Nanoparticles as vectors for antibiotic resistance: The association of silica nanoparticles with environmentally relevant extracellular antibiotic resistance genes.
A relevant but yet unconsidered subset of particles that may alter the fate of extracellular antibiotic resistance genes (eARGs) are nano-scale particles (NPs), which are ubiquitous in natural environments and have unique properties. In this study, sorption isotherms were developed describing the association of linear DNA fragments isolated from widespread eARGs (blaI and nptII) with either micon-sized kaolinite or silica nanoparticles (SNPs), to determine if sorption capacity was enhanced at the nanoscale. For each isotherm, eARG fragments were added at five starting concentrations (5-40 μg/mL) to mixed batch systems with 0.25 g of particles and nuclease-free water. Sorption was quantified by the removal of DNA from solution, as detected by a Qubit fluorimeter. Isotherms were developed for eARGs of various fragment lengths (508, 680 and 861 bp), guanine-cytosine (GC) contents (34%, 47% and 54%) and both double and single stranded eARGs, to assess the impact of DNA properties on particle association. Sorption isotherms were also developed in systems with added humic acid and/or CaCl2, to assess the impact of these environmental parameters on sorption. FTIR analysis was performed to analyze the conformation of sorbed eARGs. Desorption of eARGs was studied by quantifying the removal of eDNA from washed and vortexed post-sorption particles. Statistically significant irreversible sorption of eARGs to environmentally relevant NPs (humic acid functionalized silica nanoparticles) was demonstrated for the first time. Nano-emergent properties did not increase sorption capacity of eARGs, but led to a unique compressed conformation of sorbed eARGs. The addition of humic acid, increased CaCl2 concentration and small DNA fragment size favored sorption. NPs showed a slight preference for the sorption of single-stranded DNA over double-stranded DNA. These findings suggest that NP association with eARGs may be a significant and unique environmental phenomenon that could influence the spread of antibiotic resistance.


Variation in the technical support of radiation oncology in different practice settings.
Two surveys of radiation therapy practice in the United States have been analyzed to reflect the technical support and processes of patient evaluation in different types of facilities. A 1986 random sample of facilities including single treatment unit free standing, single treatment unit hospital based, multiple treatment unit free standing, and multiple unit hospital based facilities have been surveyed to assess procedures, support, services, and equipment. The single treatment unit free standing and the single treatment unit hospital based facilities have the fewest support services, lower energy equipment, infrequent electron capability, and less than half are able to simulate complex disease processes with a dedicated simulator. A separate survey of practice in 1983 assessed compliance with important aspects of patient evaluation and treatment. In this survey single unit facilities showed greater variability above and below the national average than facilities with multiple treatment units and free standing facilities showed greater variation above and below the national average than hospital based facilities. This study identifies specific areas for improvement in the structure and practice of radiation oncology. It is still true that one can not indict broad categories of practice but must evaluate the individual facility.


Religion involvement and quality of life in patients with schizophrenia in Latin America.
The aim of the study was to explore the relationship between religion involvement (RI) and quality of life (QoL) in patients with schizophrenia from three countries in Latin America, while considering key confounding factors such as socio-demographic and clinical characteristics. This cross-sectional study was conducted in the public mental health services in La Paz, Bolivia; Arica, Chile; and Tacna, Peru. The data collected included RI, socio-demographic information, clinical characteristics, type of treatment and QoL using the S-QoL 18 questionnaire. A multivariate analysis using multiple linear regressions was performed to determine variables associated with QoL levels. Two hundred and fifty-three patients with schizophrenia were enrolled in our study. Significant positive associations were found between RI and QoL (the S-QoL 18 index: β = 0.13; p = 0.048; autonomy dimension: β = 0.15; p = 0.027). Other socio-cultural and economic factors were also associated with low QoL level: being a woman, older patient, low education level and being Aymara. Severity of the psychotic symptoms was associated to a lower QoL for all the dimension (β from 0.15 to 0.31), except for the resilience. Our study found that socio-cultural and economic factors including RI were associated with QoL in patients with schizophrenia in Latin America, suggesting that these factors may influence positively health outcome. However, these relationships were moderate in strength, especially in comparison to symptoms severity which remained the most important features associated with QoL.


Protein NMR resonance assignment by isotropic mixing experiments on random fractionally deuterated samples.
The 108-residue protein E. coli thioredoxin has been uniformly enriched to 50% with deuterium at all carbon-bound hydrogen positions. Isotropic mixing (i.e. TOCSY) experiments have been conducted for both the deuterated and natural-abundance samples. Using a 54 ms mixing time correlation peaks can be seen for all four protons on the benzenoid ring of tryptophan in both samples. The deuteration results in an average decrease in cross-sectional area of a factor of 2-3 for the TOCSY cross-peaks. The cross-peak intensities for the deuterated sample systematically decrease as a function of the number of protons involved in the transfer process thus overcoming a common ambiguity in the TOCSY experiment.


Reconstruction of stochastic nonlinear dynamical models from trajectory measurements.
An algorithm is presented for reconstructing stochastic nonlinear dynamical models from noisy time-series data. The approach is analytical; consequently, the resulting algorithm does not require an extensive global search for the model parameters, provides optimal compensation for the effects of dynamical noise, and is robust for a broad range of dynamical models. The strengths of the algorithm are illustrated by inferring the parameters of the stochastic Lorenz system and comparing the results with those of earlier research. The efficiency and accuracy of the algorithm are further demonstrated by inferring a model for a system of five globally and locally coupled noisy oscillators.


Association between colorectal polyps and hypertension treatment.
Patients who take drugs regularly are increasing, not least due to metabolic and orthopedic diseases. In the present study we aimed to investigate the association between the use of drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin, and colorectal polyps diagnosed based on colonoscopic findings. In total, 1318 consecutive patients who underwent total colonoscopy for the first time were cross-sectionally analyzed. Personal data including comorbidities and all medications were obtained by a questionnaire. Their blood pressure, body weight and waist circumference were measured just before the colonoscopic examination. Colorectal polyps were found in 577 (43.8%) patients, with a prevalence of 57.6% (296/514) in patients receiving antihypertensive treatment and 35.0% (281/804) in patients not undergoing such treatment. A multivariate analysis showed that age, waist circumference, alcohol consumption, smoking and the use of antihypertensive drugs were independent risk factors for colorectal polyps. In a secondary multivariate analysis incorporating the parameters of measured blood pressure and medication status, the number of antihypertensive drugs was strongly associated with the risk of colorectal polyps, whereas blood pressure showed no significant association. The use of antihypertensive drug may be a risk factor for colorectal polyps. Furthermore, this risk increases with the intensive use of antihypertensive drugs.


Association between retinal nerve fiber layer thickness and abnormalities of vision in people with human immunodeficiency virus infection.
To investigate relationships between contrast sensitivity (CS), color vision, and retinal nerve fiber layer (RNFL) among people with human immunodeficiency virus (HIV) infection; to evaluate the effect of time since diagnosis of HIV infection on RNFL thickness. Noninterventional cross-sectional study. We evaluated 102 eyes of 57 HIV-infected individuals without ocular opportunistic infections. Peripapillary RNFL thickness was determined with spectral-domain optical coherence tomography in 4 quadrants. CS was measured with the Pelli-Robson technique (expressed as logCS); color vision was measured with the Lanthony desaturated 15-hue technique (expressed as color confusion index [C-index], with higher scores indicating worse color vision). Correlations between values were assessed using Spearman correlation coefficients. Median RNFL thickness (average of 4 quadrants) was 102.9 μm (range, 75.0-134.7 μm). Median logCS was 1.90 (range, 1.25-1.95). Median C-index was 1.58 (range, 0.96-4.07). Temporal RNFL thickness was correlated with logCS (r=0.295, P=.003) and C-index (r=-0.338, P=.0005). Time since diagnosis of HIV infection was shorter for those with thick average RNFL than for those with thin average RNFL (P=.18). Both worse CS and worse color vision are correlated with thinning of the temporal RNFL, with possible threshold effects. Increased prevalences of abnormal CS and abnormal color vision in this population are therefore likely attributable to neuroretinal compromise. This pattern of structural and functional losses may reflect preferential damage to small-caliber axons in the maculopapillary bundle, possibly associated with mitochondrial dysfunction, providing a potential disease mechanism for HIV-associated "neuroretinal disorder."


Long non-coding RNAs regulate treatment outcome in leukemia: What have we learnt recently?
Leukemia is a group of highly heterogeneous and life-threatening blood cancers that originate from abnormal hematopoietic stem cells. Multiple treatments are approved for leukemia, including chemotherapy, targeted therapy, hematopoietic stem cell transplantation, radiation therapy, and immunotherapy. Unfortunately, therapeutic resistance occurs in a substantial proportion of patients and greatly compromises the treatment efficacy of leukemia, resulting in relapse and mortality. The abnormal activity of receptor tyrosine kinases, cell membrane transporters, intracellular signal transducers, transcription factors, and anti-apoptotic proteins have been shown to contribute to the emergence of therapeutic resistance. Despite these findings, the exact mechanisms of treatment resistance are still not fully understood, which limits the development of effective measures to overcome it. Long non-coding RNAs (lncRNA) are a class of regulatory molecules that are gaining increasing attention, and lncRNA-mediated regulation of therapeutic resistance against multiple drugs for leukemia is being revealed. These dysregulated lncRNAs not only serve as potential targets to reduce resistance but also might improve treatment response prediction and individualized treatment decision. Here, we summarize the recent findings on lncRNA-mediated regulation of therapeutic resistance in leukemia and discuss future perspectives on how to make use of the dysregulated lncRNAs in leukemia to improve treatment outcome.


Biological characterization of the melanin biosynthesis gene Bcscd1 in the plant pathogenic fungus Botrytis cinerea.
The gray mold fungus Botrytis cinerea produces dark-colored conidia and sclerotia due to deposition of melanin on the cell wall of these structures. However, the role of melanin biosynthesis on development and function of conidia and sclerotia have not been well elucidated in this fungus. This study disrupted the melanin biosynthesis gene Bcscd1 (for scytalone dehydratase) in the wild type B05.10, and the resulting mutants were compared with B05.10 and complementary mutants (COM) for growth and development, virulence and response to biotic/abiotic stresses. Three disruption mutants were obtained, and they did not differ from B05.10 and COM in mycelial growth rate on potato dextrose agar, however, they formed brownish conidia and scleotia deficient in melanogenesis, whereas B05.10 and COM formed grayish conidia and black sclerotia with normal melanogenesis. The disruption mutants were as aggressive as B05.10 and COM in infection of tobacco leaves. TEM observation showed that the disruption mutant ΔScd1-85 formed numerous tiny grooves in the conidial cell wall, thereby causing uneven thickness in the cell wall. In contrast, B05.10 and COM rarely formed tiny grooves in their conidial cell wall with even thickness. Moreover, the sclerotial cortex cell wall of ΔScd1-85 lost rigidity and the cells became collapsed, whereas the sclerotial cortex cell wall of B05.10 and COM appeared rigid, and the cells appeared plump in shape. The disruption mutants were more sensitive than B05.10 and COM in response to chemical stresses (H2O2, NaCl, SDS, sorbitol) for conidial germination and sclerotial survival. The sclerotia of the disruption mutants were more susceptible than the sclerotia of B05.10 and COM to infection by the mycoparasite Trichoderma koningiopsis. These results confirmed previous studies about the effect of melanin production on pathogenicity of B. cinerea, and expanded our knowledge about the role of Bcscd1 in cell wall integrity and in response to biotic and abiotic stresses.


Cluster headache: the ventilatory response to transient hypoxia with pure nitrogen.
To determine whether the carotid body plays a pathogenetic role in cluster headache, 20 cluster headache patients have been studied. Of these, 11 patients were in the interparoxysmal cluster phase, and 9 were in remission. Comparison was made with healthy subjects matched for sex, age, and smoking habits. Transient hypoxia was induced by inhalation of 1-8 breaths of 100% nitrogen (N2), until the arterial oxygen saturation (SaO2) decreased to around 80%. Changes in ventilation (tidal volume, inspiratory minute ventilation (VI), and end-tidal PCO2 (PETCO2)), were analyzed breath-by-breath. Under basal conditions, cluster headache patients had a slightly higher SaO2 and VI when compared to controls. PETCO2 was significantly lower (P < 0.05) during the cluster period as measured by Wilcoxon signed rank test for paired data, and during remission, according to the Student's paired t-test, in comparison with controls. After exposure to N2, no significant difference was found in the rate of reduction of SaO2 between any of the groups. A higher absolute increase in VI, but a relative (%) decrease in VI at moderate hypoxia were measured, the differences between patients and controls being on the border of the level of significance. Chemoreceptor sensitivity of the carotid body, expressed as the slope of a regression curve obtained by plotting the increase in VI against the reduction in SaO2, showed no statistical difference between the groups. The results do not support the hypothesis of a pathogenetic role for the carotid body in cluster headache.


Effects of petrosaspongiolide R on the surface topology of bee venom PLA(2): a limited proteolysis and mass spectrometry analysis.
Petrosaspongiolides are sponge metabolites belonging to the family of the gamma-hydroxybutenolide marine terpenoids. They possess a remarkable in vitro and in vivo anti-inflammatory profile, due to the specific inhibition of group II and III secretory phospholipase A(2) enzymes, and for this reason can be considered as potential lead for the development of anti-inflammatory drugs. The molecular mechanism of bee venom phospholipase A(2) inactivation has been identified, and the ligand-enzyme complex formation is guided by either non-covalent and covalent interactions. In this work we have analyzed the conformational changes induced by petrosaspongiolide R on the bee venom phospholipase A(2) topology during the molecular recognition process, through the application of limited proteolysis and mass spectrometric methodologies. The results are indicative of structural changes at the N- and C-terminal domains producing a more compact conformational arrangement of the enzyme.


Social Genomics Model of Health Disparities.
Social stress such as financial scarcity, childhood trauma, and neighborhood violence has been associated with worse health outcomes. Furthemore, the social stress one experiences is not accidental. Rather, it can be the result of systematic economic and social marginalization through social policies, built environment and neighborhood underdevelopment from structural racism and discrimination. The psychological and physical stress associated with social exposure risk has been identified as possible explanatory variables for the disparities in health outcomes we have previously assigned to "race." We will use lung cancer as a use case to illustrate a novel model that links social exposure, behavioral risk and the stress response to outcomes.


An updated review of the new hadron states.
The past decades witnessed the golden era of hadron physics. Many excited open heavy flavor mesons and baryons have been observed since 2017. We shall provide an updated review of the recent experimental and theoretical progresses in this active field. Besides the conventional heavy hadrons, we shall also review the recently observed open heavy flavor tetraquark statesX(2900) andTcc+(3875)as well as the hidden heavy flavor multiquark statesX(6900),Pcs(4459)0,Zcs(3985)-,Zcs(4000)+, andZcs(4220)+. We will also cover the recent progresses on the glueballs and light hybrid mesons, which are the direct manifestations of the non-AbelianSU(3) gauge interaction of the Quantum Chromodynamics in the low-energy region.


Design, synthesis, and docking of novel thiazolidine-2,4-dione multitarget scaffold as new approach for cancer treatment.
Novel thiazolidine-2,4-diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR-2 against HCT-116, MCF-7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF-7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF-7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e-i and 6a-c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR-2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.


Targeted metabolomics for the quantitative measurement of 9 gut microbiota-host co-metabolites in rat serum, urine and feces by liquid chromatography-tandem mass spectrometry.
Gut microbiota-host co-metabolites play an essential role in maintaining homeostasis, and their concentration changes are closely related to a variety of diseases. Developing a targeted metabolomics analytical platform for these co-metabolites will help to elucidate the relationship between intestinal flora and host. Here we present a simple and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of nine gut microbiota-host co-metabolites in rat serum, urine and feces. The compounds were separated on a reversed-phase C18 column using gradient elution with a solvent system consisting of methanol and water (containing 0.05% formic acid) and a 7-min run time. All of the calibration curves exhibited good linear relationships (R2 ≥ 0.9984, Percent Residual Accuracy ≥93.27%). The intra- and interday precision, expressed as relative standard deviation (RSD), was ≤ 14.84%. The accuracy was within 100 ± 13.16% for all analytes. The recovery of the nine compounds in biological samples was ≥ 85.80% with an appropriate RSD (≤12.04%). The validated method was successfully applied to monitor the global changes of these metabolites in obesity. Taken together, these results demonstrate that the method can simultaneously determine the nine co-metabolites in multiple biological matrices and is an essential part of the targeted metabolomics analytical platform, which may become an approach to evaluate the occurrence, development and therapeutic effects of metabolic diseases.


Trajectories of informal care intensity among the oldest-old Chinese.
Countries around the world face increasing demand for long-term care in the older population. Yet, the longitudinal patterns of long-term care use and the underlying predictors have not been well understood, which impedes efficient care planning and timely service delivery. This study investigates the trajectories of informal care intensity in the oldest-old Chinese population and identifies the most important predictors of care trajectories. The data come from four waves of the Chinese Longitudinal Health Longevity Survey (CLHLS 2005-2014, N = 10,292). We conducted the latent trajectory analysis (LTA) to cluster people's diverse trajectories into a finite number of groups. We built machine learning (ML) models to predict people's care trajectories and ranked the relative importance of the predictors. The LTA identified three distinct trajectories of informal care intensity: the low, increased and high intensity trajectories. Care intensity increases in all three trajectories. Older people with more severe limitations, females, urban residents, people with a higher income, and people with more daughters in the first wave are more likely to follow the increased or high intensity trajectory rather than the low intensity trajectory in the following decade. The random forest classifier has the best overall prediction performance among the four machine learning models. Its prediction accuracy can be further improved via model optimisation. Oldest-old people in China follow divergent trajectories of care utilisation, and inequality of informal care intensity is discernible across time, demonstrating the need for timely and targeted delivery of government support to those who need it most. Accurate prediction of care trajectories will be of great value to policy makers and practitioners in relation to the planning of personalised care and the equitable allocation of care resources.


Retracted: Research on Probability Distribution of Short-Term Photovoltaic Output Forecast Error Based on Numerical Characteristic Clustering.
[This retracts the article DOI: 10.1155/2022/5355286.].


Effects of population growth on the success of invading mutants.
Understanding if and how mutants reach fixation in populations is an important question in evolutionary biology. We study the impact of population growth has on the success of mutants. To systematically understand the effects of growth we decouple competition from reproduction; competition follows a birth-death process and is governed by an evolutionary game, while growth is determined by an externally controlled branching rate. In stochastic simulations we find non-monotonic behaviour of the fixation probability of mutants as the speed of growth is varied; the right amount of growth can lead to a higher success rate. These results are observed in both coordination and coexistence game scenarios, and we find that the 'one-third law' for coordination games can break down in the presence of growth. We also propose a simplified description in terms of stochastic differential equations to approximate the individual-based model.


[Has dipeptidyl peptidase IV an effect on blood pressure and coagulation?].
Dipeptidyl peptidase IV is a very specific protease that attracts growing scientific interest during the last few years. The enzyme has been purified to homogeneity from various human tissues. Histochemically, this protease is found at certain border lines of many organ compartments, as in the proximal tubuli of kidney, in the bile canaliculi of liver, in the capillary endothel, or in the myofibroblasts of placenta. In the blood, especially T-helper lymphocytes contain this enzyme. Dipeptidyl peptidase IV seems to be predestinated for regulatory functions, because it is located on the outer membranes of these cells. The peptidase very specifically degrades substance P. Thus, it is discussed whether the system substance P/dipeptidyl peptidase IV is involved in the regulation of blood pressure, especially in the placenta. On the other hand, the specific attack of the peptidase on the alpha-chain of monomeric fibrin considerably reduces the clotting potency of these molecules. Therefore, dipeptidyl peptidase IV may also be involved in the regulation of blood coagulation in intact vessels, especially because the capillary endothel is lined with this enzyme. The plasma zinc concentration seems to influence the peptidase activity. An increase in plasma zinc stimulates various factors that promote blood clotting.


Surgical treatment of gastric adenocarcinoma: Are we achieving textbook oncologic outcomes for our patients?
Composite measures are increasingly used to assess quality of care in surgical oncology. We sought to define the incidence of "textbook oncologic outcome" (TOO) following resection of gastric adenocarcinoma among a large, international cohort of patients. Gastric adenocarcinoma patients undergoing resection between 2000 and 2020 were identified from an international database. TOO was defined as margin-negative resection, examination of ≥16 lymph nodes, no prolonged length-of-stay (LOS), no 30-day mortality, and stage-appropriate receipt of chemotherapy. Among a total of 910 patients, 321 patients (35.3%) achieved a postoperative TOO. While failure to evaluate ≥16 lymph nodes (n = 591, 65.0%) and receipt of chemotherapy (n = 651, 71.5%) had the greatest negative impact on the ability to obtain a TOO, no 30-day mortality (n = 880, 96.7%), margin-negative resection (n = 831, 91.3%), and no extended LOS (n = 706, 77.6%) were more commonly achieved. No postoperative complications (OR: 0.44; 95% CI: 0.31-0.63) and T1a/T1b-stage disease (OR: 2.87; 95% CI: 1.59-5.18) were independently associated with achieving a TOO (p < 0.05). The odds of achieving a TOO improved over time (p-trend < 0.05), which was largely attributable to improved odds of evaluating ≥16 lymph nodes (2010-2014 vs. 2000-2004: OR, 5.21; 95% CI: 3.22-8.45). Only about one in three patients achieved a TOO following resection of gastric adenocarcinoma. Odds of TOO increased over time, largely due to improved lymph node evaluation.


Carotenoid pigments and the treatment of erythropoietic protoporphyria.
Carotenoid pigments protect photosynthetic organisms against photosensitization by their own chlorophyll. This photoprotective function of carotenoids was utilized in the treatment of a human photosensitivity disease, erythropoietic protoporphyria.


Prognostic ability of a panel of immunohistochemistry markers - retailoring of an 'old solution'.
An urgent requirement exists for new prognostic and predictive assays in breast cancer. Despite the development of high-throughput technologies such as DNA microarrays, it would now appear that immunohistochemistry (IHC) may play an increasingly important role in the clinical management of breast cancer. In this editorial, the authors discuss the potential prognostic ability of a panel of IHC markers, and question whether this well-established assay technology may in fact allow for improved prognostic and predictive tests in breast cancer.


Cell signaling in regulation of the barrier integrity of the corneal endothelium.
The barrier integrity of the corneal endothelium, which is conferred by its tight and adherens junctions, is critical for the maintenance of deturgescence of the corneal stroma. Although characteristically leaky, the barrier integrity restricts fluid leakage into the stroma such that the rate of leak does not exceed the rate of the endothelial active fluid transport directed toward the aqueous humor. At a molecular level, the barrier integrity is influenced by the actin cytoskeleton and microtubules, which are coupled to tight and adherens junctions via a variety of linker proteins. Since the cytoskeleton is affected by Rho family small GTPases and p38 MAP kinase, among others, many pathophysiological stimuli induce plasticity to the cytoskeleton and thereby elicit dynamic regulation of the barrier integrity. This review presents an overview of the impact of several bioactive factors on the barrier integrity of the corneal endothelium through altered actin cytoskeleton and/or disassembly of microtubules. The main focus is on the effect of TNF-α (tumor necrosis factor-α) which is a pro-inflammatory molecule found in the intraocular milieu during allograft rejection and anterior uveitis. This cytokine elicits acute activation of p38 MAP kinase, induces disassembly of microtubules, disrupts the peri-junctional actomyosin ring, and concomitantly breaks down the barrier integrity. These effects of TNF-α could be inhibited by stabilizing the microtubules, co-treating with a selective p38 MAP kinase inhibitor, and elevating intracellular cAMP via A2B receptors or direct exposure to forskolin. Overall, the corneal edema following a potential breakdown of the endothelial barrier integrity can be rescued pharmacologically by inhibiting specific cell-signaling mechanisms.


Helping gay fathers come out to their children.
This paper describes the treatment of seven gay fathers who were concerned about revealing their sexual identity to their children. A time-limited group was established for the purpose of developing strategies to help them past this juncture in their development as gay men. Role playing of specific situations was the modality chiefly employed. Discussions of the effects of internalized homophobia were also held. At the conclusion of the group (eight sessions) all participants rated the experience as "highly useful." Follow-up data are presented at 6 months.


SGLT2 inhibitors.
Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM.


Prevalence of acetabular labral tears and sublabral sulci: a cadaveric study.
The objective of the present study was to evaluate the prevalence and location of acetabular labral tears and sublabral sulci in cadaveric hips. Fifty hips of 25 embalmed cadavers with the mean age of 55 years (range, 18-85 years) were studied. All labral lesions were documented in their morphologic features, size and anatomic locations. Thirty-eight labral tears were found in 33 (66%) of 50 hips with the mean length of 17 mm (range, 8-36 mm). Twenty-two (58%) tears were located in the anterosuperior quadrant and 13 (34%) tears were identified in the posterosuperior quadrant. Thirty-one (82%) tears were detachments of the labrum form the bony acetabulum. Eight sublabral sulci were seen bilaterally in 8 hips of 4 cadavers (16%). Of these, 4 (50%) were located anterosuperiorly, 2 (25%) anteroinferiorly and 2 (25%) posteroinferiorly. The acetabular labral tears were common findings with a high prevalence. They were most commonly located in the anterosuperior quadrant of the acetabulum. Sublabral sulci are anatomic variants that can be found bilaterally in different quadrants of the hips.


Parasites of domestic and wild animals in South Africa. XIII. The seasonal incidence of adult ticks (Acarina: Ixodidae) on cattle in the Northern Transvaal.
Ticks were collected over a period of 13 months, at approximately fortnightly intervals, from 6 Africaner oxen kept on the farm Nylsvley in the Naboomspruit District. The 8 species of Ixodidae collected were, in order of abundance, Rhipicephalus appendiculatus, R. evertsi evertsi, Hyalomma marginatum rufipes, H. truncatum, Amblyomma hebraeum, R. simus, Boophilus decoloratus and Ixodes cavipalpus. The relative abundance of adult ticks of these species, their predilection feeding sites and seasonal fluctuations in numbers are discussed.


gp140, a C3b-binding membrane component of lymphocytes, is the B cell C3dg/C3d receptor (CR2) and is distinct from the neutrophil C3dg receptor (CR4).
gp140, previously identified as a 140-kDa C3b-binding membrane glycoprotein present on Raji cell surface, was shown to be the C3dg/C3d receptor of B lymphocytes (CR2). Specific polyclonal anti-gp140, prepared by immunizing rabbits with this highly purified C3 receptor, blocked Raji cell rosettes with EC3b, EC3bi, EC3dg and EC3d, and also blocked normal lymphocyte rosettes with EC3dg and EC3d without affecting CR1 or CR3 activity. Moreover, a monoclonal anti-C3 (C3b/#130), described by others as reacting with the d region highly expressed on EC3bi, EC3dg and EC3d and poorly exposed on EC3b, completely inhibited EC3bi, EC3dg and EC3d rosettes with Raji cells, but had no effect on EC3b rosettes. Treatment of Raji cells with rabbit anti-gp140 blocked the uptake of three 125I-labeled monoclonal antibodies anti-B2, HB-5 and OKB7 reported to react with C3d-binding proteins, indicating that each of these monoclonal antibodies recognizes epitopes present on gp140. The neutrophil C3dg receptor was examined to determine its relationship to lymphocyte CR2. While neutrophil rosettes with EC3d were undetectable, a specificity for C3d was suggested by the inhibition of EC3dg rosettes by fluid phase C3d-complexes bearing no detectable C3dg. However, such neutrophil EC3dg and EC3bi rosettes were not inhibited by rabbit anti-gp140 nor an excess of anti-CR1, anti-CR2, and anti-CR3. In addition, neutrophils did not bind 125I-labeled anti-gp140, anti-B2, or HB-5. Thus, the neutrophil C3dg receptor is distinct from gp140, the lymphocyte CR2, and should be designated CR4.


Latent 1,3-β-D-glucan acts as an adjuvant for allergen-specific IgE production induced by Japanese cedar pollen exposure.
The pollen grains of several plant species contain 1,3-β-D-glucan (BG). BG activates dendritic cells (DCs) and subsequently regulates the innate immune responses. Within Japan, the most common disease associated with type-I hypersensitivity is Japanese cedar pollinosis. However, the role of BG in Japanese cedar pollen (JCP) remains unclear. This study examined the localization and immunological effects of BG in JCP. The localization of BG in JCP grain was determined by immunohistochemical staining using a soluble dectin-1 protein probe and a BG recognition protein (BGRP). The content of BG extracted from JCP was measured by a BGRP-based ELISA-like assay. The cytokine production by bone marrow-derived DCs (BMDCs) obtained from wild-type and BG receptor (dectin-1) knock-out mice was examined in vitro. The mice were intranasally administered JCP grains and the specific serum Ig levels were then quantified. BG was detected in the exine and cell wall of the generative cell and tube cell of the JCP grain. Moreover, BG in the exine stimulated production of TNF-α and IL-6 in the BMDCs via a dectin-1-dependent mechanism. Meanwhile, JCP-specific IgE and IgG were detected in the serum of wild-type mice that had been intranasally administered with JCP grains. These mice also exhibited significantly enhanced sneezing behavior. However, dectin-1 knock-out mice exhibited significantly lower JCP-specific IgE and IgG levels compared to wild-type mice. Latent BG in JCP can act as an adjuvant to induce JCP-specific antibody production via dectin-1.


Natural history study on Riccardoella tokyoensis: life history with ontogeny and host distribution records.
Riccardoella tokyoensis is a snail parasite recently recorded in Japan. To understand the basic ecology of this mite, we surveyed the life history of a population, including seasonal dynamics, host range, and geographical distribution in East Japan. Seasonal dynamics of the mite were studied in Rinshi-no-mori Park, Tokyo, Japan, from June 2016 to May 2018; thereafter, the morphology of each stage was described. In this park, the host population was infected with the mite in all seasons; however, the prevalence and infection intensities were highest during the warm seasons. Larvae and nymphs were found in the warm seasons. Proto- and tritonymphs were uncommon. To study the host range and geographical distribution, we sampled 1135 terrestrial mollusks from 16 families at 21 locations in Kanto and east Tokai areas from June 2016 to May 2020. Mites were detected at 13 locations, and only clausiliid snails were infected with the mite. Through a laboratory experiment, our observations confirmed that the mite was transmitted to the host lung via the pneumostome. None of the artificially infected snails died, although we maintained the snails for 2 months. No inflammation was found in naturally infected host tissue, suggesting that their virulence against the host snails was low. Riccardoella tokyoensis was not found in the litter layer in the field surveys, and no mite was observed on the external surface of the hosts, suggesting that the major habitat of this mite was the host lung.


Isolation of FRET-positive cells using single 408-nm laser flow cytometry.
Flow cytometry may be used to isolate large amounts of living, fluorescently labeled cells. Certain fluorescent labels, like enhanced cyan fluorescent protein (ECFP) and enhanced yellow fluorescent protein (EYFP), allow the assessment of direct protein-protein interaction in situ, by fluorescence resonance energy transfer (FRET). However, current flow cytometric methods either require elaborate technical adaptations or, using a single laser protocol, are hampered by background signal. We optimized a single 408-nm laser protocol to detect FRET between ECFP/EYFP-tagged proteins. Cell lines stably expressing ECFP and/or EYFP or an EYFP-ECFP fusion protein were used to design the settings for the flow cytometer to detect FRET-positive cells using a single 408-nm laser. Using these settings, interactions between the subunits of the transcription factor NF-Y were studied. Flow cytometric analysis of the cells expressing an EYFP-ECFP fusion protein yielded a discrete FRET-positive population. Using the same settings, in cells expressing NF-YB-CFP and NF-YC-YFP fusion proteins, FRET could also be detected. These cells were sorted and FRET was confirmed by confocal microscopy. FRET-positive cells, expressing ECFP- and EYFP-tagged proteins, can be detected using single 408-nm laser excitation, with low background signal. This allows high-throughput analysis and isolation of viable FRET-positive and -negative cells for subsequent biological experiments.


Can BMI be a predictor of perioperative complications in Head and Neck cancer surgery?
Introduction: The effect of BMI on development of perioperative complications in head and neck cancer surgeries is not welldefined.

  Aim: This study aims to evaluate the effect of body mass index (BMI) on the development of surgical complications during the perioperative period in head and neck carcinoma (HNC) patients.

 Materials and methods: This study was conducted from 2019 to 2020. Electronic medical records of 210 patients undergoing major (clean-contaminated) surgeries were analysed. Chi-square test or Fisher exact test for determining association in categorical data and independent T-test or Mann-Whitney U test for comparison between the presence of complications and relation with continuous clinical parameters were used.

 Results: The majority of patients were within normal-weight range (68.57%). Only 12.85% of patients had BMI under 18.5 kg/m2 and 18.57% of patients had BMI equal to or more than 25 kg/m2. Coexisting comorbidities were present in 48.7% of patients with BMI of more than 25 kg/m2. Major and minor complications were present in 10.5% and 16.7% of all patients, respectively. Surgical site infections were present in 18.1% of patients. There was no statistical difference in the rate of complications (major, minor and SSI) in underweight, normal weight and overweight categories. The complications were significantly associated with the extent of surgery (P = 0.00413) and blood loss of more than 775 mL (P-value 0.005).

  Conclusions: In conclusion, the rate of surgical complications in head and neck onco-surgeries is not related to BMI of the patients. The perioperative management of these patients might require some modification due to co-existing comorbidities, but the overall impact on the development of complications could not be proven in this study.


A preliminary study to understand the effect of Fasciola hepatica tegument on naïve macrophages and humoral responses in an ovine model.
Fasciola hepatica, the liver fluke, is a highly evolved endo-parasite that uses various mechanisms to evade the host immune system. The immunosuppressive capabilities of the parasite's excretory/secretory products have been well demonstrated by previous independent studies. However, the role of the parasite's tegument in the immune responses remains to be investigated. In this study, the effect of the tegument and other fractions of adult F. hepatica (excretory/secretory, liver fluke homogenate and liver fluke homogenate without tegument) in the activation of naïve macrophages in vitro was investigated using an ovine model. In addition, an immunoproteomic approach was used to investigate the characteristics of humoral antibody responses developed in sheep against the tegument fraction. The results indicated significantly increased arginase expression in macrophages incubated with the tegument and excretory/secretory fractions. Two dimensional gel electrophoresis of the tegument demonstrated approximately 100 protein spots, with only four of these spots were highly reactive with the positive serum as determined by 2-DE immunoblotting. These results give a preliminary indication that the liver fluke tegument may play role in avoiding hosts' protective immune responses against itself.


Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol.
Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.


Evaluation of genetic melanoma vaccines in cdk4-mutant mice provides evidence for immunological tolerance against authochthonous melanomas in the skin.
We evaluated the efficacy of a candidate melanoma vaccine approach in mice genetically prone to develop melanoma due to the introduction of an oncogenic mutation (R24C) in the germline sequence of the cyclin-dependent kinase 4 (cdk4), a protein critically involved in cell cycle regulation. Melanomas were induced in cdk4-mutant mice by chemical carcinogenesis and UVB irradiation. A genetic prime-boost strategy targeting the clinically relevant differentiation antigen tyrosinase-related protein 2 (TRP2) was performed which was able to stimulate a melanocyte-specific cellular immune response associated with localized autoimmune vitiligo-like depigmentation. However, significant destruction of carcinogen-induced autochthonous melanocytic neoplasms in the skin was not observed following immunization. We provide evidence that autochthonous melanomas expressed TRP2 but not the MHC molecule H2-Kb and are immunologically tolerated in the skin. Our results highlight the importance of assessing melanoma vaccines in genetic mouse models that more adequately represent the expected clinical situation in order to identify strategies, which eventually may be of benefit for melanoma patients.


Temporal analysis of REM sleep after nest-building behavior in nulliparous albino rat.
EEG recording was performed, during nest-building behavior (NBB), from the hippocampus and sensorimotor cortex of nulliparous albino rats with simultaneous recordings of EMGs of neck-muscle and eye movements. The duration of NBB varied with a period of 4-5 days. However, the relative durations of behavioral transitions in NBB, i.e., nest-building, grooming, and sleeping, were regular in both long lasting and early terminated NBB. REM sleep was identified, in every instance, immediately after NBB. The latency of REM sleep was significantly tied to the termination of NBB without regard to the duration of NBB. Differences in the duration of NBB, however, affected REM-propensity: the longer the NBB was, the shorter the latency of REM sleep tended to be. NBB might accelerate the induction of the physiological condition responsible for REM sleep generation.


Development of field-applicable endogenous internally controlled recombinase-aided amplification (EIC-RAA) assays for the detection of human papillomavirus genotypes 6 and 11 using sample releasing agent.
Human papillomavirus (HPV) 6 and 11 are the two most common low-risk HPV subtypes, accounting for more than 90% of condyloma acuminatum. A simple, accurate and rapid screening method to be applied in community-level hospitals is in high demand. Endogenous internally controlled recombinase-assisted amplification (EIC-RAA) assays for HPV6 and 11 were performed in a single closed-tube at 39 °C within 30 min. The sensitivity and specificity of EIC-RAA were examined using recombinant plasmids and pre-tested HPV DNA. A total of 233 clinical samples were collected, and the DNA was extracted by traditional multi-step extraction, or sample releasing agent, before analysis by EIC-RAA. For comparison, HPV detection via Quantitative real-time PCR (qPCR) was also performed. The sensitivity of EIC-RAA analysis was 10 copies/reaction for HPV6, 100 copies/reaction for HPV11, and 100 copies/reaction for the human β-globin gene. No cross-reaction was observed with other HPV subtypes. Clinical performance of the EIC-RAA assay achieved a 100% of concordance rate with the commercial HPV qPCR kit. Further, the EIC-RAA assay achieved a 100% of concordance rate when using multi-step extracted DNA and sample releasing agent-processed DNA. The EIC-RAA assay for HPV6 and 11 detection possesses the advantages of accuracy, simplicity and rapidity, and demonstrates great potential to be used in community-level hospitals for field investigation.


Successful treatment of primary non-Hodgkin's lymphoma of the vagina with chemotherapy.
The vagina as a primary site of malignant lymphoma in woman is extremely rare. We report here a 30-year-old patient with a primary vaginal non-Hodgkin's lymphoma stage IEA, follicular large cell of B lineage, with an excellent response to cytotoxic chemotherapy (CHOP) and event-free survival of 28 months. Primary involvement of the vagina can be successfully treated by pelvic irradiation, but in young women chemotherapy should be considered to preserve fertility, as well as quality of life.


Possible high risk of transmission of the Nipah virus in South and South East Asia: a review.
Nipah virus (NiV) is a zoonotic, single-stranded RNA virus from the family Paramyxoviridae, genus Henipavirus. NiV is a biosafety-level-4 pathogen that is mostly spread by Pteropus species, which serve as its natural reservoir host. NiV is one of the major public health challenges in South and South East Asia. However, few molecular studies have been conducted to characterise NiV in a specific region. The main objective of this review is to understand the epidemiology, pathogenesis, molecular surveillance, transmission dynamics, genetic diversity, reservoir host, clinical characteristics, and phylogenetics of NiV. South and South East Asian nations have experienced NiV outbreaks. Phylogenetic analysis confirmed that two primary clades of NiV are in circulation. In humans, NiV causes severe respiratory illness and/or deadly encephalitis. NiV is mainly diagnosed by ELISA along with PCR. Therefore, we recommend that the governments of the region support the One Health approach to reducing the risk of zoonotic disease transmission in their respective countries.


Changes in the Mass-merchandise Cigar Market since the Tobacco Control Act.
This study identifies the specific product characteristics driving mass-merchandise cigar sales in the context of the changing regulatory environment. Cigar sales data in US convenience stores during 2008-2015 were purchased from Nielsen's Convenience Track system. Descriptive statistics highlight changes in the cigar market over time. Sales of flavored cigars increased by nearly 50% since 2008 and now make up over half of the cigar market. Fruit remains the most popular flavor group, but the sale of non-descript flavors such as "Jazz" and "Green" has grown substantially. Inexpensive 2- and 3-packs made up less than 1% of cigar sales in 2008, but by 2015 this packaging style held 40% of the market share. Black & Mild and Swisher Sweets dominate the convenience store channel and together are responsible for nearly 60% of total mass-merchandise cigar sales. Cigar companies take advantage of features recently banned for cigarettes, such as flavorings and small pack sizes to maintain strong sales. Given the appeal of mass-merchandise cigars to youth and young adults, the FDA and other governing bodies should regulate the manufacturing and promotion of cigars in the same way they have regulated cigarettes.


Cellulase-lactic acid bacteria synergy action regulates silage fermentation of woody plant.
Feed shortage is an important factor limiting livestock production in the world. To effectively utilize natural woody plant resources, we used wilting and microbial additives to prepare an anaerobic fermentation feed of mulberry, and used PacBio single-molecule real-time (SMRT) sequencing technology to analyse the "enzyme-bacteria synergy" and fermentation mechanism. The fresh branches and leaves of mulberry have high levels of moisture and nutrients, and also contain a diverse range of epiphytic microorganisms. After ensiling, the microbial diversity decreased markedly, and the dominant bacteria rapidly shifted from Gram-negative Proteobacteria to Gram-positive Firmicutes. Lactic acid bacteria (LAB) emerged as the dominant microbial population, resulting in increased in the proportion of the carbohydrate metabolism and decreased in the proportion of the amino acid and "global and overview map" (GOM) metabolism categories. The combination of cellulase and LAB exhibited a synergistic effect, through which cellulases such as glycanase, pectinase, and carboxymethyl cellulase decomposed cellulose and hemicellulose into sugars. LAB converted these sugars into lactic acid through the glycolytic pathway, thereby improving the microbial community structure, metabolism and fermentation quality of mulberry silage. The GOM, carbohydrate metabolism, and amino acid metabolism were the main microbial metabolic categories during ensiling. The presence of LAB had an important effect on the microbial community and metabolic pathways during silage fermentation. A "co-occurrence microbial network" formed with LAB, effectively inhibiting the growth of harmful microorganisms, and dominating the anaerobic fermentation process. In summary, PacBio SMRT was used to accurately analyse the microbial network information and regulatory mechanism of anaerobic fermentation, which provided a scientific basis for the study of woody silage fermentation theory. This study reveals for the first time the main principle of the enzyme-bacteria synergy in a woody silage fermentation system, which provides technical support for the development and utilization of woody feed resources, and achieves sustainable livestock production.


The evaluation of the 8th and 7th edition of the American joint committee on cancer tumor classification for distal cholangiocarcinoma: the proposal of a modified new tumor classification.
The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor (T) classification of distal cholangiocarcinoma (DCC), which are based on either layer or depth, may not accurately stratify patient survival. A total of 121 patients who underwent resection for DCC between 2002 and 2016 were analyzed. The impact of the AJCC staging system on survival was examined and a new T classification was established based on independent prognostic factors. Regarding overall survival, the optimal depth of invasion (DOI) cut-off value (8 mm) was the only independent prognostic factor. Regarding the relapse-free survival (RFS), a DOI >8 mm, portal vein (PV) invasion, and duodenal or pancreatic invasion were independent prognostic factors. A new T classification was developed as follows: T1, no invasion of adjacent organs; T2, invasion of the duodenum or pancreas; T3, invasion >8 mm into the bile duct wall; and T4, invasion of the PV or arteries. There were no significant differences in RFS according to the 8th edition of the AJCC. However, significant differences were observed in the RFS between T1 and T2 and between T2 and T3. A new T classification based on the layer and depth may be more feasible.


Multiple primary cancers of the breast, endometrium and ovary.
The association between cancers of the breast, endometrium and ovary is reviewed, using mainly population-based data from the cancer registries in Denmark and Connecticut, U.S.A. Breast cancer patients had an approximately three-fold increased risk of developing a cancer in the contralateral breast. The risk of breast cancer was also elevated following cancers of the corpus uteri and ovary, with relative risk (RR) estimates of about 1.5 from 1 to 4 years after the diagnosis of the first primary cancer. An increased risk of cancer of the corpus uteri subsequent to breast cancer was found in Connecticut, but not in Denmark. After an ovarian cancer, the risk of cancer of the corpus uteri was also elevated (RR = 1.6-2.3). An increased risk of ovarian cancer was observed subsequent to breast cancer (RR = 1.3-1.7), whereas the ovarian cancer risk decreased with time since the diagnosis of a cancer of the corpus uteri, probably reflecting treatment involving oophorectomy.


A sensitive enzymeless sensor for hydrogen peroxide based on the polynucleotide-templated silver nanoclusters/graphene modified electrode.
A novel, sensitive and enzymeless electrochemical sensor based on polynucleotide-templated silver nanoclusters (DNA-AgNCs)/graphene composite film was developed for the detection of hydrogen peroxide. The graphene modified glassy carbon electrode (GCE) was employed because graphene has several advantages including excellent conductivity, biocompatibility, and large surface area to volume ratio. In addition, it was found that DNA-AgNCs have remarkable electrocatalytic activity toward the reduction of hydrogen peroxide, and can be easily immobilized onto the surface of the graphene/GCE by π-π stacking. The sensor based on the (DNA-AgNCs)/graphene/GCE exhibited a rapid response (ca. 3s), a low detection limit (3 μM), a wide linear range from 15 μM to 23 mM, high selectivity, as well as good repeatability. Moreover, the common interfering species, such as ascorbic acid, uric acid, dopamine, glutathione, and l-cysteine, did not result in any interference. This present work may expand the use of silver nanoclusters in the field of electrochemical sensor.


The role of mycotoxins in the health and performance of dairy cows.
In comparison to monogastric species, ruminant animals are generally considered to be less susceptible to the adverse effects caused by contamination of feeds with mycotoxins. This is based on the assumption that the rumen flora degrade and inactivate mycotoxins, thus protecting the animal. A number of mycotoxins, however, resist rumen degradation, causing distinct clinical signs of intoxication. Moreover, due to their complex diet, dairy cows may be exposed to a varying number of mycotoxins, originating from different feed materials such as roughage and concentrates. Exposure to these complex mixtures of mycotoxins may result in unexpected health risks. Due to a pre-existing negative energy balance, cows in the transition period are considered to be particularly sensitive to the exposure to feeds contaminated with moulds, fungal spores and mycotoxins.


Epidural Spinal Cord Stimulation: A Novel Therapy in the Treatment of Restless Legs Syndrome.
We report a unique finding of a patient whose restless legs syndrome (RLS) symptoms abated after the placement of a spinal cord stimulator for chronic neuropathic pain. RLS is a common disorder, with many patients unable to find sufficient relief from their symptoms. A patient diagnosed with neuropathic pain who also suffered from RLS symptoms despite medication therapy underwent implantation of a spinal cord stimulator after a successful trial. This patient was interviewed formally about his RLS symptoms immediately before his procedure and at 6 weeks, 6 months, and 2.5 years after the procedure. The patient also completed the International Restless Legs Syndrome Scale questionnaire to objectively quantify the severity of his symptoms. Finally, the patient kept a 5-day journal detailing when the stimulator was in use. The patient reported subjective symptomatic improvement in his RLS symptoms with improved sleep quality and quantity, in addition to improvement in his back pain. The patient's score on the International Restless Legs Syndrome Scale improved after implantation from 33 to 0 on a 40-point scale. Moreover, when asked to keep a journal record of his stimulator use, the patient noted that he only used the stimulator before going to bed to help his RLS symptoms and no longer required any medication for his previous RLS symptoms. Epidural stimulation may be an additional, alternative, or novel therapy in the treatment of RLS.


A microtomographic system for the nondestructive evaluation of bone architecture.
Microtomography (micro-computed-tomography, mu-CT) is a method to image and quantify trabecular bone. It has the capability to address the role of trabecular architecture on the mechanical properties of bone and to study trabecular bone remodeling. The system described in this work is based on a compact fan-beam type tomograph that can work in spiral scanning or multislice mode. An X-ray tube with a microfocus is used as a source, a CCD-array as a detector. Samples with diameters from a few millimeters to a maximum of 14 mm can be measured, typically, bone biopsies with a diameter of 8 mm and a length of approximately 10 mm are measured. Spatial resolution is 28 microns. Usually the volume of interest contains 4 x 4 x 4 mm3 and is represented in 14 x 14 x 14 microns3 voxels. 3D stereological indices are extracted according to the standard definitions used in histomorphometry. Triangular surface representation is effected with an extended marching cube algorithm and forms a convenient basis for finite element analysis. Microtomographic measurements may be employed to "calibrate" lower-dose, lower-resolution images in vivo as well as to nondestructively assess unprocessed surgical bone biopsy specimens. These specimens remain intact for mechanical or histological testing.


Investigation of intervention methods based on different leading roles in family regarding child road safety education: An experimental study.
Children are vulnerable to traffic injuries due to their low hazard perception. Previous studies have indicated that both parents and children have potential leading roles in safety education within the family. However, the effects of different leading roles (parents or children) on the hazard perception of children have not yet been revealed, and interactive education with children in the leading roles could also be an important means to enhance children's road safety. To fill this gap, based on constructivism theory and the Feynman learning method, this study proposed two methods of enhancing children's hazard perception based on different leading roles in the family regarding child road safety education and investigated the effectiveness of the above intervention methods. Thirty sets of parents and children participated in this experiment and were divided into three groups. The children received one of three different road safety interventions: a constructivism intervention, a parental guidance intervention or a children's Feynman learning intervention. Compared with the constructivism intervention, the hazard perception of children who received road safety educations within the family were significantly improved; these children were more sensitive to potential traffic hazard factors and presented better visual search patterns. A comparative analysis showed that the two educational interventions based on different leading roles in the family regarding child road safety education were not identical with respect to effectiveness. The children's Feynman learning intervention had a more significant effect than the parental guidance intervention. The findings of this study provide insightful information for safety education researchers, governments, educators and families with children.


PE_PGRS: Vital proteins in promoting mycobacterial survival and modulating host immunity and metabolism.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), is the leading infectious cause of mortality worldwide. One of the key reasons for M. tb pathogenesis is the capability of M. tb to evade immune elimination and survive in macrophage, eventually causing chronic infection. However the pathogenicity mechanism of M. tb is not unclear yet, and thus diagnosis and therapy for TB remains a challenge. The genome of M. tb, encodes a unique protein family known as the PGRS family, with largely unexplored functions. Recently, an increasing number of reports have shown that the PE_PGRS proteins play critical roles in bacterial pathogenesis and immune evasion. The PE_PGRS protein family, characterized by a special N-terminal PE (Pro (P)-Glu (E) motif) domain and a C-terminal PGRS (Polymorphic GC-rich Repetitive Sequences) domain, is restricted mainly to pathogenic mycobacteria. Here we summarize current literature on the PE_PGRS as vital proteins in promoting bacterial survival and modulating host immunity, cell death and metabolism. We also highlight the potential of PE_PGRS as novel targets of anti-mycobacterial interventions for TB control.


Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction.
Phosphoinositide 3-kinases are a family of lipid kinases that phosphorylate the 3' position of the inositol ring on phosphatidylinositol and higher-phosphorylated polyphosphoinositides. The multiplicity of cellular functions influenced by the activity of these enzymes has captured the attention of researchers working on two important fields of cell biology--signal transduction and membrane traffic. This review discusses how the recent identification of proteins that interact directly with 3'-polyphosphoinositides has revealed novel potential interconnections between these fundamental cellular processes.


Microarrays for the study of viral gene expression during human cytomegalovirus latent infection.
Human cytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and following resolution of primary productive infection, it persists in the human host by establishing a lifelong latent infection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMV infection are healthy but it can cause neurologic deficits in infants, and remains an important cause of morbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV have provided useful information about genes that are transcriptionally active during both productive and latent phases of infection. This chapter describes how to study genes in HCMV using microarrays and two cell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloid progenitor cells).


Numerical simulation of the aqueous humor flow in the eye drainage system; a healthy and pathological condition comparison.
The present work describes the motion of aqueous humor through the anterior chamber and the trabecular drainage system, considering several distributions of the collector channels. The 3D computational model, implemented into the open-source software, was reconstructed from an optical coherence tomography. The model has been employed to simulate the aqueous humor dynamics considering buoyancy effects. The presence of the anterior chamber, the trabecular meshwork, and the Schlemm's canal were taken into consideration with 14 different distributions of collector channels. The influence of collector channels position on the intraocular pressure and shear stress has been analyzed, for a healthy and a glaucomatous condition. Aqueous humor velocity, pressure, temperature, wall shear stress, skin friction coefficient and Nusselt number, are presented for the different cases. The results indicate that the position of the collector channels has a strong influence on the wall shear stress on the Schlemm's canal and collector channels.


Detecting Counterion Dynamics in DNA-Protein Association.
Due to a high density of negative charges on its surface, DNA condenses cations as counterions, forming the so-called "ion atmosphere". Although the release of counterions upon DNA-protein association has been postulated to have a major contribution to the binding thermodynamics, this release remains to be confirmed through a direct observation of the ions. Herein, we report the characterization of the ion atmosphere around DNA using NMR spectroscopy and directly detect the release of counterions upon DNA-protein association. NMR-based diffusion data reveal the highly dynamic nature of counterions within the ion atmosphere around DNA. Counterion release is observed as an increase in the apparent ionic diffusion coefficient, which directly provides the number of counterions released upon DNA-protein association.


Immunohistochemical study of ontogeny and phylogeny of a terminal N-acetylglucosamine cluster antigen.
In this work an immunohistochemical method was used to study the ontogeny and phylogeny of a terminal N-acetylglucosamine (GlcNAc) cluster antigen which is an epitope(s) of highly branched N-linked oligosaccharides terminating in GlcNAc residues. The ontogenic studies demonstrated that expression of the antigen is developmentally regulated in lymphocytes, epithelial cells of endodermal origin and kidney mesangial cells of the chicken. The antigen was found in several other avian species studied, namely, the Japanese quail, duck, goose and turkey. Furthermore, the distribution of the antigen in all these species was similar. In adult animals, it was found in bursal and thymic lymphocytes, macrophages, spleen reticulum cells, epithelial cells of the intestine and bronchioles and capillary endothelial cells. The antigen was also detected in epithelial cells of the gastrointestinal tract of several lower vertebrates studied: the amphibian (frog), reptile (chameleon) and fish (rainbow trout). It was undetectable in various organs of the human, African green monkey, calf, pig, rat and guinea-pig, but was found in the intestinal epithelial cells of ten mouse strains. It is likely that biosynthetic processing leading to the formation of highly branched N-linked glycans terminating in GlcNAc residues is conserved during evolution in birds and other lower vertebrates.


Fluoxetine in the Management of Major Depressive Disorder in Children and Adolescents: A Meta-Analysis of Randomized Controlled Trials.
Fluoxetine is a serotonin-specific reuptake inhibitor antidepressant and is the only approved pharmacological treatment for major depressive disorder (MDD) in children and adolescent. We searched the published randomized controlled-trials to review fluoxetine efficacy and tolerability using the databases PubMed, EudraCT, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials for fluoxetine role in managing MDD in children and adolescents. A meta-analysis was conducted using the identified 7 clinical trials to assess efficacy using the outcomes: Children's Depression Rating Scale-Revised (CDRS-R), Clinical Global Impressions-Severity of Illness (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) response rate. The risk of discontinuation due to adverse effects and common side effects were examined. The mean difference in change from baseline for CDRS-R was -2.72 (95% confidence interval [CI], -3.96, -1.48) favoring fluoxetine treatment (P < .001). Similarly, mean difference for CGI-S was -0.21 (95% CI, -0.36, -0.06). The risk ratio (RR) of discontinuing due to adverse events was 0.98 (95% CI, 0.54, 1.83), with RR for headache side effects 1.34 (95% CI, 1.03, 1.74) and rash 2.6 (95% CI, 1.32, 5.14). Fluoxetine demonstrates significant improvements in symptom intensity control in young patients suffering from MDD and is considered well tolerated with similar rates of trials discontinuation; however, fluoxetine was associated with a higher risk of headache and rash side effects. These findings will guide psychiatrists and pharmacists in their clinical role for supporting the care of young mental health patients.


Sleep in amyotrophic lateral sclerosis: A systematic review and meta-analysis of polysomnographic findings.
This study explores the polysomnographic differences between amyotrophic lateral sclerosis (ALS) patients and healthy controls. An electronic literature search was conducted in MEDLINE, EMBASE, All EBM databases, Web of Science, and CNKI from inception to Oct 2022. Meta-analyses revealed significant reductions in sleep efficiency, total sleep time, N2%, slow wave sleep percentage, minimum SpO2, and mean SpO2, and increases in wake time after sleep onset and N1%, sleep latency, rapid eye movement sleep latency, time spent with SpO2 < 90%, oxygen desaturation index, and apnea hypopnea index in ALS patients compared with controls. Sensitivity analyses showed that some heterogeneity was explained by excluding patients taking medications impacting sleep, whether studies employed an adaptation night, and the use of different PSG scoring rules. Significant polysomnographic abnormalities are present in ALS. Our findings underscore the need for a comprehensive PSG assessment of sleep changes in ALS patients. When performing PSG examinations in ALS, whether the patients are taking medication impacting sleep and the scoring system used should be considered.


Substrate spectrum of tyrocidine thioesterase probed with randomized peptide N-acetylcysteamine thioesters.
Apparent kinetic constants k(cat) and K(m) were determined for tyrocidine thioesterase (TycC TE) using randomized peptide N-acetylcysteamine thioesters as substrate analogues. The enzyme has been found to be adequately active for the synthesis of positional-scanning libraries for novel antibiotic screening with reduced k(cat)/K(m) in the range of 2 to 82 folds lower than that of the wild-type sequence


The cerebellar nucleo-cortical projection in the rat studied by the retrograde fluorescent double-labelling method.
Injection of true blue into rat cerebellar cortex and nuclear yellow into either the superior cerebellar peduncle or the ventral thalamus produced double-labelled neurones in the cerebellar deep nuclei. This suggests that the nucleo-cortical projection arises from collaterals of cerebellofugal fibres. The topography of this projection, and differences in collateralization between thalamic and other cerebellofugal fibres are discussed.


[Possibility of angiogenesis stimulation in ischemia by embryonic human brain tissue (initial experimental results)].
The article proves the presence of angiogenic activity of the original specimen of biological genesis obtained from the embryogenic human brain tissue. The investigation was carried out on ischemia models of the rat's myocardium and hind limb.


Awareness of the role of physical activity in colon cancer prevention.
This study examined the prevalence and correlates of U.S. adults' awareness of the role that physical activity plays in preventing colon cancer. Data were analyzed for 1932 respondents to the Health Information National Trends Survey who answered a question about factors that reduce the chances of getting colon cancer. Individuals who listed physical activity in response to this question were denoted as being aware of its role in colon cancer prevention. Few respondents (15.0%) listed physical activity as a means of reducing colon cancer risk. Awareness was especially low among individuals aged 50 years and over, those with lower levels of education, individuals who believe that physical activity recommendations are confusing, those reporting less exposure to information about physical activity and cancer, individuals who did not report looking for information about cancer, those with poorer knowledge of colon cancer symptoms, and less physically active individuals. There is poor awareness among U.S. adults of the role that physical activity plays in preventing colon cancer. Health care providers should routinely inform their patients that engaging in regular physical activity greatly reduces the risk of developing colon cancer.


Structure and refinement of the oxidized P21 form of uteroglobin at 1.64 A resolution.
One of the monoclinic P21 forms of uteroglobin, a progesterone-binding protein secreted by the rabbit uterus, was crystallized and subjected to X-ray diffraction analysis at 1.64 A resolution. The analysis was refined to an R factor of 0.19 and the 1096 non-hydrogen atomic positions are known to an accuracy of about 0.18 A. The average isotropic temperature factor B was 10.4 A2. Uteroglobin is a dimer of two independent polypeptide chains of 70 residues linked by two disulfide bridges and related by a pseudo binary axis. Each monomer is folded into four alpha-helices. An oblong hydrophobic pocket is observed inside the dimer, and the possibility that it represents a progesterone-binding site is discussed. The present model includes 165 possible sites for water molecules, of which six are located in the hydrophobic pocket. Polar groups are involved in hydrogen bonding (intramolecular, intermolecular or with water molecules).


Mandibular coronoid fractures: treatment options.
Fractures of the coronoid process are uncommon and can easily be missed. The purpose of this study was to classify the fracture patterns and explore the treatment options. This retrospective study included 39 patients with fractures of the mandibular coronoid process. Treatment protocols were developed based on the time of fracture, degree of mouth opening, location of the coronoid fracture, types of fracture, and other concomitant fractures. All patients were followed up for 12-60 months. Sixteen patients underwent conservative management and four of these patients developed progressive trismus, which improved significantly after removal of the coronoid process. Twenty-three patients underwent open reduction and internal fixation (ORIF) via the modified retromandibular approach. Follow-up data showed significant improvement in maximum mouth opening and symptoms (diet and pain) compared to their preoperative status. In summary, conservative management is first recommended for fractures of the coronoid process with minimal displacement or restriction of mouth opening. For patients with significant fracture displacement and limited mouth opening, or with concomitant fractures of the zygoma, zygomatic arch, or mandibular ramus, ORIF via the modified retromandibular approach through the anterior border of the parotid gland is an alternative treatment method.


No OTA in fresh cocoa beans.
The presence of ochratoxin A (OTA) in cocoa and chocolates has been reported. There is no previously published data available on the source and development of OTA producing moulds and OTA itself in cocoa,i.e. where the mycotoxin enters the cocoa supply chain.A selection of fresh and undamaged cocoa pods from various growing regions was examined for mycotoxin OTA content. In addition, a small selection of damaged or mouldy cocoa pods was included in the examination. It was shown that the ripening phase of healthy cocoa pods from the tree up to being harvested was not a critical period for the occurrence of the mycotoxin OTA. The mycotoxin OTA was not detectable in any of the analysed cocoa pods.


Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe.
Toxins A and B are the primary virulence factors of Clostridium difficile. Since 2002, an epidemic of C difficile-associated disease with increased morbidity and mortality has been present in Quebec province, Canada. We characterised the dominant strain of this epidemic to determine whether it produces higher amounts of toxins A and B than those produced by non-epidemic strains. We obtained isolates from 124 patients from Centre Hospitalier Universitaire de Sherbrooke in Quebec. Additional isolates from the USA, Canada, and the UK were included to increase the genetic diversity of the toxinotypes tested. Isolate characterisation included toxinotyping, pulsed-field gel electrophoresis (PFGE), PCR ribotyping, detection of a binary toxin gene, and detection of deletions in a putative negative regulator for toxins A and B (tcdC). By use of an enzyme-linked immunoassay, we measured the in-vitro production of toxins A and B by epidemic strain and non-dominant strain isolates. The epidemic strain was characterised as toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027). This strain carried the binary toxin gene cdtB and an 18-bp deletion in tcdC. We isolated this strain from 72 patients with C difficile-associated disease (58 [67%] of 86 with health-care-associated disease; 14 [37%] of 38 with community-acquired disease). Peak median (IQR) toxin A and toxin B concentrations produced in vitro by NAP1/027 were 16 and 23 times higher, respectively, than those measured in isolates representing 12 different PFGE types, known as toxinotype 0 (toxin A, median 848 microg/L [IQR 504-1022] vs 54 microg/L [23-203]; toxin B, 180 microg/L [137-210] vs 8 microg/L [5-25]; p<0.0001 for both toxins). The severity of C difficile-associated disease caused by NAP1/027 could result from hyperproduction of toxins A and B. Dissemination of this strain in North America and Europe could lead to important changes in the epidemiology of C difficile-associated disease.


Onchocerciasis control and elimination: coming of age in resource-constrained health systems.
During the past three decades, onchocerciasis control has been successful in reducing blindness and skin disease in Africa and the Americas. In this article, I review the control and elimination of Onchocerca volvulus as a public health problem. The success of onchocerciasis control has been the result of secure financing, generous drug donation, effective partnership between stakeholders, and focused operational and implementation research. The future challenges are to ensure sustainability of existing programmes and to increase the level of integration with other health interventions in resource-deficient health systems.


Identification of the metabolites of TCM prescription Sinisan, found in miniature pig urine via intragastric administration.
The metabolic profile of the traditional Chinese medicine, Sinisan, in miniature pig urine via intragastric administration was investigated. In total, 50 compounds, including 10 unchanged parent glycosides, which were not found from Sinisan's metabolic profile in rats' urine, were identified. Among these, 36 compounds were characterized by HPLC-SPE-NMR coupled with HPLC-HRESIMS, five of which are new and nine are endogenous metabolites of miniature pig. Most of phase I and phase II metabolites are hydrolytic products of parent glycosides and glucuronide conjugates, respectively, the latter having been reported as sulfate conjugates while the experimental animal is rat. Benzoic acid, obtained from hydrolysis of albiflorin and paeoniflorin, and phenylpropenoic acids, obtained from oxidative cleavage of flavones, formed phase II glycine conjugates.


Cisplatin restores p53 function and enhances the radiosensitivity in HPV16 E6 containing SiHa cells.
Most HPV-positive cervical cancer cells possess wild type p53 gene, but its normal p53 functions are disrupted by expression of HPVs E6. Treatment with 0-20 microM cisplatin for 24 h in HPV16 E6 containing SiHa cells suppressed E6 mRNA, reduced E6 protein, and restored p53 expression in dose-dependent manners. Dual-parameter flow cytometric analysis indicated that sub-G(1) apoptotic cells, but not necrotic cells were the major species for cisplatin-induced cytotoxicity in SiHa cells. After 0-10 microM cisplatin treatment, slightly more apoptotic cells appeared from SiHa cells than those from dominant negative p53-transfected SiHa cells. There was no different ionizing radiation (IR)-induced apoptosis in these two different cells. On the other hand, cisplatin enhanced more IR-induced sub-G(1) apoptosis in SiHa than mp53-SiHa cells. These accompanied with prolonged p53 restoration in irradiated-SiHa cells after 24 h cisplatin treatment and thereafter. In contrast, it was not found in cells after irradiation alone. Similar results were also shown in Mdm2 expression in SiHa cells after combined treatment. Therefore, cisplatin restored p53 expression and prolonged IR-induced p53 restoration would be possible candidates to response more sub-G(1) apoptosis in irradiated SiHa cells. These results provided another new explanation on cisplatin sensitizing radiotherapy for HPV16 E6 containing cancer cells.


Global migration: Implications for international business scholarship.
Migration is increasingly viewed as a high-priority policy issue among politicians, intergovernmental organizations, NGOs, and civil society throughout the world. Its implications for the private sector, for economic prosperity, and for the cross-border activities of firms are undeniable and likely to grow in importance. Yet, despite its relevance to International Business, treatment of migration in the mainstream International Business literature has been limited. In this contribution, we set out key aspects of migration that are germane to International Business. Specifically, we suggest recent migratory shifts are transforming important elements of the context in which multinational enterprises operate, with significant implications for their international human resource management practices, for firms' entry modes and market selection approaches, and for the manner in which international strategies are formulated and implemented. We offer a research agenda to motivate International Business scholars to study global migration in more depth and to reevaluate the generalizability of aspects of their theories in light of developments in global migration.


The Utility of PET/Computed Tomography for Radiation Oncology Planning, Surveillance, and Prognosis Prediction of Gastrointestinal Tumors.
At present, the strongest evidence for the use of PET/computed tomography (CT) in gastrointestinal (GI) malignancies is to rule out distant metastatic disease at diagnosis, radiation treatment planning for anal malignancies, and disease recurrence monitoring in colorectal and anal malignancies. Use of PET/CT for GI malignancies continues to evolve over time, with new studies evaluating prognostic abilities of PET/CT and with increasing sensitivity and spatial resolution of more modern PET/CT scanners. The authors encourage future applications and prospective evaluation of the use of PET/CT in the staging, prognostication, and recurrence prediction for GI malignancies.


Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710.
The autoradiographic distribution of the 5-HT4 receptor was described using human postmortem brain sections and the selective radioligand [125I]SB 207710 [(1-n-butyl-4-piperidinyl)methyl-8-amino-7-[125I]iodo-1,4-benzodioxane-5-carboxylate]. The specific binding was highest in regions of the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus and substantia nigra) and the hippocampal formation (CA1 and subiculum). In the neocortex, the binding showed a distinct lamination pattern with high levels in superficial layers and a band displaying lower levels in deep cortical layers. The results confirm previous studies on the distribution of 5-HT4 receptors in the human brain in vitro and provide high-resolution correlates for in vivo imaging studies using the radioligand recently developed for single photon emission tomography (SPET), [123I]SB 207710.


Influence of nonthermal extraction technique and allergenicity characteristics of tropomyosin from fish (Larimichthys crocea) in comparison with shrimp (Litopenaeus vannamei) and clam (Ruditapes philippinarum).
Recent reports showed that patients could be sensitized to fish tropomyosin (TM), who exhibited clinical symptoms. However, little information is available on differences in TM immune cross-reactivity among fish, shrimp and clam. Moreover, allergenicity might change during the food processing owing to the change of protein structure. In this study, we developed a nonthermal extraction technique to purified TM, IgG/IgE binding, cross-reactivity and structures were compared. Results showed that raw and boiled fish-TM were not cross reactive and had weak recognition of shrimp, while, shrimp-TM and clam-TM were cross reactive. The ELISA further confirmed that fish-TM was not able to trigger allergic immune response in shrimp sensitive subjects, while, surface hydrophobicity of fish-TM was higher. The study demonstrated that fish-TM, being with high sequence similarity, did not have cross-reactivity with shrimp and clam-TM. They could have a variable degree of IgE binding depending on subject sensitivity and allergenicity.


Optimizing the discovery organization for innovation.
Strategic management is the process of adapting organizational structure and management principles to fit the strategic goal of the business unit. The pharmaceutical industry has generally been expert at optimizing its organizations for drug development, but has rarely implemented different structures for the early discovery process, where the objective is innovation and the transformation of innovation into drug projects. Here, a set of strategic management methods is proposed, covering team composition, organizational structure, management principles and portfolio management, which are designed to increase the level of innovation in the early drug discovery process.


A phase 3 study to assess the immunogenicity, safety, and tolerability of MenB-FHbp administered as a 2-dose schedule in adolescents and young adults.
The MenB-FHbp vaccine is licensed to prevent meningococcal serogroup B disease on either a 2-dose (0, 6 months) or 3-dose (0, 1-2, 6 months) series. This phase 3 study further assessed the immunogenicity and safety of the 2-dose MenB-FHbp schedule. Subjects 10-25 years of age received MenB-FHbp (months 0, 6) and the quadrivalent meningococcal conjugate vaccine MenACWY-CRM (month 0). Primary immunogenicity endpoints included percentages of subjects achieving ≥ 4-fold increases from baseline in serum bactericidal antibody using human complement (hSBA) titers for 4 diverse, vaccine-heterologous primary serogroup B test strains and titers ≥ lower limit of quantitation (LLOQ; 1:8 or 1:16) for all 4 primary strains combined (composite response) after dose 2; a titer ≥ 1:4 is the accepted correlate of protection. Percentages of participants with hSBA titers ≥ LLOQ for 10 additional vaccine-heterologous strains were also assessed; positive predictive values of primary strain responses for secondary strain responses were determined. Safety was assessed. Overall, 1057 subjects received dose 1 and 946 received dose 2 of MenB-FHbp. Percentages of participants achieving ≥ 4-fold increases in hSBA titers against each primary strain after dose 2 ranged from 67.4% to 95.0% and the composite response was 74.3%. Primary strain responses were highly predictive of secondary strain responses. Most reactogenicity events were mild-to-moderate in severity and did not lead to withdrawal from the study. Adverse events (AEs) considered by the investigator to be related to vaccination occurred in 4.2% (44/1057) of subjects, and there were no serious AEs or newly diagnosed chronic medical conditions considered related to vaccination. MenB-FHbp administered at 0, 6 months was well tolerated and induced protective bactericidal antibody responses against diverse serogroup B strains. Findings provide further support for the continued use of MenB-FHbp on a 2-dose schedule in this population.


Analysis of arterial waves by the single-pulse-response method.
This study introduces an improved method to determine experimentally the characteristic arterial impedance, and the forward and backward wave components in the carotid artery of the rabbit. This method is based on the concept of the "single-pulse response," i.e., the pressure and flow responses to a single cardiac contraction.


Experiencing bullying's impact on adolescent depression and anxiety: Mediating role of adolescent resilience.
Youth who experience bullying are at risk for psychopathology, indicating the necessity of identifying factors that may protect against the deleterious effects of being bullied. The present study expands upon prior research by examining resilience as a mediator of the effects of experiencing bullying on depression and anxiety within a sample of 2155 adolescents. Results indicated that youth who experienced bullying were more likely to have higher symptoms of depression and anxiety and lower resilience, while higher levels of resilience were associated with fewer symptoms of depression and anxiety. Resilience partially mediated the associations of experiencing bullying with depression and anxiety symptoms, suggesting that resilience may serve as a protective factor for adolescents who experience bullying. These findings have implications for programming that seeks to address bullying, peer victimization, and promotion of adolescent mental health.


Automated leucocyte adherence inhibition testing in patients with colorectal cancer.
This paper details our initial experiences with a semi-automated leucocyte adherence inhibition (SALAI) assay in patients with colorectal disease. Two assay systems were used. Leucocytes from blood donors and patients with different colorectal diagnoses were tested for sensitization to colorectal tumour extracts, and leucocytes from healthy blood donors were assayed with serum from blood donors or patients to determine whether the serum itself contained factors which would react with the non-sensitized leucocytes in the test system. The sensitivity of the SALAI assay using patients' leucocytes was 64%, and the specificity was 68%. Discriminant analysis did not affect the sensitivity of the assay for colorectal cancer (64%), although the specificity was increased for all patients except those with malignant disease other than colorectal cancer. The sensitivity of the SALAI assay using patients' serum was 50% but the specificity was 74%. Discriminant analysis increased the sensitivity of this assay to 80% but specificity was reduced to 61%. Thus, the SALAI assay with patients' serum, although potentially more advantageous than the assay using patients' leucocytes in the clinical setting, was less specific. Furthermore, samples from patients with early colorectal cancers were less reactive making the serum assay unsuitable for screening asymptomatic patients. The SALAI assay using patients' leucocytes, however, has a higher sensitivity than most reported variations of the assay but a slightly lower specificity. It is suggested that the SALAI assay is preferable to other methods for leucocyte adherence inhibition (LAI) testing.


Apnea-hypopnea index as a predictor of atrial fibrillation recurrence following initial pulmonary vein isolation: usefulness of type-3 portable monitor for sleep-disordered breathing.
The relationship between atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) and sleep-disordered breathing (SDB) evaluated using type-3 portable monitoring (PM) is still unknown. We investigated high-risk patients with AF recurrence after initial PVI using the apnea-hypopnea index (AHI) measured by type-3 PM. One hundred twenty-four (85 males; age 62 ± 10 years) AF patients undergoing initial PVI were enrolled: 83, paroxysmal AF; 41, persistent AF. At baseline, all patients were subjected to in-hospital unattended overnight polygraphy using type-3 PM for SDB. During 13 ± 7 months following initial PVI, 47 patients (38 %) experienced AF recurrence. AHI and left atrial volume index (LAVI) were significantly greater in patients with than in those without AF recurrence (AHI P = 0.011; LAVI P < 0.001). LAVI was an independent predictor of AF recurrence following initial PVI in patients with both paroxysmal AF and persistent AF (paroxysmal AF P = 0.008; persistent AF P = 0.002). However, AHI was an independent predictor of AF recurrence following initial PVI in patients with paroxysmal AF (P = 0.034) but not in those with persistent AF. The optimal cutoff value was defined as AHI = 14.1. AF recurrence following PVI is three times higher in patients with AHI ≥14.1 than in patients with AHI < 14.1. AHI measured using type-3 PM is a useful predictor of outcome following initial PVI in patients with paroxysmal AF.


Prevention of childhood obesity: sociocultural and familial factors.
This study examined sociocultural and familial factors related to the prevention of childhood obesity. Primary caregivers of 6- to 10-year-old children representing several ethnic populations in Saipan participated in 4 focus groups (N=32). Trained moderators used semi-structured interviews and qualitative methods were used in data analysis. A central theme with several related factors emerged. The theme was a conflict expressed by the primary caregiver between sociocultural values, family expectations, traditional dietary beliefs and attitudes, and knowledge about food and disease. These findings have important implications for designing culturally sensitive interventions for prevention of childhood obesity.