Moral Distress and Its Relating Factors Among Pediatric Emergency Department Nurses: A Cross-Sectional Study.
Emergency services are patient circulation units that require chaos, trauma, and high tension. It was aimed to determine the moral distress levels of pediatric nurses in pediatric emergency and emergency departments and relevant factors. This study is a descriptive and cross-sectional study. It consists of 255 nurses with their data. The Participant Information Form and the Moral Distress Scale-Revised for Pediatric Nurses (MDS-R) were used to collect data. In the study, the mean score of MDS-R frequency was found to be 27.36 ± 13.16, the mean score of MDS-R intensity to be 37.65 ± 17.53, and the mean total score of MDS-R to be 58.96 ± 39.40. It was determined that 93.7% of the nurses received training on moral distress, and education level was effective on moral distress levels of the nurses. The nurses working in the pediatric emergency service had higher moral distress levels than the nurses serving pediatric patients in the emergency department ( P(total MDS-R) = 0.02, P(frequency of MDS-R) = 0.008). Job satisfaction ( P(total MDS-R) = 0.003, P(frequency of MDS-R) < 0.001, P(intensity of MDS-R) < 0.001) and frequency of thinking about changing working unit ( P(frequency of MDS-R) = 0.02, P(intensity of MDS-R) = 0.01) were found to be effective on the level of moral distress. It was determined that the type of emergency service, the working time in the emergency service, and the level of job satisfaction significantly affected the total moral distress scores of the nurses ( P < 0.001, R2 = 0.09). It was found in the study that nurses had low levels of moral distress; however, many factors relevant to working conditions were associated with moral distress. The pediatric emergency service nurses were determined to experience a higher moral distress compared with the emergency department nurses serving pediatric patients.


Signaling Pathways Controlling Microglia Chemotaxis.
Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.


[Mn2+-doped Prussian blue nanoparticles for T1-T2 dual-mode magnetic resonance imaging and photothermal therapy in vitro].
To prepare Mn2+-doped Prussian blue nanoparticles (Mn-PB NPs) for T1-T2 dual-mode magnetic resonance imaging (MRI) and photothermal therapy in vitro. Mn-PB NPs were prepared based on manganese chloride, ferrous chloride and potassium ferricyanide using the microemulsion method. The performance of T1-T2 dual-mode MRI with Mn-PB NPs and the photothermal property of the nanoparticles were assessed. CCK-8 assay and AM/PI double staining were used to evaluate the effect of photothermal therapy in vitro using the parepared nanoparticles. The prepared Mn-PB NPs had a mean particle size of 39.46±0.42 nm with a Zeta potential of -25.9±1.2 mV and exhibited a good dispersibility and uniform particle size. In MRI using the nanoparticles, the r1 and r2 values reached 0.68 and 3.65 (mmol/L)-1s-1, respectively, indicating good performance of Mn-PB NPs for T1 and T2 enhancement in MRI. When irradiated with 808 nm laser for 10 min, Mn-PB NPs showed a temperature rise to 90 ℃ to cause significant reduction of cell survival. CCK-8 assay and AM/PI double staining confirmed that Mn-PB NPs were capable of efficient killing of HepG2 cells upon 808 nm laser irradiation. The Mn-PB NPs prepared in this work have uniform particle size and show good performances both in MRI for T1 and T2 enhancement and in photothermal therapy in vitro without obvious cytotoxicity.


Graft revascularization is essential for non-invasive monitoring of transplanted islets with radiolabeled exendin.
Islet transplantation is a novel promising strategy to cure type 1 diabetes. However, the long-term outcome is still poor, because both function and survival of the transplant decline over-time. Non-invasive imaging methods have the potential to enable monitoring of islet survival after transplantation and the effects of immunosuppressive drugs on transplantation outcome. (111)In-labeled exendin-3 is a promising tracer to visualize native and transplanted islets by SPECT (Single Photon Emission Computed Tomography). In the present study, we hypothesized that islet microvasculature plays an important role determining the uptake of exendin-3 in islets when monitoring transplant survival. We observed (111)In-exendin-3 accumulation in the transplant as early as three days after transplantation and an increase in the uptake up to three weeks post-transplantation. Islet-revascularization correlated with the increase in (111)In-exendin-3 uptake, whereas fully re-established islet vasculature coincided with a stabilized uptake of the radiotracer in the transplant. Here, we demonstrate the importance of islet vasculature for in vivo delivery of radiotracers to transplanted islets and we demonstrate that optimal and stable uptake of exendin four weeks after transplantation opens the possibility for long-term monitoring of islet survival by SPECT imaging.


Neuromagnetic evaluation of binaural unmasking.
Binaural unmasking refers to the improvement in intelligibility under conditions of masking when a tone is presented out of phase rather than in phase. In the present study, binaural unmasking was evaluated using auditory-evoked magnetoencephalography (MEG) in eight healthy right-handed volunteers (7 males and 1 female, mean age 25.9 years). Peak latency and amplitude of the N1m response to tone bursts of 250 Hz (n = 8), 1000 Hz (n = 3), and 4000 Hz (n = 3) were measured under S0N0 (binaural phase difference was zero radian (in phase) for both stimulus sound and masker noise) and SpiN0 (binaural phase difference was pi radian (out of phase) for stimulus sound and zero radian for masker noise) conditions. The level of tone bursts was swept by 5 or 10 dB steps from the level of 20 dB above the psychophysical threshold under the S0N0 condition until no significant auditory-evoked field could be observed. Identical background noise was presented to both ears continuously at 50 dB SPL. N1m responses to stimuli at or above the psychophysical threshold were found bilaterally in all subjects except one who had only right hemispheric N1m. N1m response for the SpiN0 stimulus had larger amplitude and shorter latency than that for the S0N0 stimulus in each hemisphere and at each sound level. Neuromagnetic binaural unmasking was greatest around the threshold level, corresponding to psychophysical binaural unmasking; became smaller with greater stimuli, indicating the suprathreshold unmasking effect; and disappeared at around 15-20 dB above the threshold. Psychophysical binaural unmasking can be quantitatively evaluated by MEG in the auditory cortex level of the bilateral hemispheres.


Antithrombin III. Key factor in extracorporeal circulation.
Antithrombin III plays many different roles during cardiac operations with cardiopulmonary bypass. Basically, it acts as the natural inhibitor of thrombin, which, in presence of heparin, blocks the thrombin action and avoids gross thrombus formation inside the extracorporeal circulation circuit. By acting as a "suicide substrate", antithrombin III is consumed during cardiopulmonary bypass; at the same time, thrombin is extensively formed during and after cardiopulmonary bypass. As a result, at the end of the operation there is a potential imbalance in the antithrombin III-thrombin interaction, leading to a prothrombotic status. Moreover, patients pre-treated with heparin reach the operating theater with reduced levels of circulating antithrombin III; this may lead to the heparin resistance phenomenon and may further increase the risk for postoperative thrombotic complications. Finally, the anti-inflammatory properties of antithrombin III in the setting of the "whole body inflammatory reaction" induced by the cardiopulmonary bypass represents a new and unexplored field of research.


Study on the biosynthesis of bovine enamel protein in vitro.
Biosynthesis of enamel protein was investigated by incubating bovine tooth germs with 3H-proline containing medium. The radioactivity was incorporated into two protein fractions: one had a molecular weight of about 25,000, being secreted from the ameloblast to the enamel matrix, another having a higher molecular weight was supposed to be a cell associated protein.


Automated classification of solid renal masses on contrast-enhanced computed tomography images using convolutional neural network with decision fusion.
To develop a deep learning-based method for automated classification of renal cell carcinoma (RCC) from benign solid renal masses using contrast-enhanced computed tomography (CECT) images. This institutional review board-approved retrospective study evaluated CECT in 315 patients with 77 benign (57 oncocytomas, and 20 fat-poor angiomyolipoma) and 238 malignant (RCC: 123 clear cell, 69 papillary, and 46 chromophobe subtypes) tumors identified consecutively between 2015 and 2017. We employed a decision fusion-based model to aggregate slice level predictions determined by convolutional neural network (CNN) via a majority voting system to evaluate renal masses on CECT. The CNN-based model was trained using 7023 slices with renal masses manually extracted from CECT images of 155 patients, cropped automatically around kidneys, and augmented artificially. We also examined the fully automated approach for renal mass evaluation on CECT. Moreover, a 3D CNN was trained and tested using the same datasets and the obtained results were compared with those acquired from slice-wise algorithms. For differentiation of RCC versus benign solid masses, the semi-automated majority voting-based CNN algorithm achieved accuracy, precision, and recall of 83.75%, 89.05%, and 91.73% using 160 test cases, respectively. Fully automated pipeline yielded accuracy, precision, and recall of 77.36%, 85.92%, and 87.22% on the same test cases, respectively. 3D CNN reported accuracy, precision, and recall of 79.24%, 90.32%, and 84.21% using 160 test cases, respectively. A semi-automated majority voting CNN-based methodology enabled accurate classification of RCC from benign neoplasms among solid renal masses on CECT. • Our proposed semi-automated majority voting CNN-based algorithm achieved accuracy of 83.75% for the diagnosis of RCC from benign solid renal masses on CECT images. • A fully automated CNN-based methodology classified solid renal masses with moderate accuracy of 77.36% using the same test images. • Employing 3D CNN-based methodology yielded slightly lower accuracy for renal mass classification compared with the semi- automated 2D CNN-based algorithm (79.24%).


Role of humoral and cellular factors on the growth of blast progenitors of acute myeloblastic leukemia in serum-free culture.
To determine the growth requirement of leukemic blast progenitors in acute myeloblastic leukemia (AML), leukemic cells from the peripheral blood of eight AML patients were cultured in the serum-free culture system. Blast progenitors made colonies in methylcellulose culture and showed exponential growth in suspension culture, although the growth of blast progenitors in the absence of fetal calf serum (FCS) in some patients was inferior to that in the FCS-enhanced culture system. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) stimulated the growth of blast progenitors in a dose-responsive manner. When cells were cultured at high cell density, blast colonies were formed even in the absence of CSF. Irradiated blasts also supported the growth of intact blast progenitors. These results confirm the finding noted in the FCS-enhanced culture studies that granulopoietic factor, G-CSF, plays an important role on the leukemic growth. The importance of cell to cell interaction for the growth of blast progenitors was also confirmed.


The physiologic effects of extended wear soft contact lenses.
The major physiologic effect to the eyes of soft contact lenses in general and continuously worn hydrogel lenses in particular is a decrease in the amount of oxygen normally available to the cornea. This reduction in oxygen supply produces changes as minimal as clinically undetectable epithelial edema and as severe as the anoxic overwear syndrome that produces pain and decreased vision. Induced corneal edema can produce refractive error changes and endothelial cell changes. On a long-term basis the lenses produce physical trauma to the anterior surface of the cornea as well as certain metabolic changes and have been associated with a significant degree of corneal neovascularization. Because hydrogel lenses require a different type of care than standard, hard PMMA lenses, new complications are being described, such as giant papillary conjunctivitis, lens deposits, and acute red eye syndromes that may be associated with allergic or toxic reactions to preservatives used in the cleaning processes. Research is underway to develop hydrogel materials that will allow more oxygen to reach the corneal surface and prevent surface deposits from forming.


Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function.
The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients. The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by focusing on non-amnestic symptoms. Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers. AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%. We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.


Catalytic ozonation of methylethylketone over porous Mn-Cu/HZSM-5.
The catalytic ozonation of methylethylketone (MEK) was performed at the room temperature (25 °C) using the synthesized Mn and Cu-loaded zeolite (ZSM-5, SiO2/Al2O3 = 80) catalysts. The ZSM-5 zeolite was used as a porous support material due to the large surface area and high capacity for adsorption of volatile organic compounds. Since Mn and Cu-loaded zeolite catalysts were effective for the catalytic ozonation of VOCs such as MEK, according to the loaded concentration of Mn and Cu, there are four types of metal loaded ZSM5 catalysts synthesized [5 wt% Mn/ZSM-5, 5 wt% Cu/ZSM-5, 5 wt% Mn-1 wt% Cu/ZSM-5 (5Mn1CuZSM), and 5 wt% Cu-1 wt% Mn/ZSM-5]. The catalytic efficiency for the removal of MEK and ozonation using the different catalysts was also studied. Based on various experimental analysis processes, the characteristics of the synthesized catalysts were explored and the removal efficiencies of MEK and O3 together with the COx concentration generated from the destruction of MEK and O3 were explored. The results for the decomposition of MEK and O3 at the room temperature indicated that the Mn dominant ZSM-5 catalysts showed better efficiency for the conversion of MEK and O3. The 5 wt% Mn/ZSM-5 outweighed the rest of them for the removal of MEK while the 5Mn1CuZSM showed the best catalytic reactivity for the conversion of O3 and the CO2 selectivity. It was ascertained that during the reaction time of catalyst and reactants of 120 min the Mn dominantly deposited bimetallic catalyst, 5Mn1CuZSM, was determined as the most effective for the removal of MEK and O3 due to the high capability of production of Mn3+ species and more available adsorbed oxygen sites compared to the other catalysts. Finally, the durability measurement for the 5Mn1CuZSM catalyst was performed together with the produced CO and CO2 concentration for 420 min.


N-Glycan Branching Is Required for Development of Mature B Cells.
Galectins have been implicated in inhibiting BCR signaling in mature B cells but promoting pre-BCR signaling during early development. Galectins bind to branched N-glycans attached to cell surface glycoproteins to control the distribution, clustering, endocytosis, and signaling of surface glycoproteins. During T cell development, N-glycan branching is required for positive selection of thymocytes, inhibiting both death by neglect and negative selection via enhanced surface retention of the CD4/CD8 coreceptors and limiting TCR clustering/signaling, respectively. The role of N-glycan branching in B cell development is unknown. In this study, we report that N-glycan branching is absolutely required for development of mature B cells in mice. Elimination of branched N-glycans in developing B cells via targeted deletion of N-acetylglucosaminyl transferase I (Mgat1) markedly reduced cellularity in the bone marrow and/or spleen and inhibited maturation of pre-, immature, and transitional stage 2 B cells. Branching deficiency markedly reduced surface expression of the pre-BCR/BCR coreceptor CD19 and promoted spontaneous death of pre-B cells and immature B cells in vitro. Death was rescued by low-dose pre-BCR/BCR stimulation but exacerbated by high-dose pre-BCR/BCR stimulation as well as antiapoptotic BclxL overexpression in pre-B cells. Branching deficiency also enhanced Nur77 induction, a marker of negative selection. Together, these data suggest that, as in T cells, N-glycan branching promotes positive selection of B cells by augmenting pre-BCR/BCR signaling via CD19 surface retention, whereas limiting negative selection from excessive BCR engagement.


Workplace violence experience among nurses at a selected university teaching hospital in Rwanda.
workplace violence is a global problem in the health sector, especially in the hospitals affecting healthcare works´ job satisfaction and performance. Workplace violence (WPV) is present in different forms associated with various factors and the nurses are the most affected. This study aimed to explore WPV among nurses working at a selected University Teaching Hospital in Rwanda. the research approach used was the quantitative descriptive cross-sectional design. The stratified random sampling was used to recruit 195 participants among 379 nurses. The data were collected using a structured, validated, and self-administered questionnaire that was adapted from the International Labor Organization, International Council of nurses, the World Health Organization, and Public Services International. Descriptive statistics were used for analyzing frequencies and percentages. The Chi-square test was used for evaluating the association between variables. the findings revealed that (58.5%, n=114) of nurses have experienced some types of WPV in the twelve months preceding the study, among them (44.6%, n=108) of nurses were verbally abused. The nurses providing emergency care, the nurses working in the emergency department, and nurses working with vulnerable patients like HIV/AIDS patients were associated with WPV Chi-square (1, n=195), P=<0.001). The psychological problems have been found to be the first consequences of WPV. based on the study findings, it was concluded that the hospital management needs to be aware of WPV, develop and implement appropriate policies and strategies. These will strengthen nurses´ concentration towards them and will result in service delivery improvement.


Effect of the pH of heating on the qualitative and quantitative compositions of the sera of reconstituted skim milks and on the mechanisms of formation of soluble aggregates.
The effect of the pH of heating (6.3-7.3) on the composition of sera in reconstituted skimmed milks was investigated. A combination of SDS-PAGE analysis and size exclusion chromatography (SEC) combined with an original approach to the analysis of the SEC profiles was performed. The composition of the sera varied greatly when the pH of heating was adjusted below and above the natural pH of milk. The formation, composition, and concentration of heat-induced soluble complexes depended on the combination of the effect of adjusting the pH of the milk and the heat treatment. Two types of mechanism for the formation of soluble aggregates appeared to exist, depending on the pH of the milk. The first type results from the formation of WP/kappa-casein aggregates at the surface of the micelle, and these were detached partially into the serum in larger amount as the pH increased up to 6.7, where it reaches a maximum. The second type of complexes, whose amount increased as the pH of heating increased from 6.7 to 7.3, may be formed between caseins (kappa- but also perhaps some alpha(s)-casein) and aggregated WP resulting in complexes that are smaller in size and with a higher kappa-casein/whey protein ratio than the first type.


Malignant clinical course of mycotic intracranial aneurysms in children: A review.
Mycotic aneurysms are a rare in the pediatric population. The natural history of these lesions and their appropriate management strategies is controversial. A 13-year-old male presented with the sudden onset of a headache, vomiting, and fever. Inflammatory markers were elevated, and the blood culture was positive for Streptococcus viridans. When the computed tomography angiography (CTA) showed a ruptured mycotic aneurysm accompanied by multiple small unruptured aneurysms, he was started on antibiotics and underwent an urgent craniotomy. Despite negative blood cultures, the follow-up CTA showed further enlargement of the previously diagnosed aneurysms and a new right frontal aneurysm. The second and third craniotomies were, respectively, performed to resect the additional aneurysms. Pathologically, both aneurysmal walls were markedly inflamed and attenuated, suggesting the imminent risk of aneurysmal rupture. Following the total of three craniotomies, the patient had an uneventful postoperative course. Within 2 weeks, he regained baseline neurological function. Mycotic aneurysms in children may follow a very malignant course. Aneurysms may grow, new ones may form, and repeated CTAs are required to direct further follow-up treatment.


Clinical trials with human tumor necrosis factor: in vivo and in vitro effects on human mononuclear phagocyte function.
The purpose of this investigation was to understand the biological effects of recombinant human tumor necrosis factor used as therapy for cancer. We studied changes in mononuclear phagocyte function following exposure to this cytokine in vitro or in vivo. Tumor necrosis factor increased phorbol myristate acetate-induced hydrogen peroxide production 8- to 20-fold in peripheral blood monocytes and peritoneal macrophages in vitro in a dose-dependent manner. Similarly, tumor necrosis factor increased phorbol myristate acetate-induced peroxide production 2.3-fold in monocytes isolated from nine patients following an i.v. infusion of this cytokine (40 to 200 micrograms/m2). In addition, tumor necrosis factor induced a 2.3-fold increase in tissue factor-like activity in mononuclear phagocytes in vitro. In vivo, tumor necrosis factor induced a trend toward higher procoagulant activity in monocytes, although this change was not statistically significant. We also noted a trend toward increased activated partial thromboplastin times and the presence of fibrin D-dimer in patients treated with tumor necrosis factor, demonstrating activation of the coagulation and fibrinolytic systems. Thus, in vivo treatment of humans with i.v. recombinant human tumor necrosis factor induced functional changes in mononuclear phagocytes similar to those noted with in vitro treatment.


Group-based self-evaluation outside of the laboratory: effects of global versus contextual status.
An event-contingent diary methodology was used to study the impact of intergroup and intragroup factors on self-evaluations in naturally occurring groups. Participants reported their contextual group status, group identification, and self-evaluations each time they self-categorized as a group member throughout a 1-week period. Indicators of global group status, interdependence, and permeability of group boundaries also were obtained. Multilevel modeling revealed that contextual status and global status interacted to predict self-evaluations. Contextual status had a stronger relationship with self-evaluations for members of global low-status groups than for members of high-status groups. Analyses of intragroup factors revealed that greater group interdependence but not permeability of group boundaries also was associated with higher self-evaluations. The effects of both contextual status and group interdependence were mediated by group identification.


NKG2C+ natural killer cell function improves the control of HBV replication in individuals with acute HIV infection coinfected with HBV.
Individuals infected with hepatitis B virus (HBV) are often coinfected with human immunodeficiency virus (HIV). However, individuals with chronic HBV infection living with acute HIV infection have a significantly lower HBV viral load, along with higher HBeAg and HBsAg loss than HBV-infected individuals alone. Here, we investigated the possible role of natural killer cells (NK cell) function in this progressive course to explore the relationship between phenotypic/functional changes in NK cells during acute HIV infection and HBV clearance in patients with HIV/HBV coinfection.Peripheral blood NK cells from 38 patients with primary HIV infection, including 20 with untreated HIV infection and 18 treatment-naïve patients with HIV/HBV coinfection and 16 patients with chronic HBV infection, were enrolled in this study.We found that the HIV/HBV-coinfected individuals had higher levels of NK cells than the HBV-infected individuals, due to expansion of the CD56 NK cell population. The proportion of NK cells in CD56 and CD56 NK subsets was not found significant difference between HIV/HBV-coinfected and HBV-infected individuals. However, NKG2C levels on NK cells and subsets were significantly higher in HIV/HBV-coinfected individuals than in HBV-infected individuals, whereas NKG2A levels were unaffected or decreased. In addition, the levels of degranulation CD107a, cytotoxicity and IFN-γ production of NK cells were increased in HIV/HBV-coinfected individuals than in HBV-infected individuals. The level of IL-10 production of NK cells was decreased in HIV/HBV-coinfected individuals than in HBV-infected individuals. Furthermore, the level of HBV-DNA was inversely correlated with the proportion of NKG2C and NKG2CNKG2A NK cells, while positively correlated with the proportion of NKG2A and NKG2CNKG2A NK cells. IFN-γ production was inversely correlated with levels of HBV-DNA, but the CD107a expression and IL-10 production of NK cells were not correlated with HBV-DNA levels.These results demonstrate that the upregulation of NKG2C expression, but not of NKG2A expression on the surface of NK cells increases cytolytic capacity and the amounts of cytokines produced and may play a crucial role in HBV clearance during HIV/HBV-coinfection.


[Summary of the Israeli Endocrine Society's consensus statement on the diagnosis, treatment and follow-up of well-differentiated thyroid cancer].
Well differentiated epithelial cell thyroid cancer is not classified amongst the most aggressive diseases. Notwithstanding, it can potentially both impair quality of life and affect life expectancy. Appropriate treatment has been shown to be crucial in obtaining optimal outcomes on the course of the disease. Successful treatment rests upon strict adherence to confirmed principles of diagnosis, treatment and follow-up. The aim of the position paper is to present the Israeli medical community with a set of commonly accepted principles for the diagnosis, treatment and follow-up of patients with well differentiated epithelial thyroid cancer and in addition to highlight areas of legitimate differences in approach where those differences occur. We have attempted to provide a link between the various medical disciplines involved in care of these patients: family physicians, surgeons, nuclear medicine specialists, oncologists, pathologists, radiologists and endocrinologists; and have attempted to decrease to a minimum areas of uncertainty and to offer a common approach for the best possible care of thyroid cancer patients in Israel. In addition, we find it our duty to point out those areas and resources which, in our opinion, need to be upgraded in Israel and even included in the Israeli official "health basket".


Restoration of aspirin tolerance following omalizumab treatment in a patient with chronic spontaneous urticaria.
Up to 30% of cases of chronic spontaneous urticaria (CSU) are exacerbated by COX-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAID); this clinical picture is termed NECD (NSAID-exacerbated cutaneous disease). On the other hand, multiple NSAID hypersensitivity may occur in the absence of an underlying CSU also, a situation that is termed NIUA (NSAID-induced urticaria / angioedema). The present study reports a case of multiple NSAID hypersensitivity that occurred in a man much before he developed severe CSU. Omalizumab treatment eventually induced a remission of the cutaneous disease which was associated with aspirin tolerance, as assessed by open oral challenge with the drug. Altogether, this case suggests that it might be worth to investigate tolerance to aspirin or other strong COX-1 inhibitors NECD patients showing a complete response to omalizumab, and maybe also the effects of omalizumab in NIUA patients as well.


Peroxynitrite upregulates angiogenic factors VEGF-A, BFGF, and HIF-1α in human corneal limbal epithelial cells.
Corneal neovascularization (NV) is a sight-threatening condition often associated with infection, inflammation, prolonged contact lens use, corneal burns, and acute corneal graft rejection. Macrophages recruited to the cornea release nitric oxide (NO) and superoxide anion (O2(-)), which react together to form the highly toxic molecule peroxynitrite (ONOO(-)). The role of ONOO(-) in upregulating multiple angiogenic factors in cultured human corneal limbal epithelial (HCLE) cells was investigated. Human corneal limbal epithelial cells were incubated with 500 μM of ONOO(-) donor for various times. VEGF-A, BFGF, and hypoxic-inducible factor-alpha (HIF-1α) were investigated via Western blot and RT-PCR was performed for VEGF. Functional assays using human umbilical vein endothelial cells (HUVEC) used conditioned media from ONOO(-)-exposed HCLE cells. Secreted VEGF from conditioned media was detected and analyzed using ELISA. Increased angiogenic factors were observed as early as 4 hours after HCLE exposure to ONOO(-). HIF-1 expression was seen at 4, 6, and 8 hours post-ONOO(-) exposure (P < 0.05). BFGF expression was elevated at 4 hours and peaked at 8 hours after treatment with ONOO(-) (P < 0.005). Increased VEGF-A gene expression was observed at 6 and 8 hours post-ONOO(-) treatment. Functional assays using conditioned media showed increased HUVEC migration and tube formation. Exposure to elevated extracellular concentrations of ONOO(-) results in upregulation of angiogenic factors in HCLE cells. It is possible that, in the setting of inflammation or infection, that exposure to ONOO(-) could be one contributor to the complex initiators of corneal NV. Validation in vivo would identify an additional potential control point for corneal NV.


Seven-spot ladybird optimization: a novel and efficient metaheuristic algorithm for numerical optimization.
This paper presents a novel biologically inspired metaheuristic algorithm called seven-spot ladybird optimization (SLO). The SLO is inspired by recent discoveries on the foraging behavior of a seven-spot ladybird. In this paper, the performance of the SLO is compared with that of the genetic algorithm, particle swarm optimization, and artificial bee colony algorithms by using five numerical benchmark functions with multimodality. The results show that SLO has the ability to find the best solution with a comparatively small population size and is suitable for solving optimization problems with lower dimensions.


[Assessment of the practicability of coronary risk index as a screening method for ischemic heart disease in preoperative evaluation].
Coronary risk index (CRI) is our newly developed screening method for ischemic heart disease in preoperative evaluation. In this study, we assessed the practicability of CRI examining coronary angiograms (CAG) obtained in 106 patients scheduled for operations. CAG was rated with CAG score, then CRI and CAG score were statistically analyzed. These two parameters showed a significant positive relationship; the higher CRI, the higher CAG score (P < 0.0001). When the patients were divided into five groups by their CRI (0-9, 10-14, 15-19, 20-24, and more than 25), the group with higher CRI contained significantly more patients with severe multivessel coronary lesion (P < 0.0001). Similar results were obtained even in the patient with minimal change in ECG or exercise ECG, or those with minimal chest symptoms (P < 0.001). These results suggests that CRI works effectively as a screening method for ischemic heart disease regardless of abnormalities in ECG or the chest symptoms. More cautious perioperative management should be carried out in patients with higher CRI.


Design of Radioiodinated Pharmaceuticals: Structural Features Affecting Metabolic Stability towards in Vivo Deiodination.
Radioiodinated pharmaceuticals are convenient tracers for clinical and research investigations because of the relatively long half-lives of radioactive iodine isotopes (i.e., 123I, 124I, and 131I) and the ease of their chemical insertion. Their application in radionuclide imaging and therapy may, however, be hampered by poor in vivo stability of the C-I bond. After an overview of the use of iodine in biology and nuclear medicine, we present here a survey of the catabolic pathways for iodinated xenobiotics, including their biodistribution, accumulation, and biostability. We summarize successful rational improvements in the biostability and conclude with general guidelines for the design of stable radioiodinated pharmaceuticals. It appears to be necessary to consider the whole molecule, rather than the radioiodinated fragment alone. Iodine radionuclides are generally retained in vivo on sp2 carbon atoms in iodoarenes and iodovinyl moieties, but not in iodinated heterocycles or on sp3 carbon atoms. Iodoarene substituents also have an influence, with increased in vivo deiodination in the cases of iodophenols and iodoanilines, whereas methoxylation and difluorination improve biostability.


The 31-kDa precursor of interleukin 1 alpha is myristoylated on specific lysines within the 16-kDa N-terminal propiece.
The cytokine interleukin 1 alpha (IL-1 alpha) is a critical mediator of the immune and inflammatory responses. A unique determinant of its activity as compared with IL-1 beta may be its association with the plasma membrane. While the biologic activity of "membrane IL-1" has been extensively reported, the mechanism of membrane binding remains unclear. We report that the N terminus of the 31-kDa IL-1 alpha precursor is myristoylated on specific internal lysine residues. Immunoprecipitation of [3H]myristic acid-radiolabeled human monocyte lysates with IgG antibodies to the 31-kDa IL-1 alpha precursor recovered a protein with the physicochemical properties of the IL-1 alpha N-terminal propiece (16 kDa, pI 4.45). Glycyl N-myristoylation of this protein is precluded by the absence of a glycine residue at position 2, suggesting that the propiece is myristoylated on epsilon-amino groups of lysine. To determine which lysine(s) are acylated, a series of synthetic peptides containing all lysines found in the IL-1 alpha N-terminal propiece were used in an in vitro myristoylation assay containing peptide, myristoyl-CoA, and monocyte lysate as enzyme source. Analysis of the reaction products by reverse-phase HPLC and gas-phase sequencing demonstrated the specific myristoylation of Lys-82 and Lys-83, yielding predominantly monoacylated product. A conserved sequence in the IL-1 beta propiece was myristoylated with at least 8-fold less efficiency. Acylation of the IL-1 alpha precursor by a previously unrecognized lysyl epsilon-amino N-myristoyl-transferase activity may facilitate its specific membrane targeting.


CpxR regulates the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism.
The two-component signalling systems PmrAB and PhoPQ of Salmonella have been extensively studied with regard to colistin resistance. We previously showed that overexpressed CpxR could significantly increase the colistin susceptibility (16-fold compared with the WT strain) of Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) through PmrAB and PhoPQ. To identify the potential target genes of CpxR in PmrAB- and PhoPQ-related signalling pathways. His6-CpxR was prokaryotically expressed and purified by Ni-NTA resin affinity chromatography. β-Galactosidase activity assays were conducted to investigate whether CpxR could regulate the promoters of colistin resistance-related genes (CRRGs). Electrophoretic mobility shift assays (EMSAs) were used to further detect His6-CpxR complexes with promoters of CRRGs. We demonstrated for the first time (to the best of our knowledge) that CpxR and the AcrAB-TolC efflux pump have reciprocal effects on CRRG transcription. Additionally, CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by binding directly to the promoters of phoPQ, pmrC, pmrH and pmrD at the CpxR box-like sequences or indirectly through other regulators including pmrAB and mgrB. CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism.


[Anesthetic managements for emergency cesarean section and craniotomy in patients with intracranial hemorrhage due to ruptured cerebral aneurysm and arteriovenous malformation].
We report two cases of anesthetic management for emergency cesarean sections and craniotomies in patients with intracranial hemorrhage. Case 1: A 32-year-old woman at 33 weeks gestation suffered from subarchnoid hemorrhage due to the rupture of cerebral aneurysm. Case 2: A 38-week-pregnant woman aged 32 developed intracerebral hematoma resulting from ruptured arteriovenous malformation. The weights of the fetuses were estimated to be 1756 g and 1996 g respectively, and they were expected premature. Discussions with obstetricians, neurosurgeons and neonatologists encouraged us to schedule cesarean section followed by craniotomy under general anesthesia. Before deliveries we selected isoflurane and avoided excessive hyperventilation to maintain uteroplacental circulation. After deliveries, isoflurane was changed to propofol and prostaglandin E1 was infused to control blood pressure and to avoid uterine atonic bleeding. Uneventful anesthetic course resulted in both the mothers and the fetuses surviving. It is important to develop good relationships among the specialists for the management of pregnant woman with intracranial hemorrhage.


Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy.
In this study, we evaluated the capacity of a single percutaneous injection of recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in a rapidly resorbable calcium phosphate paste (alpha-BSM) to accelerate bone-healing in a canine tibial osteotomy model. We hypothesized that the osteotomy sites would heal faster after percutaneous delivery of rhBMP-2/alpha-BSM than they would after injection of alpha-BSM alone or after no treatment. Bilateral tibial osteotomy was performed and the sites were stabilized with external fixators in sixteen dogs. Four hours after the surgery, one limb of each dog was treated with a single percutaneous injection of rhBMP-2/alpha-BSM paste or an equal volume of alpha-BSM alone. There were eight limbs in each group, and the osteotomy site in the contralateral limb served as an untreated control. The results were evaluated with serial radiography and force-plate analysis at four and eight weeks after surgery and with mechanical testing and histologic examination at eight weeks after the surgery. At four and eight weeks after the osteotomy and treatment, the scores for radiographic union were significantly greater for the rhBMP-2/alpha-BSM-treated limbs than they were for the alpha-BSM-treated or untreated, control limbs (p < 0.05). The callus area in the rhBMP-2/alpha-BSM-treated limbs was significantly greater than that in the alpha-BSM-treated and untreated, control limbs at four and eight weeks postinjection (p < 0.05). The time-integrated vertical force for the rhBMP-2-treated limbs was significantly greater than that for their contralateral controls at four weeks and significantly greater than that for the treated and control limbs of the alpha-BSM-treated dogs at four and eight weeks after the surgery (p </= 0.05). The rhBMP-2-treated limbs were significantly stiffer in bending and in torsion (p < 0.05) compared with the alpha-BSM-treated and control limbs. Histologic analysis demonstrated increased bone formation and more mature bone at the osteotomy site in the rhBMP-2-treated limbs compared with that in the alpha-BSM-treated and control limbs. This study demonstrates the capacity of a single percutaneous injection of rhBMP-2 delivered in a resorbable calcium phosphate paste (alpha-BSM) four hours after surgery to accelerate the healing of tibial osteotomy sites in a canine model.


[A diagnosis of venous anomaly with dextrocardia by magnetic resonance imaging and transesophageal echocardiography].
A 56-year-old woman was admitted with the chief complaint of dyspnea. Chest radiograph and echocardiography disclosed mirror image dextrocardia with massive pleural effusion. Magnetic resonance imaging (MRI) and transesophageal echocardiography (TEE) revealed dilated coronary sinus and persistent right-sided superior vena cava which entered the coronary sinus. These findings were compatible with those of digital subtraction angiography. Anomalies of the venous system must be recognized before surgery because adequate venous drainage is essential for extra-corporeal circulation. MRI and TEE are noninvasive and useful methods and should be performed first to detect anomalies of the venous system associated with dextrocardia.


Impact of Preoperative Hematocrit Level on Length of Stay after Surgery on the Lumbar Spine.
Study Design Retrospective case series. Objective Recent studies suggest that baseline hematocrit (Hct) levels may affect the surgical outcomes after orthopedic procedures. The authors examined whether preoperative Hct values had a significant effect on the hospital length of stay (LoS) after lumbar spinal procedures. Methods We retrospectively reviewed patients who underwent routine lumbar spine procedures from November 2012 through September 2013. Patients were included if they had both a baseline Hct and hospital LoS recorded. Patients were divided into two groups: those with an Hct ≥ 40% (nonanemic) and those with an Hct < 40% (anemic). LoS after surgery was evaluated for each group. Results One hundred seventeen patients underwent lumbar spine procedures for lumbar stenosis (n = 34), symptomatic lumbar disk herniation (n = 39), lumbar spondylolisthesis (n = 26), lumbar adjacent segment disease (n = 8), or symptomatic recurrent lumbar disk herniation (n = 10). Mean LoS was 3.3 and 2.4 days in anemic (27 patients) and nonanemic groups (90 patients), respectively (p = 0.02). The linear regression analysis demonstrated that a decrease in Hct was associated with a longer stay. A decrease from preoperative to postoperative day 1 Hct of 3.5 points resulted in an increased LoS of 1 day (R (2) = 0.145; p = 0.002). The correlation of Hct decrease with longer LoS remained (β = 0.167, p = 0.006) after adjusting for other variables with multivariate regression analysis. Conclusions Lower preoperative Hct or a substantial decrease in Hct may contribute to longer hospitalization after lumbar spine surgery. These findings should prompt an investigation into the strategies for optimizing Hct levels in patients with preoperative anemia prior to lumbar spine procedures.


Various Kinds of Functional Digestive Tract Reconstruction Methods After Proximal Gastrectomy.
The incidence of proximal gastric cancer has shown a rising trend in recent years. Surgery is still the main way to cure proximal gastric cancer. Total gastrectomy with D2 lymph node dissection was considered to be the standard procedure for proximal gastric cancer in the past several decades. However, in recent years, many studies have confirmed that proximal gastrectomy can preserve part of the stomach function and can result in a better quality of life of the patient than total gastrectomy. Therefore, proximal gastrectomy is increasingly used in patients with proximal gastric cancer. Unfortunately, there are some concerns after proximal gastrectomy with traditional esophagogastrostomy. For example, the incidence of reflux esophagitis in patients who underwent proximal gastrectomy with traditional esophagogastrostomy is significantly higher than those patients who underwent total gastrectomy. To solve those problems, various functional digestive tract reconstruction methods after proximal gastrectomy have been proposed gradually. In order to provide some help for clinical treatment, in this article, we reviewed relevant literature and new clinical developments to compare various kinds of functional digestive tract reconstruction methods after proximal gastrectomy mainly from perioperative outcomes, postoperative quality of life and survival outcomes aspects. After comparison and discussion, we drew the conclusion that various functional reconstruction methods have their own advantages and disadvantages; large scale high-level clinical studies are needed to choose an ideal reconstruction method in the future. Besides, in clinical practice, surgeons should consider the condition of the patient for individualized selection of the most appropriate reconstruction method.


The perceived scenic effects of clearcutting in the White Mountains of New Hampshire, USA.
The scenic effects of clearcutting have been a volatile issue for the American public for much of the past century. A better understanding of the scenic perceptions associated with the cumulative visible effects of clearcutting should contribute to better decisions about its use. This study evaluates the scenic impacts of simulated alternative clearcutting management systems for the White Mountain National Forest. Alternatives represented an unharvested view, and views with removal of 1-5% of the timber every 12 years using either scattered or concentrated clearcut units of 5, 15 and 30 acres in two viewsheds. A random sample of local citizens, four groups of opinion leaders, and US Forest Service employees evaluated these alternatives. Each factor accounts for significant differences in scenic value. All groups rated the scenic value of unharvested scenes very high. All groups find a large drop in scenic value with the introduction of even the least intense harvesting activity. All groups indicated a statistically significant decrease in visual quality as the intensity of harvesting increases. This effect continues throughout the range of harvesting intensities until the level of sustainable yield is reached. In addition, patches 12-15 acres in size were preferred to larger and smaller ones.


Molecular structure and vibrational spectra of spin-crossover complexes in solution and colloidal media: resonance Raman and time-resolved resonance Raman studies.
The spin-crossover system [Fe(btpa)](PF(6))(2) (btpa = N,N,N',N'-tetrakis(2-pyridylmethyl)-6,6'-bis(aminomethyl)-2,2'-bipyridine) and the predominantly low-spin species [Fe(b(bdpa))](PF(6))(2) ((b(bdpa) = N,N'-bis(benzyl)-N,N'-bis(2-pyridylmethyl)-6,6'-bis(aminomethyl)-2,2'-bipyridine) have been characterized by means of X-ray diffraction. The unit cell of [Fe(btpa)](PF(6))(2) contains two crystallographically independent molecules revealing octahedral low-spin and quasi-seven-coordinated high-spin structures. The unit cell of [Fe(b(bdpa))](PF(6))(2) contains two crystallographically independent molecules one of which corresponds to a low-spin structure, while the other reveals a disordering. On the basis of magnetic susceptibility and Mössbauer measurements, it has been proposed that this disorder involves low-spin and high-spin six-coordinated molecules. The structures of [Zn(btpa)](PF(6))(2) and [Ru(btpa)](PF(6))(2) have been determined also. Pulsed laser photoperturbation, coupled here with time-resolved resonance Raman spectroscopy (TR(3)), has been used to investigate, for the first time by this technique, the relaxation dynamics in solution on nanosecond and picosecond time scales of low-spin, LS ((1)A) --> high-spin, HS ((5)T) electronic spin-state crossover in these Fe(II) complexes. For the nanosecond experiments, use of a probe wavelength at 321 nm, falling within the pi-pi transition of the polypyridyl backbone of the ligands, enabled the investigation of vibrational modes of both LS and HS isomers, through coupling to spin-state-dependent angle changes of the backbone. Supplementary investigations of the spin-crossover (SCO) equilibrium in homogeneous solution and in colloidal media assisted the assignment of prominent features in the Raman spectra of the LS and HS isomers. The relaxation data from the nanosecond studies confirm and extend earlier spectrophotometric findings, (Schenker, S.; Stein, P. C.; Wolny, J. A.; Brady, C.; McGarvey, J. J.; Toftlund, H.; Hauser, A. Inorg. Chem. 2001, 40, 134), pointing to biphasic spin-state relaxation in the case of [Fe(btpa)](PF(6))(2) but monophasic in the case of [Fe(b(bdpa))](PF(6))(2). The picosecond results suggest an early process complete in 20 ps or less, which is common to both complexes and possibly includes vibrational relaxation in the initially formed (5)T(2) state.


CO2 alters community composition of freshwater phytoplankton: A microcosm experiment.
The effects of CO2 and related changes in water carbonate chemistry on freshwater phytoplankton were studied in in situ microcosm experiments, performed in East Lake Taihu, in August 2013 and April 2014, respectively. The microcosm treatments represented low (270ppm), present (380ppm), and high (750ppm) pCO2 conditions. Elevated CO2 decreased pH and increased aqueous CO2 concentrations, and did not change alkalinity. The maximum reduction of pH was 0.26 when CO2 increased from current level to 750ppm at the ending of experiment in the spring. The rise of pCO2 stimulated the growth of phytoplankton, and the net primary production could increase by 35% when CO2 was elevated from current level to 750ppm in summer. Interestingly, our results indicated that increasing pCO2 affected phytoplankton community structure in the microcosms. Cyanobacteria tended to be superior under high pCO2, with two species Anabaena circinalis and Anabaena eucompacta benefitting from the rising pCO2. The response of chlorophytes and diatoms to the rise of pCO2 depended on taxa. In contrast, increased CO2 did not change biomass or productivity of phytoplankton in spring, when biomass was relatively low.


The effect of lumbar epidural analgesia on the development of deep vein thrombosis of the legs after open prostatectomy.
The occurrence of deep vein thrombosis (DVT) was studied by the 125-I-fibrinogen uptake test in 38 patients subjected to retropubic prostatectomy. The patients were randomly allocated to two groups: continuous lumbar epidural analgesia for up to 24 hours and general anaesthesia with intermittent positive pressure ventilation. Two of the 17 patients in the epidural group (12%) developed DVT in contrast 11 of the 21 patients in the general anaesthetic group (51%). The difference between the groups was significant. It is concluded that epidural analgesia offers a protection against postoperative DVT and is worth further investigation.


Dynamo onset as a first-order transition: lessons from a shell model for magnetohydrodynamics.
We carry out systematic and high-resolution studies of dynamo action in a shell model for magnetohydrodynamic (MHD) turbulence over wide ranges of the magnetic Prandtl number PrM and the magnetic Reynolds number ReM. Our study suggests that it is natural to think of dynamo onset as a nonequilibrium first-order phase transition between two different turbulent, but statistically steady, states. The ratio of the magnetic and kinetic energies is a convenient order parameter for this transition. By using this order parameter, we obtain the stability diagram (or nonequilibrium phase diagram) for dynamo formation in our MHD shell model in the (PrM-1,ReM) plane. The dynamo boundary, which separates dynamo and no-dynamo regions, appears to have a fractal character. We obtain a hysteretic behavior of the order parameter across this boundary and suggestions of nucleation-type phenomena.


Specialized stomatal humidity responses underpin ecological diversity in C3 bromeliads.
The Neotropical Bromeliaceae display an extraordinary level of ecological variety, with species differing widely in habit, photosynthetic pathway and growth form. Divergences in stomatal structure and function, hitherto understudied in treatments of bromeliad evolutionary physiology, could have been critical to the generation of variety in ecophysiological strategies among the bromeliads. Because humidity is a key factor in bromeliad niches, we focussed on stomatal responses to vapour pressure deficit (VPD). We measured the sensitivity of stomatal conductance and assimilation rate to VPD in eight C3 bromeliad species of contrasting growth forms and ecophysiological strategies and parameterised the kinetics of stomatal responses to a step change in VPD. Notably, three tank-epiphyte species displayed low conductance, high sensitivity and fast kinetics relative to the lithophytes, while three xeromorphic terrestrial species showed high conductance and sensitivity but slow stomatal kinetics. An apparent feedforward response of transpiration to VPD occurred in the tank epiphytes, while water-use efficiency was differentially impacted by stomatal closure depending on photosynthetic responses. Differences in stomatal responses to VPD between species of different ecophysiological strategies are closely linked to modifications of stomatal morphology, which we argue has been a pivotal component of the evolution of high diversity in this important plant family.


Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism.
Mass spectrometric (MS) analysis of low molecular weight polar metabolites can be challenging because of poor chromatographic resolution of isomers and insufficient ionization efficiency. These metabolites include intermediates in key metabolic pathways, such as glycolysis, the pentose phosphate pathway, and the Krebs cycle. Therefore, sensitive, specific, and comprehensive quantitative analysis of these metabolites in biological fluids or cell culture models can provide insight into multiple disease states where perturbed metabolism plays a role. An ion-pairing reversed-phase ultra-high-performance liquid chromatography (IP-RP-UHPLC)/MS approach to separate and analyze biochemically relevant phosphate- and carboxylic acid-containing metabolites was developed. Diisopropylethylamine (DIPEA) was used as an IP reagent in combination with reversed-phase liquid chromatography (RP-LC) and a triple quadrupole mass spectrometer using selected reaction monitoring (SRM) and negative electrospray ionization (NESI). An additional reagent, hexafluoroisopropanol (HFIP), which has been previously used to improve sensitivity of nucleotide analysis by UHPLC/MS, was used to enhance sensitivity. HFIP versus acetic acid, when added with the IP base, increased the sensitivity of IP-RP-UHPLC/NESI-MS up to 10-fold for certain analytes including fructose-1,6-bisphosphate, phosphoenolpyruvate, and 6-phosphogluconate. It also improved the retention of the metabolites on a C18 reversed-phase column, and allowed the chromatographic separation of important isomeric metabolites. This methodology was amenable to quantification of key metabolites in cell culture experiments. The applicability of the method was demonstrated by monitoring the metabolic adaptations resulting from rapamycin treatment of DB-1 human melanoma cells. A rapid, sensitive, and specific IP-RP-UHPLC/NESI-MS method was used to quantify metabolites from several biochemical pathways. IP with DIPEA and HFIP increased the sensitivity and improved chromatographic separation when used with reversed-phase UHPLC.


TGF-β1 Gene -509C/T Polymorphism and Coronary Artery Disease: An Updated Meta-Analysis Involving 11,701 Subjects.
Background: The transforming growth factor-β1 (TGF-β1) gene -509C/T polymorphism has been suggested to be associated with increased coronary artery disease (CAD) risk. However, the individual studies results are still inconsistent. Objective and methods: To investigate the relationship between TGF-β1 gene -509C/T polymorphism and CAD, a meta-analysis involving 11,701 participants from 8 individual studies was conducted. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals were evaluated by using random or fixed effect models. Results: A significant association between TGF-β1 gene -509C/T polymorphism and CAD was detected in the total population under allelic (OR: 1.130, 95% CI: 1.060-1.200, P = 0.0001), recessive (OR: 1.390, 95% CI: 1.100-1.750, P = 0.006), dominant (OR: 0.857, 95% CI: 0.785-0.935, P = 2.507 × 10-4), homozygous (OR: 1.258, 95% CI: 1.098-1.442, P = 0.001), heterozygous (OR: 1.147, 95% CI: 1.046-1.257, P = 0.003), and additive genetic models (OR: 1.131, 95% CI: 1.063-1.204, P = 5.442 × 10-5). In the subgroup analysis, there was a significant association between them in Chinese population under all of the genetic models (P < 0.05), except under the heterozygous genetic model (P > 0.05). In the Caucasian subgroup, a significant association between them was also detected under all of the genetic models (P < 0.05), except under the recessive genetic model (P > 0.05). Conclusions:TGF-β1 gene -509C/T polymorphism was significantly associated with increased CAD risk. The people with T allele of TGF-β1 gene -509C/T polymorphism might be predisposed to CAD.


Treatment of stiff-man syndrome with intravenous immunoglobulin.
Stiff-man syndrome (SMS) is a rare disorder characterized by progressive rigidity, stiffness, and spasms of axial and extremity muscles. The etiology of SMS is unknown, but evidence suggests a possible autoimmune basis. The recent successful use of intravenous immunoglobulin (IVIG) in treating various autoimmune neuromuscular disorders led us to try IVIG in an uncontrolled pilot study on three patients. All three showed subjective and objective improvement.


Effects of a new sustained-release microsphere formulation of exenatide, DA-3091, on obese and non-alcoholic fatty liver disease mice.
The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD)-induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease.


Draft Genome Sequence of the Pelagic Photoferrotroph Chlorobium phaeoferrooxidans.
Here, we report the draft genome sequence of Chlorobium phaeoferrooxidans, a photoferrotrophic member of the genus Chlorobium in the phylum Chlorobi This genome sequence provides insight into the metabolic capacity that underpins photoferrotrophy within low-light-adapted pelagic Chlorobi.


String order in half-integer-spin antiferromagnetic Heisenberg chains.
We derive the extended string order parameter O(S) for antiferromagnetic Heisenberg chains with half-integer spin S in the valence-bond-solid picture. We obtain the analytic power-law scaling of O(S) versus the chain length L and show that O(S) scales at an extremely slow pace that decreases rapidly with growing spin magnitude. Furthermore, accurate numerical calculations show that the power-law scaling sets in only when L exceeds a characteristic length scale l(S) which increases very fast with growing S. Consequently, a pseudo-long-range string order exists in half-integer-spin Heisenberg chains. The implications of this result and its relationship to other topological features such as the end-chain states are discussed.


Wave propagation across the skull under bone conduction: Dependence on coupling methods.
This study is aimed at the quantitative investigation of wave propagation through the skull bone and its dependence on different coupling methods of the bone conduction hearing aid (BCHA). Experiments were conducted on five Thiel embalmed whole head cadaver specimens. An electromagnetic actuator from a commercial BCHA was mounted on a 5-Newton steel headband, at the mastoid, on a percutaneously implanted screw (Baha® Connect), and transcutaneously with a Baha® Attract (Cochlear Limited, Sydney, Australia), at the clinical bone anchored hearing aid (BAHA) location. Surface motion was quantified by sequentially measuring ∼200 points on the skull surface via a three-dimensional laser Doppler vibrometer (3D LDV) system. The experimental procedure was repeated virtually, using a modified LiUHead finite element model (FEM). Both experiential and FEM methods showed an onset of deformations; first near the stimulation area, at 250-500 Hz, which then extended to the inferior ipsilateral skull surface, at 0.5-2 kHz, and spread across the whole skull above 3-4 kHz. Overall, stiffer coupling (Connect versus Headband), applied at a location with lower mechanical stiffness (the BAHA location versus mastoid), led to a faster transition and lower transition frequency to local deformations and wave motion. This behaviour was more evident at the BAHA location, as the mastoid was more agnostic to coupling condition.


MED-EL Cochlear implants: state of the art and a glimpse into the future.
Cochlear implantation is an accepted treatment method for adults and children with severe to profound hearing loss. Confidence in technology has led to changes in individuals who can receive a cochlear implant and changes in expected benefit with a cochlear implant. This article describes the research and development activities at MED-EL, which make possible the implementation of new speech-coding strategies as well as the application of acoustic and electric stimulation via a combined speech processor in MED-EL devices. Research on benefits from bilateral cochlear implantation and electric-acoustic stimulation are also reviewed. Finally, the potential of drug delivery systems is considered as a way to improve cochlear implant outcomes, and results from preliminary evaluations of a hybrid cochlear implant system with drug delivery capabilities are reported.


Treatment of femoral fracture nonunion after long-term bisphosphonate use.
Bisphosphonates are a class of drugs that prevent bone loss by decreasing bone resorption. They represent a major treatment for osteoporosis and other metabolic bone diseases. Recent reports suggest that a potential complication of long-term bisphosphonate therapy may be atypical insufficiency fractures of the femur. Concern exists about delayed union after fracture stabilization in patients taking bisphosphonates.This article describes 2 patients on long-term bisphosphonate therapy treated for atypical femur fractures that failed to heal with intramedullary nailing. Both patients' fractures occurred after at least 4.5 years of bisphosphonate use and displayed classic findings of bisphosphonate fractures reported in the literature, including a subtrochanteric location, presentation after minimal trauma, transverse fracture, no comminution, and cortical beaking. The original fractures were treated at other institutions with intramedullary nails. Subsequently, both patients presented with pain and atrophic nonunion of their fractures. Evaluation included a computed tomography scan of the fracture and a metabolic workup. The patients discontinued bisphosphonate therapy. They were treated with nail removal and definitive plating to achieve compression across the fracture site. Both fractures went on to heal after this treatment with no further complications.The literature currently recommends treating bisphosphonate fractures with an intramedullary nail. Perhaps initial treatment of these fractures should be similar to an atrophic nonunion, involving compression plating to obtain bone-on-bone contact and promote healing. This would address the biologic and mechanical etiologies of the bisphosphonate fracture.


Candidate Gene Identification with SNP Marker-Based Fine Mapping of Anthracnose Resistance Gene Co-4 in Common Bean.
Anthracnose, caused by Colletotrichum lindemuthianum, is an important fungal disease of common bean (Phaseolus vulgaris). Alleles at the Co-4 locus confer resistance to a number of races of C. lindemuthianum. A population of 94 F4:5 recombinant inbred lines of a cross between resistant black bean genotype B09197 and susceptible navy bean cultivar Nautica was used to identify markers associated with resistance in bean chromosome 8 (Pv08) where Co-4 is localized. Three SCAR markers with known linkage to Co-4 and a panel of single nucleotide markers were used for genotyping. A refined physical region on Pv08 with significant association with anthracnose resistance identified by markers was used in BLAST searches with the genomic sequence of common bean accession G19833. Thirty two unique annotated candidate genes were identified that spanned a physical region of 936.46 kb. A majority of the annotated genes identified had functional similarity to leucine rich repeats/receptor like kinase domains. Three annotated genes had similarity to 1, 3-β-glucanase domains. There were sequence similarities between some of the annotated genes found in the study and the genes associated with phosphoinositide-specific phosphilipases C associated with Co-x and the COK-4 loci found in previous studies. It is possible that the Co-4 locus is structured as a group of genes with functional domains dominated by protein tyrosine kinase along with leucine rich repeats/nucleotide binding site, phosphilipases C as well as β-glucanases.


Microbial alginate dressings show improved binding capacity for pathophysiological factors in chronic wounds compared to commercial alginate dressings of marine origin.
Marine alginates are well established in wound management. Compared with different modern wound dressings, marine alginates cannot prove superior effects on wound healing. Alginates from bacteria have never been studied for medical applications so far, although the microbial polymer raises expectations for improved binding of wound factors because of its unique O-acetylation. Due to its possible positive effects on wound healing, alginates from bacteria might be a superior future medical product for clinical use. To prove the binding capacity of microbial alginates to pathophysiological factors in chronic wounds, we processed microbial alginate fibres, produced from fermentation of the soil bacterium Azotobacter vinelandii ATCC 9046, into needle web dressings and compared them with commercial dressings made of marine alginate. Four dressings were assessed: Marine alginate dressings containing either ionic silver or zinc/manganese/calcium, and microbial alginate dressings with and without nanosilver. All dressings were tested in an in vitro approach for influence on chronic wound parameters such as elastase, matrix metalloproteases-2, tumour necrosis factor-α, interleukin-8, and free radical formation. Despite the alginate origin or addition of antimicrobials, all dressings were able to reduce the concentration of the proinflammatory cytokines TNF-α and IL-8. However, microbial alginate was found to bind considerable larger amounts of elastase and matrix metalloproteases-2 in contrast to the marine alginate dressings. The incorporation of zinc, silver or nanosilver into alginate fibres did not improve their binding capacity for proteases or cytokines. The addition of nanosilver slightly enhanced the antioxidant capacity of microbial alginate dressings, whereas the marine alginate dressing containing zinc/manganese/calcium was unable to inhibit the formation of free radicals. The enhanced binding affinity by microbial alginate of Azotobacter vinelandii to pathophysiological factors may be interesting to support optimal conditions for wound healing.


Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.
Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.


Second report of AIDS related attitudes and sexual practices of the Jakarta Waria (male transvestites) in 1995.
As the second part of a community based educational campaign to convey the risk of HIV/AIDS to commercial sex workers in Jakarta, from May-July 1995, a total of 253 male transvestites (WARIA) were questioned about their sexual behavior patterns and their knowledge and attitude toward HIV/AIDS. In the previous report, 1991-1993, there was one out of 830 WARIA found HIV positive in November 1993. In this study, 1995, a total of two out of 253 WARIA were confirmed of HIV infection in July 1995. Most of them still have incorrect knowledge on HIV/AIDS transmission mode, they are still practicing high risk sexual attitudes such as an exchange partner rate of 5 men per three weeks, low condom use (1.2 out of the last 5 sexual contacts). The reasons for not using condoms were forgetfulness 35.3% and partner does not like condom 38.2% Most of WARIA know about condoms (94.5%), but it is difficult to access condom use from small shops around them. Therefore, to prevent further spread of HIV/AIDS in WARIA, condom should be used constantly and properly. It has been shown from another study, that more information, better availability and better promotion of condoms can increase condom use. Thus, attention should be placed on various ways of distributing condoms for WARIA in Jakarta, especially community-based distribution by peer leaders, social marketing and commercial sales.


Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease.
Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD. Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria. Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths. Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.


Conservative treatment of iatrogenic left main coronary artery dissection: report of two cases.
Revascularization treatment is mostly recommended for iatrogenic left main coronary artery dissection because of potential for catastrophic sequel, even in case of initial TIMI 3 flow and hemodynamic stability. However, conservative treatment seems to be feasible in asymptomatic and hemodinamically stable patient with low-grade dissection. We report two cases of iatrogenic left main coronary dissection managed conservatively.


Perinatal cerebral asphyxia: pharmacological intervention.
Perinatal asphyxia is associated with an increased risk of cerebral palsy and significant mortality. We investigated the use of flunarizine, a calcium antagonist and MK-801, an excitatory amino acid antagonist, in preventing the sequelae of severe hypoxic/ischemic insults. Flunarizine was neuroprotective in the infant rat subjected to unilateral carotid ligation and 2 h of hypoxia. Preliminary analysis of experiments in a novel model of cerebral ischemia in the fetal sheep suggests that prophylactic treatment with flunarizine greatly modified the outcome after 30 min of total ischemia. Treatment with MK-801 prevented post-ischemic seizures. The background to these developments is outlined and future prospects considered.


Suitability of customer relationship management systems for the management of study participants in biomedical research.
Longitudinal biomedical research projects study patients or participants over a course of time. No IT solution is known that can manage study participants, enhance quality of data, support re-contacting of participants, plan study visits, and keep track of informed consent procedures and recruitments that may be subject to change over time. In business settings management of personal is one of the major aspects of customer relationship management systems (CRMS). To evaluate whether CRMS are suitable IT solutions for study participant management in biomedical research. Three boards of experts in the field of biomedical research were consulted to get an insight into recent IT developments regarding study participant management systems (SPMS). Subsequently, a requirements analysis was performed with stakeholders of a major biomedical research project. The successive suitability evaluation was based on the comparison of the identified requirements with the features of six CRMS. Independently of each other, the interviewed expert boards confirmed that there is no generic IT solution for the management of participants. Sixty-four requirements were identified and prioritized in a requirements analysis. The best CRMS was able to fulfill forty-two of these requirements. The non-fulfilled requirements demand an adaption of the CRMS, consuming time and resources, reducing the update compatibility, the system's suitability, and the security of the CRMS. A specific solution for the SPMS is favored instead of a generic and commercially-oriented CRMS. Therefore, the development of a small and specific SPMS solution was commenced and is currently on the way to completion.


Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia.
Previously, we showed that expression of myeloma-associated (proto)oncogene fibroblast growth factor receptor 3 (FGFR-3) is increased in white blood cells from patients with chronic myeloid leukemia (CML). The abnormal expression was returned back to the normal levels as soon as these patients reconstituted their hematopoiesis following transplantation of allogeneic peripheral blood stem cells. The aims of this study were: (1) to define population(s) of cells overexpressing FGFR-3, and (2) to determine the expression of FGFR-3 during the clinical course of the disease. We show that the vast majority of FGFR-3 transcripts as well as FGFR-3 protein arise from CD34+ BCR-ABL+ cells. Although increased levels of FGFR-3 were found in majority of late chronic phase patients treated with interferon alpha or hydroxyurea, the expression of FGFR-3 was always lowered following treatment with BCR-ABL tyrosine kinase inhibitor STI571. Compared to unstimulated cells, high levels of FGFR-3 were also identified in CD34+ cells from granulocyte colony-stimulating factor-mobilized blood stem cell harvests from healthy donors, suggesting a potential growth factor-dependent basis for elevated expression of FGFR-3 in CML. These findings have implications for the involvement of FGFR-3 in malignant hematopoiesis and depict FGFR-3 tyrosine kinase in CD34+ leukemic cells as a possible target for tyrosine kinase inhibitors.


Pharmacogenomics of antihypertensive drugs: past, present and future.
Hypertension pharmacogenomics holds the promise of leading to individualized drug treatment approaches for the approximately 1 billion individuals worldwide with hypertension. Prior to 2000, the literature on hypertension pharmacogenomics was quite limited. The last decade has seen a substantial growth in the literature, with several examples of genes that appear to play an important role in antihypertensive response. The last decade has also made apparent the numerous challenges in hypertension pharmacogenomics, and addressing those challenges will be important. Moving forward, it seems clear that collaboration among researchers to allow replication or joint analyses will be essential in advancing the field, as will the use of genome-wide association approaches. The next decade should clearly define the clinical potential for hypertension pharmacogenomics.


Development and growth of median structures in the human tongue: A histological study using human fetuses and adult cadavers.
Glossectomy is a surgical procedure performed to remove all or part of the tongue in patients with cancer. The removal of a significant part of the tongue has a marked effect on speech and swallowing function, as patients may lose not only the tongue muscles but also the median lingual septum (MLS). Therefore, to achieve successful tongue regeneration, it is necessary to investigate the developmental processes of not only the tongue muscles but also the MLS. This study was conducted to clarify the mutual development of the tongue muscles and the MLS in human fetuses. Serial or semi-serial histological sections from 37 embryos and fetuses (aged 5-39 weeks) as well as nine adults were analyzed. The MLS appeared at Carnegie stage 15 (CS15), and until 12 weeks of gestation, abundant fibers of the intrinsic transverse muscle crossed the septum in the entire tongue. However, in near-term fetuses and adults, the contralaterally extending muscles were restricted to the deepest layer just above the genioglossus muscle. This finding indicates that the crossing transverse muscle showed the highest density at mid-term. A thorough understanding of both the MLS and the tongue muscles is necessary for successful tongue regeneration.


Investigating Chinese University Students' Enjoyment in a Web-Based Language Learning Environment: Validation of the Online Foreign Language Enjoyment Scale.
The revolution in web-based technologies has enriched pedagogical practices and motivated scholars to address learners' positive and negative emotions in the web-based language learning environment. In this study, we first examined the psychometric properties of the Foreign Language Enjoyment Scale (FLES) and then developed the Online Foreign Language Enjoyment Scale (OFLES). We adopted a mixed-method approach using a sample of 383 first language Chinese EFL undergraduates. In stage one of the research, exploratory factor analysis and confirmatory factor analysis supported an 11-item and 4-factor OFLES structure with an ideal model fit. The four sub-domains of the new enjoyment construct were OFLES- Teacher, Private, Interaction, and Competence. The Teacher domain accounted for most variance. In stage two, the qualitative analyses of feedback on an open-ended question concerning enjoyable episodes from 56 of the 383 participants revealed various sources of enjoyment for Chinese university EFL learners attending online English courses. Our findings contribute to an emerging wave of research examining the cross-contextual application of the FLES and provide important pedagogical implications for L2 practitioners and researchers. We discuss suggestions for future research.


Effect of Mn2+ on Upconversion Emission, Thermal Sensing and Optical Heater Behavior of Yb3+ - Er3+ Codoped NaGdF4 Nanophosphors.
In thiswork, we investigate the influence of Mn2+ on the emission color, thermal sensing and optical heater behavior of NaGdF4: Yb/Er nanophosphors, which the nanoparticles were synthesized by a hydrothermal method using oleic acid as both a stabilizing and a chelating agent. The morphology and crystal size of upconversion nano particles (UCNPs) can be effectively controlled through the addition of Mn2+ dopant contents in NaGdF4: Yb/Er system. Moreover, an enhancement in overall UCL spectra of Mn2+ doped UCNPs for NaGdF4 host compared to the UCNPs is observed, which results from a closed back-energy transfer between Er3+ and Mn2+ ions (4S3/2 (Er3+) → 4T1 (Mn2+) → 4F9/2 (Er3+)). The temperature sensitivity of NaGdF4:Yb3+/Er3+ doping with Mn2+ based on thermally coupled levels (2H11/2 and 4S3/2) of Er3+ is similar to that particles without Mn2+ in the 303-548 K range. And the maximum sensitivity is 0.0043 K-1 at 523 K for NaGdF4:Yb3+/Er3+/Mn2+. Interestingly, the NaGdF4:Yb3+/Er3+/Mn2+ shows preferable optical heating behavior, which is reaching a large value of 50 K. These results indicate that inducing of Mn2+ ions in NaGdF4:Yb3+/Er3+ nanophosphors has potential in colorful display, temperature sensor.


An external quality assessment feasibility study; cross laboratory comparison of haemagglutination inhibition assay and microneutralization assay performance for seasonal influenza serology testing: A FLUCOP study.
External Quality Assessment (EQA) schemes are designed to provide a snapshot of laboratory proficiency, identifying issues and providing feedback to improve laboratory performance and inter-laboratory agreement in testing. Currently there are no international EQA schemes for seasonal influenza serology testing. Here we present a feasibility study for conducting an EQA scheme for influenza serology methods. We invited participant laboratories from industry, contract research organizations (CROs), academia and public health institutions who regularly conduct hemagglutination inhibition (HAI) and microneutralization (MN) assays and have an interest in serology standardization. In total 16 laboratories returned data including 19 data sets for HAI assays and 9 data sets for MN assays. Within run analysis demonstrated good laboratory performance for HAI, with intrinsically higher levels of intra-assay variation for MN assays. Between run analysis showed laboratory and strain specific issues, particularly with B strains for HAI, whilst MN testing was consistently good across labs and strains. Inter-laboratory variability was higher for MN assays than HAI, however both assays showed a significant reduction in inter-laboratory variation when a human sera pool is used as a standard for normalization. This study has received positive feedback from participants, highlighting the benefit such an EQA scheme would have on improving laboratory performance, reducing inter laboratory variation and raising awareness of both harmonized protocol use and the benefit of biological standards for seasonal influenza serology testing.


Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions.
The 'placebo effect' and 'nocebo effect' are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a 'no treatment' arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of 'drucebo' (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin-induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy. This preferred reporting items for systematic reviews and meta-analysis-compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer. Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open-label conditions. The contribution of the drucebo effect to statin-associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta-analysis) of the results. The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life-prolonging lipid-lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.


Comparison of Minimally Invasive Percutaneous Plate Osteosynthesis and Open Reduction Internal Fixation on Proximal Humeral Fracture in Elder Patients: A Systematic Review and Meta-Analysis.
The study aims to compare minimally invasive percutaneous plate osteosynthesis (MIPO) and open reduction internal fixation (ORIF) in the treatment of proximal humeral fracture in elder patients. PubMed, Medline, EMbase, Ovid, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wangfang, and VIP Database for Chinese Technical Periodicals were searched to identify all relevant studies from inception to October 2016. Data were analyzed with Cochrane Collaboration's Review Manage 5.2. A total of 630 patients from 8 publications were included in the systematic review and meta-analysis. The pooled results showed that MIPO was superior to ORIF in the treatment of proximal humeral fracture in elder patients. It was reflected in reducing blood loss, operation time, postoperative pain, or fracture healing time of the surgery and in improving recovery of muscle strength. Concerning complications, no significant difference was seen between MIPO and ORIF. The MIPO was more suitable than ORIF for treating proximal humeral fracture in elder patients.


Cationic Dextran Stearate (Dex-St-GTMAC): Synthesis and Evaluation as Polymeric Micelles for Indomethacin Corneal Penetration.
Background Indomethacin as a non-steroidal anti-inflammatory drug (NSAID) is commonly used to treat some ocular inflammatory disorders. Unfortunately, indomethacin is a drug that is poorly soluble in water; therefore, it has low efficacy. An attractive approach is the targeted delivery of indomethacin to the cornea using cationic dextran stearate as a polymeric micelle drug carrier. Methods A dextran stearate-glycidyl trimethylammonium chloride (Dex-St-GTMAC) copolymer was prepared through the reaction of GTMAC, stearoyl chloride, and dextran. Then, Dex-St-GTMAC was characterized by Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy. Dex-St-GTMAC forms micelles in the presence of indomethacin. The prepared polymeric micelles were characterized for size, ζ-potential, drug loading, particle morphology, critical micelle concentration, and encapsulation efficiency. To study the irritation potential of the indomethacin-loaded Dex-St-GTMAC, Het-Cam and Draize tests have been performed. Prepared cationic micelles were subjected to the in vitro drug release and ex vivotrans-corneal permeation test. Results The dialysis method was used for the preparation of indomethacin-loaded micelles (10, 20, and 30%). Measurement of the particle size showed a mean diameter of 122.1 and 150.9 nm for the drug-loaded micelles. Scanning electron microscopy (SEM) images showed that the morphology of the particles is spherical. 10% formulation was chosen as the best formulation due to more surface charge and reasonable drug loading. ζ-potential measurement for the 10% drug-containing micelles showed a value of +39.1 mV. Drug loading efficiency and the encapsulation efficiency for 10% drug-containing micelles were 6.36 and 63.61%, respectively. The results of the Het-Cam and Draize tests indicated that the indomethacin-loaded Dex-St-GTMAC formulation had no toxicity to eye tissues. Based on our results, the prepared micelles (indomethacin-loaded Dex-St-GTMAC) exhibited a sustained drug release pattern compared to the control group. Indomethacin penetration from the micelles to the excised bovine cornea was 1.75-fold greater than the control (indomethacin 0.1% in phosphate-buffered saline (PBS)). Conclusions Data from the ζ-potential, SEM, drug loading capacity, and in vitro drug release studies indicated that cationic dextran stearate polymeric micelles are an appropriate carrier for the efficient penetration of indomethacin into cornea tissues.


Optic pathway glioma of childhood.
Optic pathway gliomas (OPG) are the most common tumor of the anterior visual pathway and can involve the optic nerve, chiasm, tract, and optic radiations. They are typically benign lesions, often pilocytic astrocytomas, which are diagnosed in childhood. We review the epidemiology, clinical presentation, diagnosis, and management of these lesions in patients with and without neurofibromatosis type 1 (NF-1). Most commonly, patients diagnosed with OPG have NF-1 especially if the lesions are bilateral. Such lesions tend to have a relatively indolent course and at least 50% of patients have no evidence of visual loss. Rarely, children without NF-1 may sporadically develop OPG with such lesions often having a more aggressive nature and greater propensity for visual dysfunction. The gold standard for diagnosis and follow-up are thorough neuro-ophthalmic examinations with specific attention to visual acuity. Management must be individualized and may comprise conservative follow-up, chemotherapy, radiation and/or surgical intervention. OPG may range in their behavior based upon the nature of the tumor (NF-1 or sporadic). Current guidelines recommend following patients with regular clinical examinations. Management of these lesions is highly individualized based upon the nature and extent of the lesion, visual function and side-effect profile of the treatment. Clinicians should be aware of the available options to determine which may be best suited for their patient.


T cell responses to ovarian tumor vaccines: identification and significance for future immunotherapy.
The cellular immune responses to ovarian cancer patients treated with viral oncolysates (VO) ovarian tumor vaccines to vaccines are described. CD3+ cells proliferated after stimulation with the tumor vaccines in a dose-dependent manner. The proliferation of CD3+ cells stimulated with the tumor vaccine was blocked by anti-HLA-DR monoclonal antibody and anti-CD4 mAb indicating that CD3+ CD4+ cells from the blood of the patients treated with VO recognize tumor derived determinants in conjunction with MHC class II antigens. The regulatory activity of the T cells collected after VO treatment was assayed by co-cultivation with PBMC collected before VO treatment. These cells demonstrated increased helper activity for immunoglobin production by cells collected before vaccination and secreted IL-2 in response to stimulation by vaccine. Finally, when biochemical fractionation of the components of VO was attempted, PBMC from VO treated patients responded by proliferation to several fractions suggesting that they recognize multiple epitopes in the ovarian tumor vaccine. Therefore, these data provide novel evidence for the involvement of the T cells in response to ovarian tumor vaccines.


Clinical characteristics of zinc phosphide poisoning in Thailand.
The objectives of this study were to describe the clinical characteristics and outcomes of poisoning by zinc phosphide, a common rodenticide in Thailand, and to evaluate whether these outcomes can be prognosticated by the clinical presentation. A 3-year retrospective cohort study was performed using data from the Ramathibodi Poison Center Toxic Exposure Surveillance System. In total, 455 poisonings were identified. Most were males (60.5%) and from the central region of Thailand (71.0%). The mean age was 39.91±19.15 years. The most common route of exposure was oral (99.3%). Most patients showed normal vital signs, oxygen saturation, and consciousness at the first presentation. The three most common clinical presentations were gastrointestinal (GI; 68.8%), cardiovascular (22.0%), and respiratory (13.8%) signs and symptoms. Most patients had normal blood chemistry laboratory results and chest X-ray findings at presentation. The median hospital stay was 2 days, and the mortality rate was 7%. Approximately 70% of patients underwent GI decontamination, including gastric lavage and a single dose of activated charcoal. In all, 31 patients were intubated and required ventilator support. Inotropic drugs were given to 4.2% of patients. Four moribund patients also received hyperinsulinemia-euglycemia therapy and intravenous hydrocortisone; however, all died. Patients who survived and died showed significant differences in age, duration from taking zinc phosphide to hospital presentation, abnormal vital signs at presentation (tachycardia, low blood pressure, and tachypnea), acidosis, hypernatremia, hyperkalemia, in-hospital acute kidney injury, in-hospital hypoglycemia, endotracheal tube intubation, and inotropic requirement during hospitalization (P<0.05). Zinc phosphide poisoning causes fatalities. Most patients have mild symptoms, and GI symptoms are the most common. Patients who present with abnormal vital signs or electrolytes might have more severe poisoning and should be closely monitored and aggressively treated. All patients should be observed in the hospital for 2 days and followed up for cardiovascular and respiratory symptoms, electrolyte balances, kidney function, and blood glucose.