Bloodstream infections in pediatric hematology/oncology patients: Six years' experience of a single center in Turkey
Bloodstream infections are the major cause of morbidity, increased cost, prolonged hospitalization, and mortality in pediatric patients. Identifying the predominant microorganisms and antimicrobial susceptibilities in centers helps to select effective empirical antimicrobials which leads to positive clinical outcomes. We aimed to identify the causative microorganisms and their antimicrobial susceptibilities in patients with bloodstream infections. Data belonging to patients with hematological and/or oncological diseases admitted to our hospital with fever between January 2010 and November 2015 were analyzed. In total, 71 patients who had 111 bloodstream infection episodes were included. Responsible pathogens were detected as follows: 35.1% gram-positive microorganisms, 60.5% gram-negative bacteria, and 4.4% fungi. The most common causative gram-negative pathogen was Escherichia coli and the most commonly isolated gram-positive microorganism was coagulase-negative staphylococci. Gram-negative microorganisms were predominant pathogens in bloodstream infections. Escherichia coli and coagulase-negative staphylococci were the most commonly isolated responsible pathogens. Beta-lactam/lactamase inhibitors were suitable for empirical treatment. However, in critical cases, colistin could have been used for empirical treatment until the culture results were available. Routine glycopeptide use was not required. By identifying the causative microorganisms and their antimicrobial resistance patterns, it will be possible to obtain positive clinical results.


Photoinduced Electron Transfer in 9-Substituted 10-Methylacridinium Ions.
A series of 9-substituted 10-methylacridinium ions (Acr+ -R) in which an electron-donor moiety (R) is directly linked with an electron-acceptor moiety (Acr+ ) at the 9-position was synthesized, and the photodynamics was fully investigated to determine the rate constants of photoinduced electron transfer (ET) and back electron transfer. The driving forces of photoinduced electron transfer and back electron transfer were determined by means of electrochemical and photophysical measurements. The dependence of the ET rate constants on driving force was well analyzed in the light of the Marcus theory of ET. The quantum yields of formation of the triplet ET states vary significantly, depending on the interaction between the donor (R) and acceptor (Acr+ ) moieties. Among the Acr+ -R examined, the 9-mesityl-10-methylacridinium ion (Acr+ -Mes) exhibits the best performance in terms of the lifetime of the triplet ET state and the quantum yield. Photoexcitation of Acr+ -Mes results in formation of the triplet ET state [3 (Acr. -Mes.+ )], which has a long lifetime, a high energy (2.37 eV), and a high quantum yield (>75 %) in acetonitrile. The triplet ET state exhibits both the oxidizing and reducing activity of the Mes.+ and Acr. moieties, respectively.


The role of the Thomsen-Friedenreich antigen as a tumor-associated molecule.
The Thomsen-Friedenreich antigen (Gal-GalNAc) represents a tumor-associated molecule, which is assumed to be one of the few chemically well-defined antigens with a proven association with malignancy. In order to analyze the role of the carbohydrate structure Gal-GalNAc for gastrointestinal tumors, we immunized Balb/c mice with MCF-7 breast tumor cells together with synthetic Gal-GalNAc linked to a BSA carrier. One monoclonal antibody (82-A6) was established which recognizes the Thomsen-Friedenreich antigen according to the biochemical and serological analysis presented here. In contrast to the studies performed in the past, immunohistochemical results using this antibody 82-A6 did not exhibit a reactivity clearly restricted to tumors. Preliminary biochemical analysis revealed that the T-determinant is detectable in the high-molecular weight range (about 1000 kD), suggesting that the Gal-GalNAc epitope is found on mucinlike glycoproteins. Tumor restriction of Thomsen-Friedenreich antigen may therefore be determined either by the protein backbone or by the beta-glycosidic linkage of the carbohydrate structure to the protein.


Predicting whether aromatic molecules would prefer to enter a carbon nanotube: A density functional theory study.
The interaction of a carbon nanotube (CNT) with various aromatic molecules, such as aniline, benzophenone, and diphenylamine, was studied using density functional theory able to compute intermolecular weak interactions (B3LYP-D3). CNTs of varying lengths were used, such as 4-CNT, 6-CNT, and 8-CNT (the numbers denoting relative lengths), with the lengths being chosen appropriately to save computation times. All aromatic molecules were found to exhibit strong intermolecular binding energies with the inner surface of the CNT, rather than the outer surface. Hydrogen bonding between two aromatic molecules that include N and O atoms is shown to further stabilize the intermolecular adsorption process. Therefore, when benzophenone and diphenylamine were simultaneously allowed to interact with a CNT, the aromatic molecules were expected to preferably enter the CNT. Furthermore, additional calculations of the intermolecular adsorption energy for aniline adsorbed on a graphene surface showed that the concavity of graphene-like carbon sheet is in proportion to the intermolecular binding energy between the graphene-like carbon sheet and the aromatic molecule.


Comparison of the cardiovascular and biochemical profiles of a new positive inotropic drug, AR-L 115 BS, with those of theophylline.
Cardiac and coronary vasodilator effects of AR-L 115 BS and theophylline were compared in isolated, blood-perfused papillary muscle, sino-atrial (SA) node, and atrioventricular (AV) node preparations of dogs. Furthermore, the inhibitory effects of both drugs on crude cyclic AMP phosphodiesterase (PDE) prepared from the dog heart ventricle were examined. In the blood-perfused dog-heart preparations, AR-L 115 BS (3 micrograms-1 mg) and theophylline (3 micrograms-1 mg) were injected intra-arterially. Both drugs increased sinus rate and force of contraction and rate of automaticity of the papillary muscle, and decreased AV nodal conduction time in the respective preparations. The 2 drugs both increased blood flow. However, AR-L 115 BS was far more selective for inotropy than for chronotropy as compared with theophylline. AR-L 115 BS was also more selective for inotropy than for coronary blood flow as compared with theophylline, whereas the latter had the opposite selectivity. Both drugs were less effective on ventricular automaticity. Both drugs (0.3-3 mM) inhibited PDE activity; however, AR-L 115 BS was less effective than theophylline in this respect, although the former was about 3 times as potent as the latter in producing a positive inotropic effect. The present results suggest that unknown mechanisms other than PDE-inhibition greatly contribute to the positive inotropic effect of AR-L 115 BS.


Encapsulated nano-heat-sinks for thermal management of heterogeneous chemical reactions.
This paper describes a new way to control temperatures of heterogeneous exothermic reactions such as heterogeneous catalytic reaction and polymerization by using encapsulated nanoparticles of phase change materials as thermally functional additives. Silica-encapsulated indium nanoparticles and silica encapsulated paraffin nanoparticles are used to absorb heat released in catalytic reaction and to mitigate gel effect of polymerization, respectively. The local hot spots that are induced by non-homogenous catalyst packing, reactant concentration fluctuation, and abrupt change of polymerization rate lead to solid to liquid phase change of nanoparticle cores so as to avoid thermal runaway by converting energies from exothermic reactions to latent heat of fusion. By quenching local hot spots at initial stage, reaction rates do not rise significantly because the thermal energy produced in reaction is isothermally removed. Nanoparticles of phase change materials will open a new dimension for thermal management of exothermic reactions to quench local hot spots, prevent thermal runaway of reaction, and change product distribution.


Measuring US fertility using administrative data from the Census Bureau.
Longitudinal data available for studying fertility in the United States are not representative at the state level, limiting analyses of subnational variation in US fertility. The US Census Bureau makes available restricted data that may be used for measuring fertility, but the data have not previously been described for a scholarly audience or used for fertility research. This paper describes and analyzes restricted-use administrative birth data available through the Census Numident for nearly all US births for more than the last century. Within these data, most births since 1997 are linked to parents through the Census Household Composition Key (CHCK). These analyses are designed to illustrate the scope and limitations of these data for the study of US fertility. We describe the creation and content of the Census Numindent and CHCK data sets and compare the data to published US vital statistics. We also analyze the geographic coverage of both data sets and compare the demographic composition of the new data sources to national demographic composition. We further illustrate how these novel data sources may be used by comparing them to survey responses at the individual level. This paper describes an underutilized source of national US data for studying fertility, shows the quality of these data by performing analyses, and explains how scholars can access these data for research.


Perfusable and stretchable 3D culture system for skin-equivalent.
This study describes a perfusable and stretchable culture system for a skin-equivalent. The system is comprised of a flexible culture device equipped with connections that fix vascular channels of the skin-equivalent and functions as an interface for an external pump. Furthermore, a stretching apparatus for the culture device can be fabricated using rapid prototyping technologies, which allows for easy modifications of stretching parameters. When cultured under dynamically stretching and perfusion conditions, the skin-equivalent exhibits improved morphology. The epidermal layer becomes thicker and more differentiated than that cultured without the stretching stimuli or under statically-stretched conditions, and the dermal layer was more densely populated with dermal fibroblasts than that cultured without perfusion due to the nutrient and oxygen supply by perfusion via the vascular channels. Therefore, the system is useful for the improvement and biological studies of skin-equivalents.


Ab initio computer simulations of non-equilibrium radiation-induced cascades in amorphous Ge2Sb2Te5.
Ion irradiation corresponds to a process that involves the production of non-equilibrium cascades in the host material, and the atomistic modelling of such events in glasses is challenging. Here, non-equilibrium cascades in amorphous Ge2Sb2Te5 phase-change memory material have been investigated by means of first-principles molecular-dynamics simulations. A stochastic boundary-conditions approach is employed to treat the thermal nature of the cascades and drive the modelled system back to equilibrium in a natural way, while four different initial thermal-spike energies are considered. A comprehensive analysis of the cascade evolution is presented with respect to the kinetic profile and the dynamics of the cascade inside the glass structure. The modelling results show that the instantaneous maximum kinetic energy decays rapidly with time, and that the time-scale of the ballistic phase of the cascade inside the glass model is very short. The quality of the implemented approach is validated through a comparison of the calculated structure factor for the modelled glasses with experimental data from the literature. Analysis of the bonding for all the species in the glass structure highlights particular structural modifications in the connectivity of the amorphous network due to the simulated cascade.


A surprising increase in the affinity of estrogen for rat alpha-fetoprotein after it is treated with N-ethylmaleimide.
Incubation of rat alpha-fetoprotein (AFP) with mM concentrations of N-ethylmaleimide (MalNEt) at 22 degrees, pH7.8 for several hours yields a form of AFP with an equilibrium dissociation constant of 0.1 nM for estrone. This affinity for estrone is about 10 fold higher than that for untreated rat AFP. MalNEt-treated AFP still binds inhibitors and substrates of serine proteases suggesting that the binding of these compounds to AFP does not involve an interaction with a thiol group. MalNEt-treated AFP may be useful for studying the mechanism of estrogen action in vitro and in vivo, estrogen-protein interactions, and the functioning of AFP.


Gathering Real World Evidence Through the Evaluation of Decision History.
Clinical Practice Guidelines (CPGs) gather latest evidence-based results to guide and support clinicians over the decision-making process to provide best care. Nevertheless, clinical cases may be subject to some biases (understood as non-compliance with CPGs) that can lead to adapt care delivery. In this work an experience-based decision support leaning on the structuration of the Decisional Event concept for tracking and storing each clinical decision is presented. Moreover, a visual analytics tool is provided in order to facilitate the visualization of biases from guideline-based decision support and the identification and inclusion of real-world evidence into the reasoning process by augmenting the knowledge formalized in the implemented guidelines.


An isolated limb infusion technique: a guide for the perfusionist.
Isolated limb perfusion with the administration of cytotoxic drugs has been successfully used to treat melanomas of the extremity since it was first introduced in 1958. The use of hyperthermia (40 degrees C) combined with chemotherapy agents, primarily melphalan, has resulted in greater cytotoxicity in laboratory studies, which led to the application of hyperthermia in clinical studies during the 1960s. The effectiveness of this regional technique and the absence of any good systemic therapy made hyperthermic-isolated limb perfusion (HILP) the main treatment for patients with regionally advanced melanoma. HILP involves open surgical dissection and cannulation of the peripheral vessels and is associated with moderate morbidity rates. Blood transfusions, systemic drug leak, infection, and damage to the blood vessels and nerves are all potential hazards associated with this technique. Recently, however, there has been increased interest in an alternative technique termed isolated limb infusion (ILI), which was first reported in 1994 from the Sydney Melanoma Unit in Australia. Based on a few single institution experiences, it was found that there are fewer morbidities associated with HILP than with ILI but no compromise in patient outcomes. ILI is a less invasive procedure involving the use of angiographically placed catheters inserted percutaneously through the femoral vessels that does not require blood donor exposure or use of a heart lung machine. Preliminary data suggest that the resultant local hypoxia and acidosis induced by this procedure potentiates the cytotoxic effects of melphalan. Response rates comparing ILI to HILP seem similar, and both are markedly better than systemic chemotherapy. ILI may be a more desirable option because morbidity is greatly reduced and outcomes appear similar. There is a potential role for the perfusionist in the application of ILI, an evolving area of cancer therapy.


Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI).
Lactate dehydrogenase (LDH) catalyzes the reversible conversion of L-lactate to pyruvate. LDH-A deficiency is an autosomal recessive disorder (glycogenosis type XI, OMIM#612933) caused by mutations in the LDHA gene. We present two young adult female patients presenting with intolerance to anaerobic exercise, episodes of rhabdomyolysis, and, in one of the patients, psoriasis-like dermatitis. We identified in the LDHA gene a homozygous c.410C>A substitution that predicts a p.Ser137Ter nonsense mutation in Patient One and a compound heterozygous c.410C>A (p.Ser137Ter) and c.750G>A (p.Trp250Ter) nonsense mutation in Patient Two. The pathogenicity of the variants was demonstrated by electrophoretic separation of LDH isoenzymes. Moreover, a flat lactate curve on the forearm exercise test, along with the clinical combination of myopathy and psoriatic-like dermatitis, can also lead to the diagnosis.


Gold nanoparticle-based optical nanosensors for food and health safety monitoring: recent advances and future perspectives.
Modern society has been facing serious health-related problems including food safety, diseases and illness. Hence, it is urgent to develop analysis methods for the detection and control of food contaminants, disease biomarkers and pathogens. As the traditional instrumental methods have several disadvantages, including being time consuming, and having high cost and laborious procedures, optical nanosensors have emerged as promising alternative or complementary approaches to those traditional ones. With the advantages of simple preparation, high surface-to-volume ratio, excellent biocompatibility, and especially, unique optical properties, gold nanoparticles (AuNPs) have been demonstrated as excellent transducers for optical sensing systems. Herein, we provide an overview of the synthesis of AuNPs and their excellent optical properties that are ideal for the development of optical nanosensors based on local surface plasmon resonance (LSPR), colorimetry, fluorescence resonance energy transfer (FRET), and surface-enhanced Raman scattering (SERS) phenomena. We also review the sensing strategies and their mechanisms, as well as summarizing the recent advances in the monitoring of food contaminants, disease biomarkers and pathogens using developed AuNP-based optical nanosensors in the past seven years (2015-now). Furthermore, trends and challenges in the application of these nanosensors in the determination of those analytes are discussed to suggest possible directions for future developments.


HaloTag technology: a versatile platform for biomedical applications.
Exploration of protein function and interaction is critical for discovering links among genomics, proteomics, and disease state; yet, the immense complexity of proteomics found in biological systems currently limits our investigational capacity. Although affinity and autofluorescent tags are widely employed for protein analysis, these methods have been met with limited success because they lack specificity and require multiple fusion tags and genetic constructs. As an alternative approach, the innovative HaloTag protein fusion platform allows protein function and interaction to be comprehensively analyzed using a single genetic construct with multiple capabilities. This is accomplished using a simplified process, in which a variable HaloTag ligand binds rapidly to the HaloTag protein (usually linked to the protein of interest) with high affinity and specificity. In this review, we examine all current applications of the HaloTag technology platform for biomedical applications, such as the study of protein isolation and purification, protein function, protein-protein and protein-DNA interactions, biological assays, in vitro cellular imaging, and in vivo molecular imaging. In addition, novel uses of the HaloTag platform are briefly discussed along with potential future applications.


Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and meta-analysis.
Hip fractures are common, morbid, and costly health events that threaten independence and function of older patients. The purpose of this systematic review and meta-analysis was to determine if orthogeriatric collaboration models improve outcomes. Articles in English and Spanish languages were searched in the electronic databases including MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, and the Cochrane Registry from 1992 to 2012. Studies were included if they described an inpatient multidisciplinary approach to hip fracture management involving an orthopaedic surgeon and a geriatrician. Studies were grouped into 3 following categories: routine geriatric consultation, geriatric ward with orthopaedic consultation, and shared care. After independent review of 1480 citations by 2 authors, 18 studies (9094 patients) were identified as meeting the inclusion criteria. In-hospital mortality, length of stay, and long-term mortality outcomes were collected. A random effects model meta-analysis determined whether orthogeriatric collaboration was associated with improved outcomes. The overall meta-analysis found that orthogeriatric collaboration was associated with a significant reduction of in-hospital mortality [relative risk 0.60; 95% confidence interval (95% CI), 0.43-0.84) and long-term mortality (relative risk 0.83; 95% CI, 0.74-0.94). Length of stay (standardized mean difference -0.25; 95% CI, -0.44 to -0.05) was significantly reduced, particularly in the shared care model (standardized mean difference -0.61; 95% CI, -0.95 to -0.28), but heterogeneity limited this interpretation. Other variables such as time to surgery, delirium, and functional status were measured infrequently. This meta-analysis supports orthogeriatric collaboration to improve mortality after hip repair. Further study is needed to determine the best model of orthogeriatric collaboration and if these partnerships improve functional outcomes.


Alternative approach for angioplasty of stenosed left pulmonary artery following intracardiac repair of tetralogy of Fallot.
A 5-year-old boy with stenosed left pulmonary artery following total correction of tetralogy of Fallot underwent surgical pulmonary arterioplasty through a left anterolateral thoracotomy on a normothermic perfused heart under cardiopulmonary bypass. We found this to be a convenient approach, and recommend it for correction of this lesion in the absence of gross pulmonary regurgitation and right ventricular outflow tract dilatation.


Daytime noise stress and subsequent night sleep: interference with sleep patterns, endocrine and neurocrine functions.
The effects of strong daytime noise stress on subsequent undisturbed night sleep were studied in six male volunteers. They slept for seven consecutive nights in the laboratory, two nights being preceded by an 8 h exposure to 83 dB (A) pink noise. Continuously during all nights EEG, EOG, EMG, ECG and respiration were recorded. Additionally, during five nights, blood samples were taken every 30 min by an indwelling venous catheter for the determination of ACTH, hGH, PRL, TRP, 5-HT and 5-HIAA. After daytime noise load, increased sleep stage 4 stability, partly elevated hGH and PRL levels and decreased levels of the metabolites of the serotonergic system were found. This result may be explained by the assumption that high daytime noise stress is an additional load for the CNS which demands an intensification of recovery processes during the sleep of the subsequent night.


Factors influencing the development of bone starvation syndrome after total parathyroidectomy in patients with renal hyperparathyroidism.
To investigate the factors affecting the development of bone starvation syndrome (HBS) after total parathyroidectomy in patients with renal hyperparathyroidism (SHPT). The clinical data and perioperative indices of 141 patients who underwent PTX for SHPT were retrospectively analyzed. The patients were divided into HBS and non-HBS groups based on postoperative minimum blood calcium <1.87 mmol/L. The differences in general clinical data and perioperative related indices between the two groups were compared; logistic regression analysis was performed to analyze the risk factors influencing HBS occurrence after surgery. Multiple linear regression method was used to analyze the factors influencing the maintenance time of intravenous calcium supplementation and total amount of calcium supplementation during intravenous calcium supplementation. The threshold value for the diagnosis of HBS was analyzed using the ROC subjects' working curve. HBS occurred in 46 (32.6%) patients. Univariate analysis showed statistically significant differences in dialysis age, preoperative calcitonin, preoperative parathyroid hormone, preoperative blood phosphorus, and preoperative alkaline phosphatase between both groups (P < 0.05). Logistic regression analysis using stepwise entry method concluded that preoperative alkaline phosphatase was an independent factor for the development of HBS after surgery. Preoperative parathyroid hormone was an independent factor for the duration of intravenous calcium supplementation and total calcium supplementation during intravenous calcium supplementation in the HBS group. Based on the ROC curve, for postoperative HBS, the cut-off ALP value was 199.5 U/L, with a sensitivity of 80.85% and specificity of 82.61%. Preoperative serum ALP may be an independent factor for HBS occurrence after surgery. When preoperative ALP > 199.5 U/L, patients with SHPT are prone to HBS after surgery, and the higher the preoperative ALP, the higher the incidence of HBS, and vice versa. In addition, preoperative PTH may be the factor in the timing of postoperative intravenous calcium supplementation and the total amount of calcium supplementation during intravenous calcium supplementation in patients with HBS.


Fly photoreceptors demonstrate energy-information trade-offs in neural coding.
Trade-offs between energy consumption and neuronal performance must shape the design and evolution of nervous systems, but we lack empirical data showing how neuronal energy costs vary according to performance. Using intracellular recordings from the intact retinas of four flies, Drosophila melanogaster, D. virilis, Calliphora vicina, and Sarcophaga carnaria, we measured the rates at which homologous R1-6 photoreceptors of these species transmit information from the same stimuli and estimated the energy they consumed. In all species, both information rate and energy consumption increase with light intensity. Energy consumption rises from a baseline, the energy required to maintain the dark resting potential. This substantial fixed cost, approximately 20% of a photoreceptor's maximum consumption, causes the unit cost of information (ATP molecules hydrolysed per bit) to fall as information rate increases. The highest information rates, achieved at bright daylight levels, differed according to species, from approximately 200 bits s(-1) in D. melanogaster to approximately 1,000 bits s(-1) in S. carnaria. Comparing species, the fixed cost, the total cost of signalling, and the unit cost (cost per bit) all increase with a photoreceptor's highest information rate to make information more expensive in higher performance cells. This law of diminishing returns promotes the evolution of economical structures by severely penalising overcapacity. Similar relationships could influence the function and design of many neurons because they are subject to similar biophysical constraints on information throughput.


One week pulse therapy with itraconazole (200 mg day-1) for onychomycosis. Evaluation of treatment results according to patient background.
We investigated background factors of patients that affect the response of onycomycosis to pulse therapy with itraconazole. The regimen used in this study involved administering 200 mg of itraconazole orally on a daily basis for 1 week as one pulse, which is half of the normally recommended dose. The number of pulses was fixed at one per month, and altered in accordance with improvements in the infected nails and/or the patients' request. Patient background (n = 63) including sex, age, occupation, duration of the disease, site of lesion (fingernail, toenail), number of affected nails, clinical types, severity of thickening, presence or absence of pathogens, the presence or absence of underlying diseases such as adult onset diseases, turbidity of the target nails before therapy and the number and duration of pulses was investigated. The efficacy of the therapy was evaluated after 12 months. A complete cure was judged to have taken place if an entirely healthy nail plate re-grew in place of the diseased nail, whereas lack of success was defined as the persistence of lesions beyond the designated time period. The average number and duration of pulses were 4.7 +/- 3.2 times over 5.6 +/- 4.3 months, respectively. The rate of complete cure was 62%. Factors in the patients' background that were judged to have an influence on treatment results were the relative duration of the disease, the number of affected nails, and severity of thickening. With regard to the efficacy of the therapy in terms of the number and duration of pulses, 78% of 23 patients who were given pulse therapy two to six times during a course of 2 to 6 months achieved total cure.


Arousal and stress effects on consolidation and reconsolidation of recognition memory.
This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on consolidation and reconsolidation of a nonaversive learning paradigm, the object recognition task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (ie, elevated platform stress) impaired long-term consolidation and reconsolidation of object recognition. RU-486, a glucocorticoid receptor (GR) antagonist, infused into the basolateral amygdala (BLA), reversed the impairing effects of the stressor. In contrast, the nonhabituated aroused rats were impaired when consolidation was examined, but their memory was intact following reactivation of the memory trace. Exposure of nonhabituated rats to an out-of-context stressor enhanced the long-term consolidation of recognition memory, but impaired reconsolidation, and the effects were reversed by a GR antagonist infused into the BLA. Additionally, nonhabituated control rats showed intact retrieval following microinfusion of propranolol to the BLA immediately after the training, suggesting an involvement of beta-adrenoceptors in the BLA in the arousal-induced impairment of consolidation. These findings demonstrate opposite effects, detrimental and facilitative, of arousal and stress on memory consolidation and reconsolidation. In addition, the data suggests that although some general features underlie consolidation and reconsolidation, there is a possible dissimilarity between the two processes, which is dependent on the arousal level of the animal during training.


Forensic characterization and genetic polymorphisms of 19 X-chromosomal STRs in 1344 Han Chinese individuals and comprehensive population relationship analyses among 20 Chinese groups.
X-chromosomal short tandem repeats (X-STRs) may assist resolution of complex forensic kinship cases and complement autosomal and Y-chromosomal STRs in routine forensic practice and population genetics. In the present study, we investigated the allele/haplotype diversity and forensic genetic characteristics of 19 X- STRs in 206 Guizhou Han and 1344 Meta-Han Chinese individuals using AGCU X19 PCR amplification system. Population relationships within five Han Chinese population groups (1344 individuals), between Guizhou Han and other 19 Chinese reference populations belonging to four language families (5074 individuals), as well as between Meta-Han Chinese and other 15 minorities (3730 individuals) were performed using Reynolds's, Nei's and Fst genetic distances, principal component analysis (PCA), multidimensional scaling (MDS), Structure and Neighbor-Joining tree. Mean paternity exclusion chance (MEC) in Duos > 0.99999999453588 and in trios > 0.99999999999781, as well as power of discrimination (PD) > 0.99999999999980 in Guizhou Han on the basis of allele frequencies. Consistent high MECs and PDs can be observed in Meta-Han Chinese population based on both allele diversities of 19 markers and haplotype diversities of seven linkage groups (LG). DXS10135 and LG1 are the most informative and polymorphic in Han Chinese group. The comprehensive population comparisons reveal that Han Chinese is a homogenous population and has the genetically closer relationship with Hmong-Mien-speaking groups than Tibetan-Burman-speaking and Turkic-speaking populations. In summary, AGCU X19 PCR amplification system is highly polymorphic and informative in Guizhou Han and Han Chinese populations. The comprehensive population data from 20 Chinese populations analyzed in this study may be used as a reference Chinese frequency database of X-STRs for forensic casework applications.


Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.
This study is to evaluate whether thymidylate synthase (TS) or thyroid transcription factor 1 (TTF1) protein expression can predict clinical outcomes for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC). Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy were immunohistochemically analyzed for the expressions of TS and TTF1. TS and TTF1 expression were successfully analyzed in 193 and 284 cases, respectively. Tumors with TS-negativity or TTF1-positivity were more frequent in patients who were female, younger, had adenocarcinoma, or had never smoked. Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity (33.7% versus 14.1%, p = 0.002) and TTF1-positivity (28.1% versus 9.8%, p < 0.001). In univariate analysis, progression-free survival for pemetrexed-based chemotherapy was significantly longer in groups with adenocarcinoma (2.9 versus 1.4 months, p = 0.001), TS-negativity (4.1 versus 2.0 months, p = 0.001), and TTF1-positivity (3.8 versus 1.3 months, p < 0.001). In multivariate analysis, TS-negativity (hazard ratio [HR] = 0.70; 95% confidence interval [CI], 0.51-0.97) and TTF1-positivity (HR = 0.51; 95% CI, 0.35-0.73) were associated with longer progression-free survival. Patients with TTF1-positive tumors also had significantly longer overall survival times than patients with TTF1-negative tumors (25.4 versus 14.2 months, HR = 0.55; 95% CI, 0.39-0.77). Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression should be further validated in a prospective randomized study.


Dose-ranging efficacy of new once-daily extended-release minocycline for acne vulgaris.
A multicenter, 12-week, randomized, double-blinded, placebo-controlled, dose-ranging study was conducted in 233 subjects with moderate to severe facial acne vulgaris to determine the lowest effective once-daily oral dose of a new extended-release (ER) minocycline hydrochloride formulation with the safest adverse effect profile. Subjects randomly were assigned to treatment with daily dosages of ER-minocycline 1-, 2-, or 3-mg/kg tablets, or daily placebo tablets, for 84 days. At the end of the 12 weeks, the number of inflammatory lesions decreased approximately 50% from baseline levels in the dose groups. No dose-dependent effect was observed, with the percentage decrease in the number of inflammatory lesions in the 1-mg/kg treatment group being equal to or greater than higher doses. The pairwise difference between the ER-minocycline 1 mg/kg and placebo groups in the percentage decrease in inflammatory lesions was statistically significant (P = .015). Acute vestibular adverse events (AVAEs) appeared to be dose proportional, with the incidence being similar in the lowest (1 mg/kg) dosing group (24%) and in the placebo group (26%). Higher-dose regimens were associated with a higher incidence of central nervous system side effects and AVAEs. A 1-mg/kg daily dosage of the new ER-minocycline formulation is the lowest effective dose with the safest side effect profile, with higher-dose regimens offering no substantial therapeutic advantages.


Comparison of mating designs for establishing nested association mapping populations in maize and Arabidopsis thaliana.
The nested association mapping (NAM) strategy promises to combine the advantages of linkage mapping and association mapping. The objectives of my research were to (i) investigate by computer simulations the power and type I error rate for detecting quantitative trait loci (QTL) with additive effects using recombinant inbred line (RIL) populations of maize derived from various mating designs, (ii) compare these estimates to those obtained for RIL populations of Arabidopsis thaliana, (iii) examine for both species the optimum number of inbreds used as parents of the NAM populations, and (iv) provide on the basis of the results of these two model species a general guideline for the design of NAM populations in other plant species. The computer simulations were based on empirical data of a set of 26 diverse maize inbred lines and a set of 20 A. thaliana inbreds both representing a large part of the genetic diversity of the corresponding species. I observed considerable differences in the power for QTL detection between NAM populations of the same size but created on the basis of different crossing schemes. This finding illustrated the potential to improve the power for QTL detection without increasing the total resources necessary for a QTL mapping experiment. Furthermore, my results clearly indicated that it is advantageous to create NAM populations from a large number of parental inbreds.


Cytochrome c-552 from gram-negative alkaliphilic Pseudomonas alcaliphila AL15-21T alters the redox properties at high pH.
A soluble class I cytochrome c of an alkaliphile was purified and characterized, and its primary structure was determined. This is the first example of a soluble class I cytochrome c in alkaliphiles. Cells the alkaliphilic gram-negative bacterium Pseudomonas alcaliphila AL15-21(T) grown at pH 10 had a soluble cytochrome c content that was more than twofold that of strain AL15-21(T) cells grown at pH 7 under air-limited conditions. Cytochrome c-552, a soluble cytochrome c with a low molecular weight, was purified from strain AL15-21(T) cells grown at pH 10 under air-limited conditions. Cytochrome c-552 had a molecular mass of 7.5 kDa and exhibited an almost fully reduced state in the resting form, which exhibited absorption maxima at wavelengths of 552, 523 and 417 nm. In the oxidized state, it exhibited an absorption maximum at 412 nm when it was oxidized by ferricyanide, its isoelectric point (pI) was 4.3 and it contained one heme c as a prosthetic group. Cytochrome c-552 was autoreduced at pH 10, and the autoreduction was reproducible. On the other hand, the autoreduction of cytochrome c-552 was not observed at pH 7.0. When pH was increased from 7.0 to 8.3, its midpoint redox potentials (E(m) values) increased from +228 mV to +276 mV as determined by redox titrations, and from +217 mV to +275 mV as determined by cyclic voltammetric measurements. The amino acid sequence deduced by cytochrome c-552 gene analysis revealed that the sequence consists of 96 residues, including 19 residues as an amino-terminal signal peptide. A phylogenetic tree based on amino acid sequence indicated that the protein belongs to group 4, cytochrome c(5) in class I cytochrome c.


Aptamer-functionalized nano-biosensors.
Nanomaterials have become one of the most interesting sensing materials because of their unique size- and shape-dependent optical properties, high surface energy and surface-to-volume ratio, and tunable surface properties. Aptamers are oligonucleotides that can bind their target ligands with high affinity. The use of nanomaterials that are bioconjugated with aptamers for selective and sensitive detection of analytes such as small molecules, metal ions, proteins, and cells has been demonstrated. This review focuses on recent progress in the development of biosensors by integrating functional aptamers with different types of nanomaterials, including quantum dots, magnetic nanoparticles (NPs), metallic NPs, and carbon nanotubes. Colorimetry, fluorescence, electrochemistry, surface plasmon resonance, surface-enhanced Raman scattering, and magnetic resonance imaging are common detection modes for a broad range of analytes with high sensitivity and selectivity when using aptamer bioconjugated nanomaterials (Apt-NMs). We highlight the important roles that the size and concentration of nanomaterials, the secondary structure and density of aptamers, and the multivalent interactions play in determining the specificity and sensitivity of the nanosensors towards analytes. Advantages and disadvantages of the Apt-NMs for bioapplications are focused.


Regulation of LL-37 in Bone and Periodontium Regeneration.
The goal of regenerative therapy is to restore the structure and function of the lost tissues in the fields of medicine and dentistry. However, there are some challenges in regeneration therapy such as the delivery of oxygen and nutrition, and the risk of infection in conditions such as periodontitis, osteomyelitis, etc. Leucine leucine-37 (LL-37) is a 37-residue, amphipathic, and helical peptide found only in humans and is expressed throughout the body. It has been shown to induce neovascularization and vascular endothelial growth factor (VEGF) expression. LL-37 also stimulates the migration and differentiation of mesenchymal stem cells (MSCs). Recent studies have shown that LL-37 plays an important role in the innate defense system through the elimination of pathogenic microbes and the modulation of the host immune response. LL-37 also manifests other functions such as promoting wound healing, angiogenesis, cell differentiation, and modulating apoptosis. This review summarizes the current studies on the structure, expression, and function of LL-37 and highlights the contributions of LL-37 to oral cavity, periodontium, and bone regeneration.


The Modified Rivermead Mobility Index: reliability and convergent validity in a mixed neurological population.
To assess the inter-rater reliability, internal consistency and convergent validity of the Modified Rivermead Mobility Index (MRMI) in a mixed neurological population. The MRMI was scored for 30 consecutive patients (mean age 54.5+/-15.6 years) by two individual testers. Reliability was examined using intraclass correlation coefficients (ICC3,1) and Bland and Altman plots; internal consistency reliability using Cronbach's alpha (alpha) and convergent validity using Spearman's correlation coefficient (rho) test to compare the MRMI to the 10-m walk test as a gold standard of mobility. As the majority of patients had bilateral deficits, the MRMI was measured and added independently for both sides. The inter-rater reliability was excellent: ICC (95% CI)=0.93(0.86, 0.96). The Bland and Altman plots contained most data points and there was perfect agreement between raters bilaterally in 27% of cases, with a difference of one point in 60% of cases on the left and 63% of cases on the right. Internal consistency was good at alpha=0.72 (Rater 1) and 0.80 (Rater 2). The Spearman rho between MRMI and the 10-m walk test was high at 0.86. The MRMI was shown to have high levels of reliability in a mixed neurological population but we recommend that its psychometric properties are further investigated to establish the true clinical utility of this measure.


PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance.
Human plasmacytoid dendritic cells (PDC) are blood dendritic cell antigen 2 (BDCA2) and blood dendritic cell antigen 4 (BDCA4) positive leukocytes that do not express common lineage markers. They have been described as proinflammatory innate immune cells and are the major source of alphaIFN in the human body. PDC-derived secretion of type I IFNs upon triggering of nucleic acid-sensing toll-like receptors (TLR) primes immune cells to rapidly respond to microbial stimuli and promotes a Th1 response. Here, we report that human PDC express CD36 and CD61 (beta3 integrin), both involved in uptake of apoptotic cells and in induction of tolerance. Freshly isolated PDC and PDC within human blood leukocytes constitutively express IL-10. Thus, PDC may possess a so far neglected role in propagation of immune tolerance.


Comparative evaluation between re-irradiation and demand endoscopic dilatation vs endoscopic dilatation alone in patients with recurrent/reactivated residual in-field esophageal malignancies.
Esophageal cancer has emerged as a major health challenge in many regions of the world, including the valley of Kashmir, which is situated adjacent to the esophageal cancer belt on its Southern side. Radiotherapy is one of the main modalities of treatment. However, residual/recurrent disease is common and salvage options for these patients are limited. Scarce literature is available regarding the use of re-irradiation in this setting though re-irradiation has been successfully used in recurrent tumors at various other anatomical sites. In the present study, external beam re-irradiation with demand dilatation vs per-oral endoscopic dilatation alone were compared with regard to the impact of these modalities on symptom control, survival, and quality of life of the patients. Treatment-related sequelae were also compared. Prospective and randomized. The study included 34 cases who were palliated with re-irradiation and 35 cases who refused to enter the experimental protocol and, therefore, received per-oral demand dilatation alone, with the disease being allowed to follow its natural course. Both groups were statistically cross-matched with regard to their demographic and clinical parameters. STATISTICAL METHOD USED: Mann-Whitney U-test, Chi-square test, Student's t-test, and Kaplan-Meier test for survival analysis. The results favor the use of re-irradiation as it significantly improves dysphagia-free survival and quality of life. The treatment-related complications/morbidity of this protocol was acceptable. A trial of re-irradiation with external beam is justified in selected patients.


Validation of Spanish version of the human papilloma virus impact profile (HIP).
Objective: To examine the construct validity and reliability of the Spanish version of the HPV Impact Profile scale (HIP) among women in Medellin, Colombia.Methods: We conducted a nested analysis of data from the pragmatic randomized controlled trial "Evaluation of Strategies for Optimal Clinical Management of Women with Atypical Squamous Cells of Undetermined Significance" (ASCUS-COL; NCT02067468). Women with Atypical Squamous Cells of Undetermined Significance (ASCUS) were randomly assigned to one of three triage strategies (Pap smear, colposcopy, HPV). Participants completed a questionnaire with sociodemographic information and the HIP scale translated into Spanish at baseline, two weeks after receiving triage test results, and one year after the second questionnaire. We conducted exploratory and confirmatory factorial analysis, and then assessed test reliability using Cronbach's alpha. Subsequently, we conducted multigroup confirmatory factor analysis to assess differences according to women´s age, and configurational invariance of the factor structure over the three time measures.Results: The sample consisted of 675 women, with a mean age of 40 years. The exploratory and confirmatory factor analysis for the HIP showed a seven-factor structure with appropriate adjustment indicators ([Formula: see text]= 1466.783, p < .0001). Only two items (1 and 10) had low factor loads and were removed from the confirmatory analysis. Multigroup analysis according to women's age showed acceptable goodness of fit (RMSEA = 0.037, CFI/TLI:0.998/0.998). The factor structure was similar among the tree measures and the model preserved acceptable goodness of fit (RMSEA = 0.079, CFI:0.86). The Cronbach's alpha for the total score was 0.91, with the lowest score for sexual impact (0.49) and the highest score for worries and concerns (0.90).Conclusions: The Spanish version of the HIP had adequate reliability and construct validity, and its use could be considered in clinic and research settings.


25-hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis.
Hypovitaminosis D may play a role in multiple sclerosis (MS), but little is known about intrathecal vitamin D. 25-Hydroxyvitamin D was measured in cerebrospinal fluid and sera from 36 patients with relapsing-remitting MS, 20 patients with other inflammatory neurological diseases and 18 patients with non-inflammatory neurological diseases with liquid chromatography-mass spectrometry. There were no significant differences in cerebrospinal fluid concentrations of 25-hydroxyvitamin D, but the cerebrospinal fluid:serum ratio was significantly lower in MS compared with other inflammatory neurological diseases (p=0.0012) and non-inflammatory neurological diseases (p=0.041) patients. The concentrations of 25-hydroxyvitamin D in cerebrospinal fluid and serum were positively correlated and their ratio was similar to that of albumin. Neither the concentrations of 25-hydroxyvitamin D in cerebrospinal fluid or serum nor their ratio were associated with the presence of relapses or gadolinium-enhanced lesions. These results do not support that 25-hydroxyvitamin D is actively transported to the cerebrospinal fluid, or that the cerebrospinal fluid or serum levels or their ratio exert a major impact on MS activity.


Chitosan scaffold modified with D-(+) raffinose and enriched with thiol-modified gelatin for improved osteoblast adhesion.
The aim of the present study was to investigate whether chitosan-based scaffolds modified with D-(+) raffinose and enriched with thiol-modified gelatin could selectively improve osteoblast adhesion and proliferation. 2, 3 and 4.5% chitosan films were prepared. Chitosan suitability for tissue engineering was confirmed by protein adsorption assay. Scaffolds were incubated with a 2.5 mg ml(-1) BSA solution and the decrease of protein content in the supernatants was measured by spectrophotometry. Chitosan films were then enriched with thiol-modified gelatin and their ability to bind BSA was also measured. Then, 2% chitosan discs with or without thiol-modified gelatin were used as culture substrates for MC3T3-E1 cells. After 72 h cells were stained with trypan blue or with calcein AM and propidium iodide for morphology, viability and proliferation assays. Moreover, cell viability was measured at 48, 72, 96 and 168 h to obtain a growth curve. Chitosan films efficiently bound and retained BSA proportionally to the concentration of chitosan discs. The amount of protein retained was higher on chitosan enriched with thiol-modified gelatin. Moreover, chitosan discs allowed the adhesion and the viability of cells, but inhibited their proliferation. The functionalization of chitosan with thiol-modified gelatin enhanced cell spreading and proliferation. Our data confirm that chitosan is a suitable material for tissue engineering. Moreover, our data show that the enrichment of chitosan with thiol-modified gelatin enhances its biological properties.


[Chronic venous disease. A state of art].
Chronic venous disease affecting one-third of the European population has a considerable socioeconomic impact. There is increasing evidence, that the structural remodelling of the vein wall is caused by two etiological factors: the disturbed flow patterns in cosequence of the high venous pressure and a progressive inflammatory cascade. In the microcirculation the trapping of the white cells and the leukocyte-endothelium interaction lead to skin changes and leg ulcer. The CEAP classification has been adopted world-wide to faciliate the uniform communication and the description of all classes of the disease. For the practising physician the duplex scan is a valuable instrument to provide correct diagnosis and to guide the treatment. This ultrasound technique gives lot of useful information about the venous system of the lower leg, helps to identify the presence and sites of the reflux and the potential occlusion of the proximal veins. The possible treatments are the followings: conservative basis therapy - including compression, venoactive drugs, venous excersises, giving advice to patients and health care - as well as surgery and sclerotherapy. New promising therapeutic procedures, such as endovenous operations with radiofrequency or laser and foam sclerotherapy are spreading rapidly all over the world.


Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge.
Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4-), and, to a lower extent, in B-cells from healthy controls. Notably, IDE's surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE's surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4- T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4- T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.


Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors.
The neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]). A whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat-mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice). Orexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons. Our results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina.


Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.
We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.


Evaluation, prevention and management of radiotherapy-induced xerostomia in head and neck cancer patients.
As part of the multidisciplinary approach to head and neck cancer patients, radiation therapy plays an essential role, improving locoregional control. Radiation therapy-induced xerostomia is a late side-effect that increases the risk for developing dental caries and compromises oral mucosal integrity, resulting in oral pain, loss of taste, difficulties with swallowing and chewing, sleep disorders and worse quality of life. This review focuses on evaluation, prevention and management of radiation therapy-induced xerostomia. In terms of xerostomia prevention, some clinical trials evaluating amifostine and intensity-modulated radiation therapy have shown positive results. Pilocarpine is a useful agent as a treatment of radiation-induced xerostomia in head and neck cancer patients. Despite some advances in radiation therapy-induced xerostomia prevention, its treatment is an area in which advances are urgently needed.


DNA repair-deficient Xpa and Xpa/p53+/- knock-out mice: nature of the models.
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease in which repair of ultraviolet (UV)-induced DNA damage is impaired or is totally absent due to mutations in genes controlling the DNA repair pathway known as nucleotide excision repair (NER). XP is characterized, in part, by extreme sensitivity of the skin to sunlight, and XP patients have a more than 1000-fold increased risk of developing cancer at sun-exposed areas of the skin. To study the role of NER in chemical-induced tumorigenesis in more detail, the authors developed Xpa-/- homozygous knockout mice with a complete defect in NER (designated as Xpa mice or XPA model). Xpa mice develop skin tumors at high frequency when exposed to UV light, and as such, they mimic the phenotype of human XP. Moreover, the Xpa mice also appear to be susceptible to genotoxic carcinogens given orally. Based on these phenotypic characteristics, the Xpa mice were considered to be an attractive candidate mouse model for use in identifying human carcinogens. In an attempt to further increase both the sensitivity and specificity of the XPA model in carcinogenicity testing, the authors crossed Xpa mice with mice having a heterozygous defect in the tumor suppressor gene p53. Xpa/p53+/- double knockout mice develop tumors earlier and with higher incidences upon exposure to carcinogens as compared to their single knockout counterparts. Here the authors describe the development and features of the Xpa mouse and present some examples of the Xpa and Xpa/p53+/- mouse models' sensitivity towards genotoxic carcinogens. It appeared that the Xpa/p53+/- double knockout mouse model is favorable over both the Xpa and p53+/- single knockout models in short-term carcinogenicity testing. In addition to the fact that the double knockout mice respond more robustly to carcinogens, they also appear to respond in a very discriminative way. All compounds identified thus far are true (human) carcinogens, and, therefore, the authors believe that the Xpa/p53+/- mouse model is an excellent candidate for a future replacement of the chronic mouse bioassay, at least for certain classes of chemicals.


Quantitative study of Au(III) and Pd(II) ion biosorption on genetically engineered Tobacco mosaic virus.
One major obstacle in the mineralization of metal onto biologically derived templates is the lack of fundamental information pertaining to the relationship between metal ion loading and overall metal deposition onto the biotemplate. This study focuses on Au(III) and Pd(II) biosorption on the genetically-modified model biological template Tobacco mosaic virus (TMV1Cys). Metal ion (Au(III) or Pd(II)) loading on the TMV1Cys template was measured as a function of the equilibrium concentration of Au(III) or Pd(II) ions in solution at several temperatures. In addition, the Pd(II) loading on the TMV-wild (wild-type TMV) and TMV1Cys were compared to estimate the improvement of metal ion loading by genetic modification of the biotemplate. The gold or palladium coatings on the TMV1Cys were prepared using various metal ion loadings. Results show, for a range of metal ion loadings, a positive correlation existed between the concentration of the metal ions and the coating density of the metals deposited on the virus surface.


Effectiveness and cost-effectiveness of a group-based intervention to improve social-emotional development of young children in poverty-stricken areas: A cluster randomized controlled trial.
Social-emotional ability is key to the well-being and future success of children; however, disparities in social-emotional development during an individual's early age can last a lifetime, which is particularly evident among children living in poverty-stricken areas. We aimed to determine the effectiveness, cost-effectiveness, and feasibility of a group-based intervention called the Care Group on social-emotional development for families living in poverty-stricken counties. We conducted a cluster (township) randomized controlled trial (C-RCT) every two weeks from July 2019 to June 2020 in a poverty-stricken area located in Shanxi, China. The outbreak of the COVID-19 pandemic suspended the implementation of the intervention in January 2020. The caregiver-child pairs in the intervention group participated in 12 group-based sessions with a structured curriculum and learning materials emphasizing nurturing ability and early childhood development. We applied a difference-in-differences (DID) model to estimate the intervention's impact. The analysis follows the intention-to-treat (ITT) principle. We used standard economic costing methods to estimate the cost of implementing the Care Group over the intervention period and adopted a societal perspective in the analysis. We included 322 eligible caregiver-child pairs in the baseline (intervention n = 136, control n = 186) and surveyed 258 pairs in the endline (intervention n = 117, control n = 141). Compared with the control group, children in the intervention group had significantly fewer social-emotional problems (adjusted mean difference of Z score = -0.374, 95% CI = -0.718, -0.030, P = 0.033) six months after intervention. In the first year, the annual cost of implementing Care Group was US$146.10 per child, reduced to US$47.20 per child in the second year due to the exclusion of non-recurrent costs. The incremental cost-effectiveness ratio (ICER) was US$390.60. Care Group is an effective approach for promoting children's social-emotional development in poverty-stricken areas at an affordable cost and with high feasibility for scale-up. Considering the planned per capita health expenditure of the Chinese government for 2022, we believe that the presented evidence makes a solid scientific and financial case for integrating the Care Group intervention into the basic public health services (BPHS) package. Chinese Clinical Trials Registry (ChiCTR): ChiCTR1900022894.


Early form of ovarian cancer originating in inclusion cysts. A case report.
Most surface epithelial-stromal tumors of the ovary are thought to arise from epithelial inclusion cysts; thus, those cysts and the original surface epithelium are precursor lesions of ovarian carcinoma. A 46-year-old woman underwent a hysterectomy, right salpingo-oophorectomy and wedge biopsy of the left ovary because of a uterine myoma and right dermoid cyst. Histologic examination incidentally showed a tiny focus of well-differentiated serous carcinoma originating in inclusion cysts in the biopsied left ovary. Relaparotomy was performed, and only metaplastic epithelium in the inclusion cysts was found in the remnant of the left ovary. This finding was thought to be the origin of an ovarian cancer. Carcinoma precursors should occur in epithelial inclusion cysts of the ovary, as in the cervix and endometrium, but have been reported only rarely. Their incidental finding may help identify patients at risk of developing ovarian carcinoma.


Comparison of Barricor™ vs. lithium heparin tubes for selected routine biochemical analytes and evaluation of post centrifugation stability.
Obtaining suitable results unaffected by pre- or postanalytical phases is pivotal for clinical chemistry service. We aimed comparison and stability of nine biochemical analytes after centrifugation using Barricor™ plasma tubes with mechanical separator vs standard Vacutainer® lithium heparin tubes. We collected samples on six healthy volunteers and nine patients from intensive care units into 6 mL plastic Vacutainer® lithium heparin tubes and 5.5 mL plastic Barricor™ plasma tubes. All tubes were centrifuged within 30 minutes after venipuncture. First, we compared results of nine biochemical analytes from lithium heparin tubes with Barricor™ tubes for each analyte using Passing-Bablok and Bland-Altman analyses. Second, we calculated the difference of analyte concentrations between baseline and time intervals in tubes stored at + 4 °C. Based on the total change limit we calculated the maximum allowable concentrations percentage change from baseline. The majority of correlation coefficients were close to 0.99 indicating good correlation in the working range. Bland-Altman analyses showed an acceptable concordance for all analytes. In consequence, the Barricor™ tube might be an alternative to regular lithium heparin tube. Stability with this new generation tube is improved for eight analytes (except for aspartate aminotransferase) in comparison with regular lithium heparin tubes. By using Barricor™ tubes and prompt centrifugation, supplemental analysis or re-analysis for eight analytes including alanine aminotransferase, alkaline phosphatase, C-reactive protein, high sensitivity troponin T, lactate dehydrogenase, NT-pro BNP, potassium and sodium could be performed within 72 h of specimen collection.


Red blood cell types and living related renal transplantation.
We studied the effects of red blood cell types on 34 cases of living related renal transplantation. Red blood cell types were examined retrospectively concerning the ABO, Lewis, P, Rh-Hr, Kell, Duffy and MNSs systems in both donors and recipients. The correlation between red blood cell type and acute rejection in HLA identical pairs and the effects of the Lewis, P and other systems on graft outcome in HLA semi-identical pairs were considered. In the HLA identical group, the Rh-Hr and MNSs systems participated in acute rejection. In addition to the ABO and Rh-Hr systems, the Lewis and P systems influenced the graft rejection in the HLA semi-identical group.


Pertuzumab in HER2-positive breast cancer.
Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer. Pertuzumab showed positive results in clinical studies and agents in routine clinical usage are updated. The PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to June 2012 by using the terms 'pertuzumab' and 'anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors. The presented trials of phase II and phase III randomized trials of CLEOPATRA, NEOSPHERE and TRYPHAENA have showed pertuzumab action to be complementary to trastuzumab without increasing adverse events. Adding pertuzumab to trastuzumab in the first line of HER2-positive metastatic breast cancer and in the neoadjuvant treatment of locally advanced HER2-positive breast cancer is usually well tolerated. The evaluation of health-related quality of life showed that combining pertuzumab with docetaxel and trastuzumab compared to placebo have no detrimental effect with adding pertuzumab. Pertuzumab is the first HER dimerization inhibitor with a mechanism of action complementary to trastuzumab. Studies with anti-HER2 combination treatments indicate that the use of more than one HER2-targeted therapy was superior to one of these agents alone. Pertuzumab has produced impressive anti-tumor activity in combination with trastuzumab. There are ongoing studies with pertuzumab with an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.


Compilation of international standards for patch testing methodology and allergens.
Recommendations for patch testing methodology and allergens differ between contact dermatitis groups worldwide. Currently, there is no compilation of these recommendations. This study aims to summarize the current recommendations for patch testing methodology and allergens. Data was collected through a literature search and by contacting representatives from 24 known contact dermatitis groups. Thirteen groups responded to our inquiry. As expected, recommendations for allergens and methodology varied between different groups; however, most groups based their recommendations on the European baseline series. We have compiled tables of methodologies and commonly tested allergens. The differences between groups underscore the need for further international collaboration among contact dermatitis groups.


Physiology of 24,25-dihydroxyvitamin D3 in normal human subjects.
We determined the metabolic clearance and production rates of 24,25-dihydroxyvitamin D3 in four normal healthy adults. We also examined the excretion of radioactivity in stool, urine, and bile after the intravenous administration of 24,25-[3H]dihydroxyvitamin D3 to human subjects. 24,25-Dihydroxyvitamin D3 is rapidly cleared from the plasma with a half-life of approximately 390 +/- 25 min (mean +/- SE). The metabolic clearance rate of 24,25-dihydroxyvitamin D3 was 9.2 +/- 1.5 liters/day with a production rate of 26.4 +/- 7.2 micrograms/day (mean +/- SE). Within 1 day 13.0 +/- 4.2% (mean +/- SE) of the administered dose had appeared in the stool; by day 7, 48.8 +/- 2.7% of the dose had appeared in the feces. Within 24 hr, 6.4 +/- 0.8% of the administered dose appeared in the urine; 7.4 +/- 1.8% of the dose had appeared in the urine within 2 days. The biliary excretion of 24,25-dihydroxyvitamin D3 was studied in two subjects. By 8 h, 15.3 +/- 1.3% of the administered dose had appeared in the bile. The metabolites present in bile, feces, and urine were much more polar than 24,25-dihydroxyvitamin D3. These results demonstrate that 24,25-dihydroxyvitamin D3 is rapidly cleared from plasma and is excreted in the feces (probably via the bile) and urine of normal human subjects.


[Activation sequence of the left atrium studied by esophageal leads].
The intracardiac electrogram recorded in upper, middle and lower right atrium showed a positive, biphasic and negative P wave, respectively. This concept has been widely used in positioning the electrode in transesophageal atrial pacing (TEAP). However, in examination of the P wave figure in the unipolar lead along the esophagus by each two cm distance in 100 normal adults, we found that 32 subjects did not fulfill the above-mentioned criteria partially or completely. In order to study the underlying mechanism of such phenomenon, 190 patients undergone TEAP were examined by simultaneous recording of 2 unipolar esophageal leads (interelectrode distance 2-3 cm) with surface ECG. The patients were classified into 3 groups according to the morphology relation between the upper and lower esophageal P waves: Group A consisting of 155 cases (81.6%) in which the fashion of P wave changes was consistent with the usual criteria; Group B 17 cases (8.9%) was not consistent with the criteria; Group C 18 cases (9.5%) was in a reversed manner. The PEP-PED interval (measured from the peak of P wave in proximal esophageal lead to that in distal esophageal lead) was used as an indicator of left atrium activation sequence in vertical direction. Its value in these three groups was 6.3 +/- 10.1, -6.8 +/- 6.9 and -15.7 +/- 7.3 ms, respectively (P less than 0.001), suggesting in the latter two groups the left atrium activation was directed upward.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative expression of different antibody formats in mammalian cells and Pichia pastoris.
Generation of recombinant antibody fragments has been advanced by phage display technology but their broad use in biochemical or analytical applications is often hindered by their univalence. For enhancement of functional affinity and overall applicability, the fusion of scFvs (single-chain variable fragments) to IgG constant domains has become an attractive approach. In order to evaluate characteristics and expression behaviour of different IgG-analogous antibody formats, we fused an scFv to different portions of the heavy chain constant region of human IgG1. Two types of antibodies, an scFv-C(H)2-3 antibody and an scFv-C(H)1-3 antibody, a new intermediate with retained C(H)1 domain, were generated with or without an affinity tag for purification. Additionally, the scFv was reconverted into the heterotetrameric IgG molecule. To allow a reliable comparison of expression behaviours of different antibodies, we established vector systems that allow isogenetic and efficient expression of the recombinant antibodies based on site-specific recombination. Upon recombinant expression in mammalian cells and the methylotrophic yeast Pichia pastoris, disulfide-linked and glycosylated oligomers were obtained. Establishment of isogenetic cell lines revealed that the presence of the C(H)1 domain is not critical for secretion efficiency. Reactivity of the different constructs with antigen and Fc receptors was verified by ELISA, surface plasmon resonance approaches, as well as FACS analysis of HEK-293 cells (human embryonic kidney cells) stably transfected with human FcgammaRI (high-affinity IgG receptor) (CD64). In summary, the results obtained provide evidence for comparable behaviour of the different antibody formats and the vectors for isogenetic expression will contribute to a broader application of phage display-derived antibodies.


Clinical Characteristics and Outcomes of COVID-19 in West Virginia.
This study examines the clinical characteristics, outcomes and types of management in SARS-CoV-2 infected patients, in the hospitals affiliated with West Virginia University. We included patients from West Virginia with SARS-CoV-2 infection between 15 April to 30 December 2020. Descriptive analysis was performed to summarize the characteristics of patients. Regression analyses were performed to assess the association between baseline characteristics and outcomes. Of 1742 patients, the mean age was 47.5 years (±22.7) and 54% of patients were female. Only 459 patients (26.3%) reported at least one baseline symptom, of which shortness of breath was most common. More than half had at least one comorbidity, with hypertension being the most common. There were 131 severe cases (7.5%), and 84 patients (4.8%) died despite treatment. The mean overall length of hospital stay was 2.6 days (±6.9). Age, male sex, and comorbidities were independent predictors of outcomes. In this study of patients with SARS-CoV-2 infection from West Virginia, older patients with underlying co-morbidities had poor outcomes, and the in-hospital mortality was similar to the national average.


Far-from-equilibrium growth of magnetic thin films with Blume-Capel impurities.
We investigate the irreversible growth of (2+1)-dimensional magnetic thin films. The spin variable can adopt three states (s(I)=±1,0), and the system is in contact with a thermal bath of temperature T. The deposition process depends on the change of the configuration energy, which, by analogy to the Blume-Capel Hamiltonian in equilibrium systems, depends on Ising-like couplings between neighboring spins (J) and has a crystal field (D) term that controls the density of nonmagnetic impurities (s(I)=0). Once deposited, particles are not allowed to flip, diffuse, or detach. By means of extensive Monte Carlo simulations, we obtain the phase diagram in the crystal field vs temperature parameter space. We show clear evidence of the existence of a tricritical point located at D(t)/J=1.145(10) and k(B)T(t)/J=0.425(10), which separates a first-order transition curve at lower temperatures from a critical second-order transition curve at higher temperatures, in analogy with the previously studied equilibrium Blume-Capel model. Furthermore, we show that, along the second-order transition curve, the critical behavior of the irreversible growth model can be described by means of the critical exponents of the two-dimensional Ising model under equilibrium conditions. Therefore, our findings provide a link between well-known theoretical equilibrium models and nonequilibrium growth processes that are of great interest for many experimental applications, as well as a paradigmatic topic of study in current statistical physics.


Cysteine-scanning mutagenesis supports the importance of Clostridium perfringens enterotoxin amino acids 80 to 106 for membrane insertion and pore formation.
Clostridium perfringens enterotoxin (CPE) causes the gastrointestinal symptoms of the second most common bacterial food-borne illness. Previous studies suggested that a region named TM1, which has amphipathic characteristics and spans from amino acids 81 to 106 of the native CPE protein, forms a β-hairpin involved in β-barrel pore formation. To further explore the potential role of TM1 in pore formation, the single Cys naturally present in CPE at residue 186 was first altered to alanine by mutagenesis; the resultant rCPE variant, named C186A, was shown to retain cytotoxic properties. Cys-scanning mutagenesis was then performed in which individual Cys mutations were introduced into each TM1 residue of the C186A variant. When those Cys variants were characterized, three variants were identified that exhibit reduced cytotoxicity despite possessing binding and oligomerization abilities similar to those of the C186A variant from which they were derived. Pronase challenge experiments suggested that the reduced cytotoxicity of those two Cys variants, i.e., the F91C and F95C variants, which model to the tip of the β-hairpin, was attributable to a lessened ability of these variants to insert into membranes after oligomerization. In contrast, another Cys variant, i.e., the G103C variant, with impaired cytotoxicity apparently inserted into membranes after oligomerization but could not form a pore with a fully functional channel. Collectively, these results support the TM1 region forming a β-hairpin as an important step in CPE insertion and pore formation. Furthermore, this work identifies the first amino acid residues specifically involved in those two steps in CPE action.


Knowledge and beliefs regarding type 2 diabetes mellitus in rural Mexico.
To investigate adults with Type 2 diabetes mellitus (DM) in a rural area of Mexico in order to explore their knowledge and beliefs regarding diabetes. A pilot study was conducted in a rural town in Morelos, Mexico. Adults over the age of 40 were invited to participate in a screening program for DM, and those who had been previously diagnosed with Type 2 DM were invited for an interview to learn about their knowledge and beliefs regarding diabetes. The glucose screening project enrolled 521 participants, including 56 previously diagnosed with Type 2 DM. Interviews were conducted with 37 of those with previously diagnosed DM. Almost all individuals in the interview sample held causal explanations based on non-scientific beliefs. Home remedies were used by a majority, and most informants used one or more methods. Blood glucose monitoring was virtually non-existent. The most frequently reported source of social support was family members. Physicians appeared to be a less important source of support. Most respondents would like to improve management of their DM, and they try to do so with whatever resources they can afford; however, a lack of information and restricted economic resources appear to limit the availability of modern medical resources. Without the availability of glucose monitoring/screening programs and affordable medication, it appears unlikely that improved treatment of Type 2 DM will occur. Dietary changes and other management approaches may be best modified through family and community influence, instead of the individual lifestyle modification strategies described in the US Type 2 DM management model.


The hunt for 8-oxoguanine deaminase.
An enzyme from Pseudomonas aeruginosa, Pa0142 (gi|9945972), that is able to catalyze the deamination of 8-oxoguanine (8-oxoG) to uric acid has been identified for the first time. 8-Oxoguanine is formed by the oxidation of guanine residues within DNA by reactive oxygen species, and this lesion results in G:C to T:A transversions. The value of k(cat)/K(m) for the deamination of 8-oxoG by Pa0142 at pH 8.0 and 30 degrees C is 2.0 x 10(4) M(-1) s(-1). This enzyme can also catalyze the deamination of isocystosine and guanine at rates that are approximately an order of magnitude lower. The three-dimensional structure of a homologous enzyme (gi|44264246) from the Sargasso Sea has been determined by X-ray diffraction methods to a resolution of 2.2 A (PDB entry). The enzyme folds as a (beta/alpha)(8) barrel and is a member of the amidohydrolase superfamily with a single zinc in the active site. This enzyme catalyzes the deamination of 8-oxoG with a k(cat)/K(m) value of 2.7 x 10(5) M(-1) s(-1). Computational docking of potential high-energy intermediates for the deamination reaction to the X-ray crystal structure suggests that active-site binding of 8-oxoG is facilitated by hydrogen-bond interactions from a conserved glutamine that follows beta-strand 1 with the carbonyl group at C6, a conserved tyrosine that follows beta-strand 2 with N7, and a conserved cysteine residue that follows beta-strand 4 with the carbonyl group at C8. A bioinformatic analysis of available protein sequences suggests that approximately 200 other bacteria possess an enzyme capable of catalyzing the deamination of 8-oxoG.


Influence of Recovery Mode on the Maximum Number of Intervals Until Exhaustion During an Aerobic Interval Training Session.
Varela-Sanz, A, Sánchez-Otero, T, Tuimil, JL, Boullosa, D, and Iglesias-Soler, E. Influence of recovery mode on the maximum number of intervals until exhaustion during an aerobic interval training session. J Strength Cond Res 37(9): e510-e520, 2023-We analyzed work capacity, cardiometabolic, perceptual, and neuromuscular responses to an aerobic interval training (AIT) running session until exhaustion, with active (AR) vs. passive recovery (PR). Eight well-trained male endurance runners (36.88 ± 7.14 years, 58.22 ± 3.39 ml·kg -1 ·minute -1 ) randomly completed, after familiarizations and the University of Montreal Track Test (UMTT), 2 AIT track running sessions until exhaustion consisting in 2-minute bouts at 100% of maximum aerobic speed (MAS), with 2 minutes of recovery at 80% of the velocity associated to the second ventilatory threshold (vVT 2 ) (i.e., AR), or no exercise (i.e., PR). Oxygen consumption (V̇O 2 ), heart rate (HR), blood lactate [La], rating of perceived exertion (RPE), and countermovement jump (CMJ) were continuously monitored during sessions. The level of statistical significance was set at p ≤ 0.05. PR resulted in longer time to exhaustion during sessions (13.9 vs. 11.6 bouts, p = 0.045), but lower HR ( p < 0.01) when compared with AR. Time spent over 90% of maximum oxygen consumption (V̇O 2max ), blood lactate concentrations, neuromuscular performance, and RPE did not differ between AR and PR ( p > 0.05). Thus, PR allowed runners to perform more work intervals and, therefore, to accumulate a greater volume. On the other hand, when training goals are focused on reaching a higher chronotropic stress (i.e., higher HR) during the training session, athletes would obtain more benefits from AR. This study also demonstrates that the current volume recommendations for AIT are far below (54-64.5%) the maximum training capacity of well-trained runners.


Greedy Projected Gradient-Newton Method for Sparse Logistic Regression.
Sparse logistic regression (SLR), which is widely used for classification and feature selection in many fields, such as neural networks, deep learning, and bioinformatics, is the classical logistic regression model with sparsity constraints. In this paper, we perform theoretical analysis on the existence and uniqueness of the solution to the SLR, and we propose a greedy projected gradient-Newton (GPGN) method for solving the SLR. The GPGN method is a combination of the projected gradient method and the Newton method. The following characteristics show that the GPGN method achieves not only elegant theoretical results but also a remarkable numerical performance in solving the SLR: 1) the full iterative sequence generated by the GPGN method converges to a global/local minimizer of the SLR under weaker conditions; 2) the GPGN method has the properties of afinite identification for an optimal support set and local quadratic convergence; and 3) the GPGN method achieves higher accuracy and higher speed compared with a number of state-of-the-art solvers according to numerical experiments.


Effects of Netrin-1 and NHE1 Participation on the Migration of Macrophages Driven by CCL2.
This experiment was designed to investigate the relationship between NHE1 gene expression differences between Netrin-1 and NHE1. For this purpose, the blank control, CCL2, CCL2 + Netrin-1 groups were constructed, and cell migration ability was detected by scratch tests and Transwell experiments; Commercial over-expressed NHE1 adenovirus vector (over-expressed NHE1 group), shRNA adenoviral vector silencing NHE1 (silencing NHE1 group) and negative control without carrying virus (negative control group) were subjected to RT-PCR test 24h after infection and pH recovery rate after acid loading was measured. The percentage of wound healing area and the number of cell migration of macrophages in the blank control group, CCL2 group, CCL2+Netrin-1 group, over-expressed NHE1 group, silencing NHE1 group and negative control group were compared. Results showed that in terms of migration ability, the percentage of wound healing area and migration in CCL2 increased (P <0.05), in CCL2 + Netrin-1 (P <0.05) and increased NHE1 mRNA (P <0.05), and not in NHE1 (P <0.05).pH response rate after acid load (NHE1 activity) showed that NHE1 activity was enhanced compared with the blank group, while NHE1 activity in silent NHE1 group decreased (P <0.05); from macrophage migration ability after overexpression/silencing, the percentage of macrophage wound healing area and cell migration increased/decreased compared with CCL2 group and Netrin-1 + CCL2 group (P <0.05). Then Upregulation of NHE1 can promote CCL2-driven macrophage RAW264.7 cell migration, and the downregulation of NHE1 can inhibit its cell migration; Netrin-1 can inhibit CCL2-driven RAW264.7 cell migration regardless of NHE1 regulation.


Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees.
Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log(10) reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.


Nanotechnology for Cancer Therapy Based on Chemotherapy.
Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.


"At risk" languages and the road to recovery: a case from the Yukon.
This article traces the various ways that "languages at risk" in the Yukon Territory, Canada, are imagined and managed across a range of "stakeholders." Predicated on a history of oppression and the management of risk in the U.S. and Canada, aboriginal language endangerment has arisen from insecurities about communicative diversity. Conversely language revitalization has arisen from insecurities about the loss of diversity. As this article demonstrates, ideologies of loss and the insecurities entailed therein resonate differently across different speakers, language activists, and institutions, resulting in different perceptions of loss, different experiences of risk, and different approaches to recovery. Moving from policy and the institutionalization of aboriginal languages to people's reflections and concerns about their own welfare, this article argues that insecurities about language are ultimately insecurities about other vulnerabilities, including the shifting political-moral terrain of the nation-state and First Nations.


The influence of resident and faculty gender on assessments in anesthesia competency-based medical education.
Competency-based medical education (CBME) relies on frequent workplace-based assessments of trainees, providing opportunities for conscious and implicit biases to reflect in these assessments. We aimed to examine the influence of resident and faculty gender on performance ratings of residents within a CBME system. This retrospective cohort study took place from August 2017 to January 2021 using resident assessment data from two workplace-based assessments: the Anesthesia Clinical Encounter Assessment (ACEA) and Entrustable Professional Activities (EPAs). Self-reported gender data were also extracted. The primary outcome-gender-based differences in entrustment ratings of residents on the ACEA and EPAs-was evaluated using mixed-effects logistic regression, with differences reported through odds ratios and confidence intervals (α = 0.01). Gender-based differences in the receipt of free-text comments on the ACEA and EPAs were also explored. In total, 14,376 ACEA and 4,467 EPA assessments were analyzed. There were no significant differences in entrustment ratings on either assessment tool between men and women residents. Regardless of whether assessments were completed by men or women faculty, entrustment rates between men and women residents were not significantly different for any postgraduate year level. Additionally, men and women residents received strengths-related and actions-related comments on both assessments at comparable frequencies, irrespective of faculty gender. We found no gender-based differences in entrustment ratings for both the ACEA and EPAs, which suggests an absence of resident gender bias within this CBME system. Given considerable heterogeneity in rater leniency, future work would be strengthened by using rater leniency-adjusted scores rather than raw scores.


Doubling the Carbonate-Binding Capacity of Nanojars by the Formation of Expanded Nanojars.
Anion binding and extraction from solutions is currently a dynamic research topic in the field of supramolecular chemistry. A particularly challenging task is the extraction of anions with large hydration energies, such as the carbonate ion. Carbonate-binding complexes are also receiving increased interest due to their relevance to atmospheric CO2 fixation. Nanojars are a class of self-assembled, supramolecular coordination complexes that have been shown to bind highly hydrophilic anions and to extract even the most hydrophilic ones, including carbonate, from water into aliphatic solvents. Here we present an expanded nanojar that is able to bind two carbonate ions, thus doubling the previously reported carbonate-binding capacity of nanojars. The new nanojar is characterized by detailed single-crystal X-ray crystallographic studies in the solid state and electrospray ionization mass spectrometric (including tandem MS/MS) studies in solution.


3D self-assembled plasmonic superstructures of gold nanospheres: synthesis and characterization at the single-particle level.
The synthesis of 3D self-assembled plasmonic superstructures of gold nanospheres as well as the characterization of their structural and optical properties at the single-particle level is presented. This experimental work is complemented by FEM (finite element method) simulations of elastic scattering spectra and the spatial |E|(4) distribution for establishing structure-activity correlations in these complex 3D nanoclusters.