAs were included. The endpoints for the present study included overall survival and progression-free survival. We analyzed 9 randomized controlled trials including 3631 patients with ROC. The pooled analysis indicated that a combination of MTAs with chemo could markedly increase objective response rate in those patients (P = .012). Nevertheless, the survival rate of those patients was not markedly changed (P = .19). Besides, the combination of MTAs with chemo dramatically aggravated the occurrence of adverse events (P < .05). Moreover, it resulted in the termination of treatment (P = .044) in those patients, but it had no effect on fatal adverse events (P = .16). Our results indicated that the combination of MTAs with chemo notably improved objective response rate in patients with platinum-resistant ROC, but its benefit did not translate into survival benefits.


Forebrain neurogenesis: From embryo to adult.
A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16-17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis: From embryo to adult. The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with 'state of the art' techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.


Chemical synthesis of homogeneous glycopeptides and glycoproteins.
Oligosaccharides linked to proteins are known to play important roles in several biological events. However, oligosaccharides are heterogeneous, which has hindered detailed elucidation of oligosaccharide functions. In order to solve this problem, glycoproteins having homogeneous oligosaccharides have long been required. For this purpose, an efficient preparative method of complex-type oligosaccharides has been investigated from a natural source and this method was found to afford over 24 kinds of diverse complex-type oligosaccharides by use of chemical methods and branch-specific sequential glycosidase digestion. The sufficient amount of homogeneous complex type oligosaccharides obtained enabled us to examine the synthesis of homogeneous glycopeptides as well as glycoproteins by use of solid phase glycopeptide synthetic method and native chemical ligation. This review describes recent progress related to the efficient method of oligosaccharide preparation and synthesis of glycoproteins including bioactive erythropoietin.


Thermoresponsive Brushes Facilitate Effective Reinforcement of Calcium Phosphate Cements.
Calcium phosphate ceramics are frequently applied to stimulate regeneration of bone in view of their excellent biological compatibility with bone tissue. Unfortunately, these bioceramics are also highly brittle. To improve their toughness, fibers can be incorporated as the reinforcing component for the calcium phosphate cements. Herein, we functionalize the surface of poly(vinyl alcohol) fibers with thermoresponsive poly(N-isopropylacrylamide) brushes of tunable thickness to improve simultaneously fiber dispersion and fiber-matrix affinity. These brushes shift from hydrophilic to hydrophobic behavior at temperatures above their lower critical solution temperature of 32 °C. This dual thermoresponsive shift favors fiber dispersion throughout the hydrophilic calcium phosphate cements (at 21 °C) and toughens these cements when reaching their hydrophobic state (at 37 °C). The reinforcement efficacy of these surface-modified fibers was almost double at 37 versus 21 °C, which confirms the strong potential of thermoresponsive fibers for reinforcement of calcium phosphate cements.


Effects of dietary exposure to brominated flame retardant BDE-47 on thyroid condition, gonadal development and growth of zebrafish.
Little is known about the effects of brominated flame retardants in teleosts and some of the information currently available is inconsistent. This study examined effects of dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on thyroid condition, body mass and size, and gonadal development of zebrafish. Pubertal, 49-day-old (posthatch) fish were fed diets without BDE-47 (control) or with 1, 5 or 25 μg/g BDE-47/diet. Treatments were conducted in triplicate 30-L tanks each containing 50 zebrafish, and 15 fish per treatment (5 per tank) were sampled at days 40, 80 and 120 of exposure. Measurements were taken of body mass, standard length, head depth and head length. Sex (at 40-120 days of exposure), germ cell stage (at 40 days) and thyroid condition (at 120 days; follicular cell height, colloid depletion, angiogenesis) were histologically determined. Whole-body BDE-47 levels at study completion were within the high end of levels reported in environmentally exposed (wild) fishes. Analysis of variance was used to determine differences among treatments at each sampling time. No effects were observed on thyroid condition or germ cell stage in either sex. Reduced head length was observed in females exposed to BDE-47 at 80 days but not at 40 or 120 days. In males, no apparent effects of BDE-47 were observed at 40 and 80 days, but fish exposed to 25 μg/g had lower body mass at 120 days compared to control fish. These observations suggest that BDE-47 at environmentally relevant whole-body concentrations does not affect thyroid condition or pubertal development of zebrafish but does affect growth during the juvenile-to-adult transition, especially in males.


Current gene-mapping strategies in experimental models of multiple sclerosis.
Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesis-driven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers.


In Silico Evaluation of Ferulic Acid Based Multifunctional Conjugates as Potential Drug Candidates.
Recent research has shown that ferulic acid (FA, trans-4-hydroxy-3- methoxycinnamic acid) has remarkable antioxidant properties and a wide range of biological activities. Conjugation of two or more biologically active compounds to produce a novel molecular scaffold is justified by the need to enhance biological activity against a single target or obtain a conjugate that behaves as a multi-target-directed ligand. In addition, the conjugation strategy decreases dose-dependent side effects by promoting the use of smaller doses of conjugated components to treat the disease. Moreover, the patient's compliance is positively affected when conjugating two active compounds into a single more active compound as this reduces the number of pills to be taken daily. This study aims to shed light on studies that design and synthesize FA-based hybrid compounds with enhanced biological activities and to in silico assess these compounds as potential drug candidates. The conjugate compounds were found by searching the literature using the keywords (ferulic acid-based hybrid or ferulic acid-based conjugate). To study conjugate pharmacokinetic parameters and toxicity (ADMET), software suites from Biovia Inc. (San Diego, California) were integrated into Discovery Studio 4.5. The structures were created using ChemDraw Ultra 7.0. 14 conjugates exhibiting variable biological activities were collected and three of them (compounds 3,5,and 6) in addition to the cis FA (compound 12) are the best-predicted compounds with low Daphnia toxicity and hepatotoxicity with acceptable pharmacokinetic properties. Cis FA, FA conjugates 3,5,and 6 act as good drug candidates that can be used to modify new hits.


Laparoscopic Pyeloplasty for Ureteropelvic Junction Obstruction Following Open Pyeloplasty in Children.
Few studies have evaluated the role of laparoscopic dismembered pyeloplasty in the setting of recurrent ureteropelvic junction (UPJ) obstruction following open dismembered pyeloplasty in the pediatric population. We present our experience at a single institution. A retrospective analysis was performed of patients treated with laparoscopic pyeloplasty for secondary UPJ obstruction from March 2003 to August 2011 at a single institution. These patients were age and temporally matched with a control group of patients undergoing primary laparoscopic pyeloplasty. In total, 5 patients were identified as having undergone laparoscopic pyeloplasty for secondary UPJ obstruction following open dismembered pyeloplasty. Operative time was longer in the secondary repair group compared with the control group (190 versus 141 minutes; P = .24), although this was complicated by 1 patient in the secondary repair group undergoing multiple procedures. Morphine equivalent use and length of stay were similar (4.1 versus 6.6 mg [P = .21] and 1.4 versus 1.2 days [P = .67] in control patients versus secondary repair patients, respectively). All of the 5 (100%) patients undergoing secondary repair had successful outcomes with improved hydronephrosis on ultrasound, and 4 of 4 (100%) had improved or normal T½ times on postoperative mercaptoacetyltriglycine (MAG3) renal scan. One family in each group declined the renal scan for personal reasons. No complications were noted with a mean follow-up time of 13 months in both groups. Laparoscopic repair of secondary UPJ obstruction is a well-tolerated and effective option. When this technique is compared with primary laparoscopic pyeloplasty, results appear equivalent even after failed open repair, with comparable postoperative narcotic requirement and length of stay. Further studies are needed to better define the role of secondary laparoscopic pyeloplasty in the pediatric population, especially with regard to cost compared with other open and minimally invasive techniques.


Induction therapy with short-term high-dose intravenous cyclophosphamide followed by mycophenolate mofetil in proliferative lupus nephritis.
For decades, high-dose intravenous cyclophosphamide (ivCY) given for 24-30 months was regarded as the standard therapy for proliferative lupus nephritis, despite serious side effects. Our aim was to evaluate the effect of induction therapy with short-term high-dose ivCY followed by mycophenolate mofetil (MMF) on disease parameters, mortality and health-related quality of life (HRQoL) in patients with proliferative lupus nephritis. Between January 2003 and November 2006, 71 patients with biopsy-proven proliferative lupus nephritis were included in the second Dutch Lupus Nephritis Study. All patients were treated with ivCY (750 mg÷m2, six monthly pulses) plus oral prednisone, followed by MMF (2000 mg÷day) plus oral prednisone for 18 months, and then azathioprine (2 mg÷kg÷day) plus oral prednisone. Study endpoints included the occurrence of renal relapse, end-stage renal disease (ESRD) and mortality. After a median follow-up of 3.8 years (range 0.1-4.5), four (5.6%) of the 71 patients had a renal relapse, one (1.4%) failed treatment, one (1.4%) reached ESRD, and two (2.8%) died. Systemic lupus erythematosus (SLE) Disease Activity Index, serum creatinine, proteinuria and antibodies against anti-dsDNA decreased significantly during treatment and serum levels of complement factor 3 and 4 increased significantly. Furthermore, six of eight domains of the Short Form-36 as well as the number of symptoms and total distress level according to the SLE Symptom Checklist improved significantly over time. This open-label study shows that induction therapy with short-term (six monthly pulses) high-dose ivCY followed by MMF is effective in preventing renal relapses, ESRD and mortality and improving HRQoL in patients with proliferative lupus nephritis.


An EPID-based method for comprehensive verification of gantry, EPID and the MLC carriage positional accuracy in Varian linacs during arc treatments.
In modern radiotherapy, it is crucial to monitor the performance of all linac components including gantry, collimation system and electronic portal imaging device (EPID) during arc deliveries. In this study, a simple EPID-based measurement method has been introduced in conjunction with an algorithm to investigate the stability of these systems during arc treatments with the aim of ensuring the accuracy of linac mechanical performance. The Varian EPID sag, gantry sag, changes in source-to-detector distance (SDD), EPID and collimator skewness, EPID tilt, and the sag in MLC carriages as a result of linac rotation were separately investigated by acquisition of EPID images of a simple phantom comprised of 5 ball-bearings during arc delivery. A fast and robust software package was developed for automated analysis of image data. Twelve Varian linacs of different models were investigated. The average EPID sag was within 1 mm for all tested linacs. All machines showed less than 1 mm gantry sag. Changes in SDD values were within 1.7 mm except for three linacs of one centre which were within 9 mm. Values of EPID skewness and tilt were negligible in all tested linacs. The maximum sag in MLC leaf bank assemblies was around 1 mm. The EPID sag showed a considerable improvement in TrueBeam linacs. The methodology and software developed in this study provide a simple tool for effective investigation of the behaviour of linac components with gantry rotation. It is reproducible and accurate and can be easily performed as a routine test in clinics.


Red organic light-emitting radical adducts of carbazole and tris(2,4,6-trichlorotriphenyl)methyl radical that exhibit high thermal stability and electrochemical amphotericity.
Synthesis and characterization of new carbazolyl derivatives with a pendant stable radical of the TTM (tris-2,4,6-trichlorophenylmethyl radical) series are reported. The EPR spectra, electrochemical properties, absorption spectra, and luminescent properties of these radical adducts have been studied. All of them show electrochemical amphotericity being reduced and oxidized to their corresponding stable charged species. The luminescence properties of them cover the red spectral band of the emission. The luminescence of the electron-rich carbazole adducts shows the donor-acceptor nature of the excited state. On the other hand, the EPR parameters of these radical adducts show an imperceptible variation with the substituents in the carbazole.


Anatomical Relationships between Muscles Overlying Distal Transverse Carpal Ligament and Thenar Motor Branch of the Median Nerve.
The purpose of the current study is to investigate anatomical relationships between the muscle overlying the distal transverse carpal ligament (TCL) and the thenar motor branch of the median nerve. Of the 192 wrists that underwent open carpal tunnel release, a muscle belly overlying the TCL was observed on the distal margin of TCL in 25 wrists and ligament exposure could not be achieved without transection of it. We recorded surgical findings of these 25 wrists. The origin of the recurrent motor branch arising from the major median nerve was marked on the axial and coronal section diagrams of the wrist. The presence of muscle overlying the TCL was seen in 25 wrists (21 patients, 13%). The locations of origin were distributed not only on the radial side but anterior or ulnar side of the major median nerve. Abnormal branches originated from the unusual side in 14 cases (56% of those with a muscle overlying the TCL): central-anterior side in eight cases, ulnar-anterior side in five cases, and ulnar side in one case. These anomalous branches were frequently associated with the muscle belly overlying the TCL in our study regardless of the origin site. The branches were prone to cut if careless midline incision along the third web space was performed. Unusual origin and aberrant pathway of the recurrent thenar motor branch were associated with the presence of a muscle overlying the TCL. A thorough knowledge of the standard and variant anatomy of the muscle belly and recurrent motor branch in the carpal tunnel is fundamental to prevention of complications such as muscle wasting or atrophy by iatrogenic motor branch injury during carpal tunnel release.


Elastic properties and structure of the radial artery in patients with type 2 diabetes.
Alterations of elastic properties may contribute to the accelerated atherosclerosis in patients with T2D. Little is known, however, about radial artery distensibility in this patient group. A total of 19 patients with T2D and 19 controls were investigated.An echotracking system coupled to a plethysmograph was used to assess the morphologic and elastic properties of radial artery. Distensibility and compliance were evaluated using Langewouters' equations. Distensibility and compliance did not differ significantly in patients with diabetes compared with controls. In contrast, radial IMT and WCSA were significantly higher in patients with T2D than in controls. Multiple regression analyses revealed a significant association between SBP and IMT (r(2) = 0.40, p<0.001) as well as WCSA (r = 0.54; r(2) = 0.30; p<0.001 ) in individuals with diabetes. In conclusion, distensibility and compliance of the radial artery are not reduced in patients with T2D. In contrast, radial IMT and WCSA are significantly higher in patients with T2D than in controls.These modifications are chiefly and positively related to SBP.


An integrated psychosocial-spiritual model for cancer pain management.
Cancer pain is known to be a multidimensional and complex experience that can cause severe suffering and can lessen quality of life. The psychosocial and spiritual aspects of cancer pain play an important role in this phenomenon. This article describes a multidisciplinary model for cancer pain management that focuses on the psychosocial and spiritual aspects of cancer pain and the needs of patients. This multidisciplinary model has been organized to provide the most effective pain management to a variety of patients within a comprehensive cancer center. Our model includes multiple oncology mental health professionals, including psychologists, social workers, spiritual care providers, and psychiatrists. Each discipline provides a unique assessment and an evaluation of the needs of patients with cancer pain and their support system that is integrated into a comprehensive treatment plan. Regular collaboration occurs between disciplines to ensure that the patients receive optimal pain management. This model provides a framework from which treatment interventions can be implemented. The emphasis on consistent collaboration between disciplines is a vital component in providing effective cancer pain management. This multidisciplinary psychosocial-spiritual model can be replicated, modified, or both, to become standard practice in other comprehensive cancer centers.