Effects of proteins from hen egg yolk on human platelet aggregation and blood coagulation.
We studied the effect on both platelet aggregation and blood coagulation, known to be major risk factors in thrombogenesis, of proteins from hen egg yolk (EP). EP potently inhibited collagen-induced human platelet aggregation in a dose-dependent manner. Furthermore, EP has a synergistic effect on the inhibition of human platelet aggregation with both molsidomine, an inhibitor of cGMP-specific phosphodiesterase, and theophylline, an inhibitor of cAMP-specific phosphodiesterase. These results indicate that the active mode of EP might be involved in elevation of the levels of both cGMP and cAMP. Prothrombin time and activated partial thromboplastin time were potently prolonged by EP. These data suggest that EP prolongs the time interval between the conversion of fibrinogen to fibrin. Accordingly, these findings demonstrate that EP might have antithrombotic effects by inhibiting platelet aggregation and fibrin formation.


Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.


Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation.
Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such "high-resolution" detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.


Anti-PRL-3 Monoclonal Antibody inhibits the Growth and Metastasis of colorectal adenocarcinoma.
Background: Colon cancer is the one of leading causes of cancer-related death. Chemotherapy, radiotherapy and immunotherapy will be the mainstream in inoperable advanced cancer in clinics. Precision treatment is still lack in colon cancer. Materials and Methods: We developed a series of mAbs targeting PRL-3 through different types of immunogens. The binding domains of mAbs were identified through the ELISA and Western blotting experiments. The antitumor activity of mAbs was verified by cell proliferation, migration and invasion experiments. Xenograft subcutaneous and metastatic models and patient derived Xenograft (PDX) model were established. Results: mAb 12G12 targeting 77-120AA exhibited inhibition in migration and invasion experiments. 12G12 inhibited the migration of multiple types of cancer cells, including colon cancer, gastric cancer, esophagus cancer, liver cancer, lung cancer and pancreatic cancer cells. 12G12 decreased the tumor growth and metastasis in Xenograft subcutaneous and metastatic tumor model, respectively. The antitumor activity of mAb 12G12 was also confirmed in PDX model of gastric cancer. PRL-3 interacted with Golgi protein TMED10. Knockdown of TMED10 expression attenuated the cell migration triggered by purified GST-PRL-3 protein. Conclusion: Our results confirmed the antitumor activity of mAb 12G12 in colorectal adenocarcinoma and provided a new potential targeted therapy of colon cancer.


Properties of lymphocytes in chronic HBAg-positive hepatitis. An approach to pathogenetic problems.
Lymphocytes from 22 children affected by chronic hepatitis were studied and a comparison was made with a control group of 32 healthy children in the same age range with respect to PHA dose-response curves. E-rosette formation and membrane immunoglobulin (Ig). From the results it appeared that PHA dose-response curves were displaced to the left (low PHA dose), DNA synthesis was significantly higher for all PHA dosages tested, and that the plasma of chronic hepatitis patients acted neither as inhibitor nor stimulator. The percentage of E-rosette-forming cells decreased, but the total number was normal. The mean percentage of Ig-bearing cells was normal but the single values were spaced over a wide range. It can be assumed that, at least in the chronic stage, there is an enhanced response to PHA and an increased percentage of cells without markers either for T or for B cells.


Carbonyl bonding on oxophilic metal centers: infrared photodissociation spectroscopy of mononuclear and dinuclear titanium carbonyl cation complexes.
Mononuclear and dinuclear titanium carbonyl cation complexes including Ti(CO)(6)(+), Ti(CO)(7)(+), TiO(CO)(5)(+), Ti(2)(CO)(9)(+) and Ti(2)O(CO)(9)(+) are produced via a laser vaporization supersonic cluster source. The ions are mass selected in a tandem time-of-flight mass spectrometer and studied with infrared photodissociation spectroscopy in the CO stretching frequency region. The structures are established by comparison of the experimental spectra with simulated spectra derived from density functional calculations. Only one IR band is observed for the 15-electron Ti(CO)(6)(+) cation, which is characterized to have an octahedral O(h) structure. The Ti(CO)(7)(+) cation is determined to be a weakly bound complex involving a Ti(CO)(6)(+) core ion instead of the seventh coordinated ion. The TiO(CO)(5)(+) cation has a completed coordination sphere with a C(4v) structure. The Ti(2)(CO)(9)(+) cation is determined to have a doublet C(s) structure with two four-electron donor side-on bridging CO groups and one semibridging CO group. The Ti(2)O(CO)(9)(+) cation has a doublet C(s) structure involving a planar cyclic Ti(2)O(η(2)-μ-CO) core with a four electron donor side-on bridging CO. Bonding analysis indicates that the Ti(2)(CO)(9)(+) and Ti(2)O(CO)(9)(+) cations each have a Ti-Ti single bond. The results suggest that metal-metal multiple bonding is not favorable, and the oxophilic titanium centers failed to satisfy the 18-electron configuration in these metal carbonyl complexes.


Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.
Peroxisome proliferator-activated receptor-δ-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (-7.3%), triglycerides (-16.9%), apoB (-14.9%), and free fatty acids (-19.4%). The exploratory study showed significant reductions in the concentration of very LDL (-19%), intermediate-density lipoprotein (-52%), and LDL (-14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.


Acupoint Catgut Embedding for Obesity: Systematic Review and Meta-Analysis.
Acupoint catgut embedding (ACE) was applied widely to antiweight in China. The aim of this review is to estimate the effectiveness and safety of ACE on obesity. A literature search was conducted in PubMed, Cochrane Library, EBASE, CNKI, and so forth, using combination subject terms of obesity (or overweight, weight loss, etc.) and acupoint catgut embedding (or catgut implantation, catgut embedding). Improvement rate, reduction of body weight and body mass index (BMI), and so forth were analyzed. 43 studies were included for systematic review and meta-analysis. Although with poor methodological quality, ACE was superior to manual acupuncture (MA), sham, and cupping in improvement rate and presented a better tendency (OR > 1) compared with drugs and electroacupuncture (EA). Mean values of weight loss by ACE were 1.14 kg, 1.26 kg, 1.79 kg, and 3.01 kg comparing with MA, drugs, EA, and sham, respectively. Mean of BMI reduced to 0.56 kg/m(2), 0.83 kg/m(2), 0.79 kg/m(2), and 1.63 kg/m(2) comparing with MA, drugs, EA, and sham. Less adverse effects were reported. Pooled outcomes presented a tendency of equal or superior effects to other interventions and fewer side effects. Future high quality trials with rigorous design and positive FDA approved drug as control are urgent to assess the effect of ACE for obesity. PROSPERO registration number is as follows: CRD42015016006.


Activation of Tag1 transposable elements in Arabidopsis dedifferentiating cells and their regulation by CHROMOMETHYLASE 3-mediated CHG methylation.
Dedifferentiation, that is, the acquisition of stem cell-like state, commonly induced by stress (e.g., protoplasting), is characterized by open chromatin conformation, a chromatin state that could lead to activation of transposable elements (TEs). Here, we studied the activation of the Arabidopsis class II TE Tag1, in which two copies, situated close to each other (near genes) on chromosome 1 are found in Landsberg erecta (Ler) but not in Columbia (Col). We first transformed protoplasts with a construct in which a truncated Tag1 (ΔTag1 non-autonomous) blocks the expression of a reporter gene AtMBD5-GFP and found a relatively high ectopic excision of ΔTag1 accompanied by expression of AtMBD5-GFP in protoplasts derived from Ler compared to Col; further increase was observed in ddm1 (decrease in DNA methylation1) protoplasts (Ler background). Ectopic excision was associated with transcription of the endogenous Tag1 and changes in histone H3 methylation at the promoter region. Focusing on the endogenous Tag1 elements we found low level of excision in Ler protoplasts, which was slightly and strongly enhanced in ddm1 and cmt3 (chromomethylase3) protoplasts, respectively, concomitantly with reduction in Tag1 gene body (GB) CHG methylation and increased Tag1 transcription; strong activation of Tag1 was also observed in cmt3 leaves. Notably, in cmt3, but not in ddm1, Tag1 elements were excised out from their original sites and transposed elsewhere in the genome. Our results suggest that dedifferentiation is associated with Tag1 activation and that CMT3 rather than DDM1 plays a central role in restraining Tag1 activation via inducing GB CHG methylation.


Anisotropy driven ultrafast nanocluster burrowing.
We explore the occurrence of low-energy and low-temperature transient cluster burrowing leading to intact cluster inclusions. In particular, the anomalously fast (ballistic) Pt nanocluster implantation into Al and Ti substrates has been found by molecular dynamics simulations using a tight-binding many-body potential with a 1-10 eVatom low impact energy. A similar behavior has also been found for many other cluster/substrate couples such as CuAl, NiTi, and CoTi. At this few eV/atom low impact energy regime, instead of the expected stopping at the surface we find the propagation of the cluster through a thin Al slab as thick as approximately 50 A with a nearly constant speed ( proportional, variant1 eVatom). Hence the cluster moves far beyond the range of the impact energy, which suggests that the mechanism of cluster burrowing cannot be explained simply by collisional cascade effects. In the couples with reversed succession (e.g., TiPt, AlPt) no burrowing has been found; the clusters remain on the surface (the asymmetry of burrowing). We argue that cluster penetration occurs at a few eV/atom impact energy when the cluster/substrate interaction is size mismatched and mass anisotropic atomically.


Characterization of histological subtypes of clear cell renal cell carcinoma using contrast-enhanced ultrasound (CEUS).
The aim of this study was to analyze the histological subtypes of clear cell renal cell carcinoma (RCC) examined by means of contrast-enhanced ultrasound (CEUS) and a second generation blood pool agent (SonoVue®, Bracco, Milan, Italy) during the pre-operative phase. 29 patients with histologically proven subtypes of clear cell RCC were examined. A total of three patients were diagnosed with highly differentiated clear cell RCC, 21 out of 29 cases with moderately differentiated clear cell RCC and five out of 29 patients had insufficiently differentiated clear cell RCC. An experienced radiologist examined the patients with CEUS. The following parameters were analyzed: maximum signal intensity (PEAK), time elapsed until PEAK is reached (MTT), local blood flow (RBF), area under the time intensity curve (AUC) and the signal intensity (SI) during the course of time. For the groups all comparisons are made based on healthy renal parenchyma. In the clear cell RCC significant differences (significance level p < 0.05) between cancerous tissue and the healthy renal parenchyma were noticed in all four parameters. Therefore, the clear cell RCC stands out due to its reduced blood volume. However, it reached the PEAK reading relatively rapidly and its signal intensity was always lower than that of the healthy renal parenchyma. In the arterial phase retarded absorption of the contrast agent was observed, followed by fast washing out of the contrast agent bubbles.In all three histological subgroups no significant differences were noticed in PEAK and SI. However, the diagrams showed the possible bias, that the group of the insufficiently differentiated clear cell RCC had the highest PEAK-value and the highest signal intensity when compared with highly and moderately differentiated clear cell RCC. Our study suggests that CEUS may be an additional tool for non-invasive characterisation and differentiation of the three histological subtypes of clear cell RCC. Furthermore, it seems to have an additional diagnostic value in daily clinical.


Interprofessional Education and Practice Guide No. 6: Developing practice-based interprofessional learning using a short placement model.
Offering undergraduate and post-qualified learners opportunities to take part in, and reflect on, the nature of interprofessional working when in practice remains an important goal for interprofessional educators. There are a plethora of opportunities within hospital and community care for learners to actively participate in health and social care delivery where collaborative practice prevails. However, it remains challenging to know how to establish and sustain meaningful interprofessional practice-based learning. This is because profession-specific teaching is prioritised and many teams are under-resourced, leaving little time for additional teaching activities. In some instances, practitioners lack the knowledge concerning how to design meaningful interprofessional learning and often feel unprepared for this teaching because of limited interprofessional faculty development. Others are simply unaware of the presence of the different students within their practice area. This guide offers key lessons developed over many years for setting up practice-based interprofessional education. The learning model has been adapted and adopted in different settings and countries and offers a method for engaging clinical front-line practitioners in learning with, and from learners who can help support and in some instances advance care delivery.


Tree diet: reducing the treewidth to unlock FPT algorithms in RNA bioinformatics.
Hard graph problems are ubiquitous in Bioinformatics, inspiring the design of specialized Fixed-Parameter Tractable algorithms, many of which rely on a combination of tree-decomposition and dynamic programming. The time/space complexities of such approaches hinge critically on low values for the treewidth tw of the input graph. In order to extend their scope of applicability, we introduce the TREE-DIET problem, i.e. the removal of a minimal set of edges such that a given tree-decomposition can be slimmed down to a prescribed treewidth [Formula: see text]. Our rationale is that the time gained thanks to a smaller treewidth in a parameterized algorithm compensates the extra post-processing needed to take deleted edges into account. Our core result is an FPT dynamic programming algorithm for TREE-DIET, using [Formula: see text] time and space. We complement this result with parameterized complexity lower-bounds for stronger variants (e.g., NP-hardness when [Formula: see text] or [Formula: see text] is constant). We propose a prototype implementation for our approach which we apply on difficult instances of selected RNA-based problems: RNA design, sequence-structure alignment, and search of pseudoknotted RNAs in genomes, revealing very encouraging results. This work paves the way for a wider adoption of tree-decomposition-based algorithms in Bioinformatics.


Gastric intestinal metaplasia is associated with gastric dysplasia but is inversely correlated with esophageal dysplasia.
To determine which clinical factors might be associated with gastric intestinal metaplasia (IM) in a North American population. Pathology and endoscopy databases at an academic medical center were reviewed to identify patients with and without gastric IM on biopsies for a retrospective cohort study. Patient demographics, insurance status, and other clinical factors were reviewed. Four hundred and sixty-eight patients with gastric IM (mean age: 61.0 years ± 14.4 years, 55.5% female) and 171 without gastric IM (mean age: 48.8 years ± 20.8 years, 55.0% female) were compared. The endoscopic appearance of atrophic gastritis correlated with finding gastric IM on histopathology (OR = 2.05, P = 0.051). Gastric IM was associated with histologic findings of chronic gastritis (OR = 2.56, P < 0.001), gastric ulcer (OR = 6.97, P = 0.015), gastric dysplasia (OR = 6.11, P = 0.038), and gastric cancer (OR = 6.53, P = 0.027). Histologic findings of Barrett's esophagus (OR = 0.28, P = 0.003) and esophageal dysplasia (OR = 0.11, P = 0.014) were inversely associated with gastric IM. Tobacco use (OR = 1.73, P = 0.005) was associated with gastric IM. Patients who smoke or have the endoscopic finding of atrophic gastritis are more likely to have gastric IM and should have screening gastric biopsies during esophagogastroduodenoscopy (EGD). Patients with gastric IM are at increased risk for having gastric dysplasia and cancer, and surveillance EGD with gastric biopsies in these patients might be reasonable.


Mothering and anxiety: Social support and competence as mitigating factors for first-time mothers.
This study investigated anxiety as a phenomenon distinct from depression and evaluated several variables that influence anxiety in first-time mothers. This explored the relationship between maternal sense of competence (both of mothering and efficacy) and perceived social support (from family, friends, and significant others) and first-time mothers' postpartum anxiety, when depression, socioeconomic status (SES), and marital status were controlled for. The population studied were 86 first-time mothers made up of women with children 24 months or younger in two populations of Kentucky and Michigan. The constructs of maternal sense of competence and perceived social support were found to be significant in explaining first-time mothers' anxiety. The study concluded that a combined association of perceived social support and maternal sense of competence were associated with a 34% (change in R-squared = .339) decrease of a first-time mothers' anxiety. However, not all types of social support, or maternal competence appeared to be equally important with regards to maternal anxiety: social support from friends and family and maternal sense of competence in regard to productivity appeared to be most significant. Lastly, some recommendations for health practitioners who work with mothers are provided.


Mechanistic Insight Into Cadmium- and Zinc-Induced Inactivation of the Candida albicans Pif1 Helicase.
Zinc and cadmium are environmental contaminants that can cause disease by affecting the activity of DNA-repair proteins. In this study, we investigated the effect of Zn2+ and Cd2+ on the Candida albicans Pif1, a DNA-repair helicase that plays a critical role in ensuring genomic stability. We show that Zn2+ and Cd2+ strongly inhibit both the ATPase and the unwinding activities of CaPif1, but have no effect on its DNA binding activity. High concentrations of Cd2+ may bind to the cysteine residues of CaPif1, and its inhibition appears to be difficult to be restored by ethylene diamine tetraacetic acid, while inhibition due to Zn2+ can. When the two ions are at low concentrations, increasing the concentration of ATP in the reaction can appropriately weaken the inhibitory effect of Zn2+, while cysteine can reduce the inhibitory effect of Cd2+. In addition, we found that for both Cd2+ and Zn2+ the inhibition effects were nearly 100 times greater in reduced environments than in non-reducing environments. When heavy metals stimulate the body's response, the environment of the body becomes less reducing, and thus the tolerance of CaPif1 to heavy metals will be stronger. We propose that CaPif1 may resist the toxicity of heavy metals through this mechanism. Altogether, our results provide new insights into the mechanisms by which heavy metals are toxic to DNA-repair proteins.


Posterior tibial tendon tears: utility of secondary signs for MR imaging diagnosis.
To assess the range of appearance of both torn and normal posterior tibial tendons (PTTs) and to evaluate secondary signs related to abnormal biomechanics as aids in diagnosing PTT tears, 23 patients with complete PTT tears and 34 control patients were examined with magnetic resonance imaging at 1.5 T. Examiners were blinded to diagnosis. The diameter of the PTT was measured at the insertion and at the level of the ankle. The torn and control PTTs were bulbous distally (respective mean values, 6.2 mm vs 4.6 mm), with overlap in the range of tendon size. All PTTs also had overlap in the frequency of intra-tendon signal intensity (torn PTTs, 83%, vs control PTTs, 41%; T1-weighted, 61%, vs T2-weighted, 22%). The presence of a talonavicular abnormality was both a sensitive (82%) and specific (100%) sign of a PTT tear. The presence of medial tubercle hypertrophy (sensitivity, 89%; specificity, 75%) and an accessory navicular bone (sensitivity, 20%; specificity, 100%) were useful secondary signs of a complete PTT tear.


Neural crest development is regulated by the transcription factor Sox9.
The neural crest is a transient migratory population of stem cells derived from the dorsal neural folds at the border between neural and non-neural ectoderm. Following induction, prospective neural crest cells are segregated within the neuroepithelium and then delaminate from the neural tube and migrate into the periphery, where they generate multiple differentiated cell types. The intrinsic determinants that direct this process are not well defined. Group E Sox genes (Sox8, Sox9 and Sox10) are expressed in the prospective neural crest and Sox9 expression precedes expression of premigratory neural crest markers. Here, we show that group E Sox genes act at two distinct steps in neural crest differentiation. Forced expression of Sox9 promotes neural-crest-like properties in neural tube progenitors at the expense of central nervous system neuronal differentiation. Subsequently, in migratory neural crest cells, SoxE gene expression biases cells towards glial cell and melanocyte fate, and away from neuronal lineages. Although SoxE genes are sufficient to initiate neural crest development they do not efficiently induce the delamination of ectopic neural crest cells from the neural tube consistent with the idea that this event is independently controlled. Together, these data identify a role for group E Sox genes in the initiation of neural crest development and later SoxE genes influence the differentiation pathway adopted by migrating neural crest cells.


Inhibition of checkpoint kinase prevents human oocyte apoptosis induced by chemotherapy and allows enhanced tumour chemotherapeutic efficacy.
Could inhibition of the checkpoint kinase (CHEK) pathway protect human oocytes and even enhance the anti-tumour effects, during chemotherapy? CHEK inhibitors prevented apoptosis of human oocytes induced by chemotherapy and even enhanced the anti-tumour effects. CHEK inhibitors showed ovarian protective effects in mice during chemotherapy, while their role in human oocytes is unclear. This experimental study evaluated the ovarian reserve of young patients (120 patients) with cancer, exposed or not exposed to taxane and platinum (TP)-combined chemotherapy. Single RNA-sequencing analysis of human primordial oocytes from 10 patients was performed to explore the mechanism of oocyte apoptosis induced by TP chemotherapy. The damaging effects of paclitaxel (PTX) and cisplatin on human oocytes were also evaluated by culturing human ovaries in vitro. A new mouse model that combines human ovarian xenotransplantation and patient-derived tumour xenografts was developed to explore adjuvant therapies for ovarian protection. The mice were randomly allocated to four groups (10 mice for each group): control, cisplatin, cisplatin + CK1 (CHEK1 inhibitor, SCH 900776), and cisplatin + CK2 (CHEK2 inhibitor, BML277). In the prospective cohort study, human ovarian follicles were counted and serum AMH levels were evaluated. RNA-sequencing analysis was conducted, and staining for follicular damage (phosphorylated H2AX histone; γH2AX), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) assays and assessments of apoptotic biomarkers (western blot and immunofluorescence) were conducted in human ovaries. After the treatments, histological analysis was performed on human ovarian samples to investigate follicular populations, and oocyte damage was measured by γH2AX staining, BAX staining, and TUNEL assays. At the same time, the tumours were evaluated for volume, weight, and apoptosis levels. Patients who received TP chemotherapy showed decreased ovarian reserves. Single RNA-sequencing analysis of human primordial oocytes indicated that TP chemotherapy induced apoptosis of human primordial oocytes by causing CHEK-mediated TAp63α phosphorylation. In vitro culture of human ovaries showed greater damaging effects on oocytes after cisplatin treatment compared with that after PTX treatment. Using the new animal model, CHEK1/2 inhibitors prevented the apoptosis of human oocytes induced by cisplatin and even enhanced its anti-tumour effects. This protective effect appeared to be mediated by inhibiting DNA damage via the CHEK-TAp63α pathway and by generation of anti-apoptotic signals in the oocytes. N/A. This was a preclinical study performed with human ovarian samples, and clinical research is required for validation. These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients. This work was financially supported by the National Natural Science Foundation of China (nos. 82001514 and 81902669) and the Fundamental Research Funds for the Central Universities (2021yjsCXCY087). The authors declare no conflict of interest.


Early chronic obstructive pulmonary disease: Associations of two spirometry criteria with clinical features.
Two spirometry criteria have been proposed for early chronic obstructive pulmonary disease (COPD) in young smokers: 1) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < the lower limit of normal (LLN), and 2) FEV1 decline ≥60 ml/year. These criteria have yet to be validated. This study explored clinical factors associated with these two spirometry criteria. This retrospective study analysed medical check-up data from 13,010 consecutive subjects aged <50 years who underwent current and 3 previous spirometry tests in Japan. Current ≥10 pack-year smokers were the main focus of analysis; those meeting one or more spirometry criteria were diagnosed with early COPD. Early COPD was categorized into three subtypes: FEV1/FVC < LLN and FEV1 decline <60 ml/year (type 1), FEV1/FVC ≥ LLN and FEV1 decline ≥60 ml/year (type 2), and FEV1/FVC < LLN and FEV1 decline ≥60 ml/year (type 3). Of the 1579 current ≥ 10 pack-year smokers, 488 (30.9%) met the early COPD criteria. Multivariate multinomial logistic models adjusted for age, sex, height, body mass index (BMI) and smoking history indicated that past BMI increase and low exercise were associated with higher type 2 early COPD incidence (odds ratio (OR) [95% confidence interval (CI)] = 4.30 [3.10, 6.04], and 0.80 [0.69, 0.93], respectively) but not with higher type 1 incidence. A history of asthma was associated with higher type 3 incidence (OR [95% CI] = 1.98 [1.18, 3.07]). The 3 types of spirometry-based early COPD have different clinical factors. Their trajectories should be explored in longitudinal studies.


Mechanism of action of bucindolol in human ventricular myocardium.
The mechanism of action of the beta-receptor antagonist bucindolol was examined in human ventricular myocardium. Bucindolol was found to be a high-affinity competitive beta-blocking agent as determined by bucindolol-[125I]iodocyanopindolol (ICYP) competition curves (KI = 3.7 +/- 1.3 x 10(-9) M, n = 10). This value was in general agreement with bucindolol KB's, determined by antagonism of isoproterenol-stimulated adenylate cyclase activity (KB = 2.8 +/- 0.55 x 10(-9) M, n = 5) or isoproterenol-augmented contraction of right ventricular trabeculae (KB = 2.9 +/- 1.9 x 10(-9) M, n = 3). In contrast, the alpha 1-receptor KI, determined at bucindolol-125IBE2254 (IBE) competition binding in rat cardiac membranes, was 1.2 x 10(-7) M. Bucindolol exhibited no beta 1- or beta 2-receptor subtype selectivity as deduced from blockade of the beta-agonist-coupled adenylate cyclase system, receptor-binding studies with preparations of human ventricular myocardium with predominantly beta 1 or beta 2 receptors, or receptor-binding studies in model systems consisting of beta 1 (guinea pig myocardial membranes) or beta 2 receptors (human mononuclear and frog myocardial membranes). In membranes derived from human ventricular myocardium and human lymphocytes, bucindolol recognized a high-affinity agonist-binding site as determined by guanine nucleotide modulation of competition-binding curves. Although bucindolol has measurable intrinsic sympathomimetic activity (ISA) in some animal systems, no increase in adenylate cyclase activity or muscle contraction was detected in preparations of human heart. In conclusion, bucindolol is a high-affinity nonselective beta-receptor antagonist with no evidence of intrinsic sympathomimetic activity in human ventricular myocardium.


Interleukin-9 Promotes Pancreatic Cancer Cells Proliferation and Migration via the miR-200a/Beta-Catenin Axis.
Background. Both IL-9 and miR-200a are involved in the pathogenesis of cancers; however, the role of IL-9 in pancreatic cancer and the possible underlying mechanisms remain unknown. The aim of this study was to investigate the effect of IL-9 on pancreatic cancer cells and its interaction with miR-200a. Methods. Pancreatic cancer cells (PANC-1 and AsPC-1) were treated with IL-9 and the expression of miR-200a and β-catenin in pancreatic cancer cells was measured. β-Catenin was examined as a target gene of miR-200a in pancreatic cancer cells. The interaction between IL-9 and miR-200a in pancreatic cancer cells was determined by infecting miR-200a mimics prior to IL-9 treatment and then measuring miR-200a and β-catenin expression. Results. IL-9 significantly promoted the proliferation, invasion, and migration of pancreatic cancer cells; however, the effect on pancreatic cancer cell apoptosis was insignificant. β-Catenin was verified as a target gene of miR-200a in pancreatic cancer cells. Overexpression of miR-200a in pancreatic cancer cells significantly attenuated proliferation and metastasis and reduced β-catenin expression. IL-9 treatment of pancreatic cancer cells decreased miR-200a expression and increased β-catenin expression. The effect of miR-200a on pancreatic cancer cells decreased following IL-9 treatment. Conclusions. IL-9 promotes proliferation and metastasis in pancreatic cancer cells; this effect may partly involve regulation of the miR-200a/β-catenin axis.


New hybrid bidentate ligands as precursors for smart catalysts.
1-Phosphanorbornadiene derivatives were grafted onto various periodically organized mesoporous powders, including a new zirconia/silica mixed oxide synthesized by aerosol techniques. After complexation with the [Rh(CO)2]+ fragment, these materials were revealed to be more active in olefin hydrogenation than their homogeneous counterparts. The reasons for this higher activity are discussed in the light of theoretical modeling. Various surface treatments, such as esterification, drying, and functionalization with PhSi(OEt)3, provided insights into the nature and mechanism of formation of the active species. Zirconia-based materials were found to be active in internal olefin hydroformylation. Investigation of the mechanism of this reaction shows that the isomerization step is catalyzed by the Lewis acidic support, whereas the hydroformylation step is driven by the rhodium catalyst. Dissociation of these two steps leads to enhancement of activity.


Comparison of Expectations and Outcomes in Rheumatoid Arthritis Versus Osteoarthritis Patients Undergoing Total Knee Arthroplasty.
We hypothesized that patients undergoing primary total knee arthroplasty (TKA) for rheumatoid arthritis (RA) would have different preoperative expectations compared to osteoarthritis (OA) patients, and that postoperative satisfaction would correlate with specific postoperative pain and functional domains. This is a retrospective cohort study of RA patients matched based on age, gender, American Society of Anesthesiologists score, and Charlson Comorbidity Index score 1:2 with OA patients (76 RA, 152 OA) who underwent primary TKA. The Hospital for Special Surgery Knee Replacement Expectations Survey, Visual Analogue Scale for Pain (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS), and the Short Form-12 (SF-12) were compared at baseline and at 2 years postoperatively. Minimum clinically important differences (MCIDs) were calculated for KOOS and SF-12 subdomains. Preoperatively, RA patients had lower expectations, worse VAS Pain, and worse KOOS Pain, Symptoms, and Activities of Daily Living (P < .05). However, at 2 years, RA patients had significantly larger improvements in VAS (P = .01) and these 3 KOOS subdomains (P < .05), achieving comparable absolute scores to OA patients. Overall, 86.1% of RA and 87.1% of OA patients were either somewhat or very satisfied with their TKA. Patient satisfaction correlated with VAS Pain and KOOS outcome scores in both groups. RA and OA patients had high rates of achieving MCID in SF-12 physical component scores and all 5 KOOS subdomains. A higher proportion of RA patients achieved MCID in KOOS Symptoms (98.4% vs 77.2%, P < .001). RA patients had lower baseline expectations compared to OA patients. However, RA patients had greater improvements in KOOS and SF-12 subdomains, and there was no difference in satisfaction compared to OA patients after TKA.


Foreign policy, ego-defense mechanisms, and balance-of-power vulnerability.
The concept of balance-of-power vulnerability is proposed as a heuristic tool to understand the varying states of anxiety which occur when America's national integrity or security is threatened. Corresponding to the different states of vulnerability are the groups of ego-defense mechanisms which are arranged in a hierarchical pattern. These defense mechanisms are defined as spontaneous or premediated strategies for problem solving, containing elements of intrapsychic and social processes. The Vulnerability-Ego Defense construct is then used to compare America's foreign policy with respect to different nations and with respect to one nation over a protracted period of time.


β-Resorcylic Acid, a Phytophenolic Compound, Reduces Campylobacter jejuni in Postharvest Poultry.
Human Campylobacter infections, a leading foodborne illness globally, has been linked with the high prevalence of this bacterium on raw retail chicken products. Reduction of Campylobacter counts on poultry products would greatly reduce the risk of subsequent infections in humans. To this end, this study investigated the potential of the phytophenolic compound β-resorcylic acid (BR) to reduce Campylobacter counts on postharvest poultry (chicken skin or meat). Four trials in total, two each on thigh skin or breast meat, were conducted in which chicken skin or meat samples (2 ± 0.1 g; 10 samples per treatment) were inoculated with 50 μL (∼106 CFU per sample) of a cocktail of four wild strains of C. jejuni. After 30 min of attachment, inoculated samples were dipped in a 0, 0.5, 1, or 2% BR solution for 30 s immediately followed by vigorously vortexing the samples in Butterfield's phosphate diluent and plating the supernatant for Campylobacter enumeration. In addition, the effect of BR on the color of skin and meat samples was studied. Moreover, the change in the expression of survival and virulence genes of C. jejuni exposed to BR was evaluated. Data were analyzed by the PROC MIXED procedure of SAS (P < 0.05; SAS Institute Inc., Cary, NC). All BR treatments significantly reduced Campylobacter populations on both chicken or meat samples by 1 to 3 log CFU/g compared with non-BR-treated washed controls. No significant difference in the lightness, redness, and yellowness of skin and meat samples was observed on exposure to BR wash (P > 0.05). Real-time PCR results revealed that BR treatment down-regulated expression of select genes coding for motility (motA, motB) and attachment (cadF, ciaB) in the majority of C. jejuni strains. Stress response genes (sodB, katA) were upregulated in C. jejuni S-8 (P < 0.05). Overall, our results suggest that BR could be effectively used as antimicrobial dip treatment during poultry processing for reducing Campylobacter on chicken carcasses.


Eighteen-month safety analysis of offspring breastfed by mothers receiving glatiramer acetate therapy for relapsing multiple sclerosis - COBRA study.
Safety data on disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) during breastfeeding are limited. Assess safety outcomes for offspring breastfed by mothers undergoing glatiramer acetate (GA; Copaxone®) treatment. This non-interventional, retrospective study used German Multiple Sclerosis and Pregnancy Registry data. Participants had RMS, a live birth, and received GA or no DMT during breastfeeding. GA cohort: 58 mothers/60 offspring; matched controls: 60 mothers/60 offspring; 86.7% (GA) and 25% (control) of offspring were born to mothers who had GA at some point during pregnancy. Maternal demographics and disease activity were comparable. Annualized number of hospitalizations was similar for breastfed offspring: 0.20 (95% confidence interval: 0.09-0.31; GA) and 0.25 (0.12-0.38, controls). Proportion of offspring requiring hospitalization was comparable between cohorts (18.33% vs. 20.00%). Annualized number of antibiotic uses was similar in both cohorts (0.22, 0.10-0.33 (GA) vs. 0.17, 0.06-0.27 (controls)) The proportion of offspring requiring antibiotics was 15.00% (both cohorts). More developmental delays were identified in controls versus the GA cohort (3 (5.36%) vs. 0). Growth parameters were comparable between cohorts. Maternal intake of GA during breastfeeding did not adversely affect offspring safety outcomes assessed during the first 18 months of life.


Optimization of a methodology for the simultaneous determination of deltamethrin, permethrin and malathion in stored wheat samples using dispersive liquid-liquid microextraction with solidification of floating organic drop and HPLC-UV.
The purpose of this study was to investigate common pesticides in stored wheat at Kermanshah province's silos in Iran. A simple, inexpensive, reliable and environmentally friendly method based on dispersive liquid-liquid microextraction with solidification of floating organic drop was developed. The analytical characteristics of the method were determined. Also, various parameters such as the materials of the silos, types of ownerships of the silos, geographic orientation of silo locations and climatic conditions of silo locations on pesticide residues in studied wheat samples were investigated. Among all the studied parameters, the climatic conditions of silo locations showed the highest influence on pesticide residues in wheat samples. Generally, 61.2% of the samples had pesticide levels below the method detection limits and 38.8% of the total samples had at least one of the understudied pesticides. Also, 13.9% of the samples had deltamethrin residues, 16.7% of the samples had permethrin, 22.2% of the samples had malathion, 11.1% of the samples had both permethrin and malathion and 2.8% of the samples had both deltamethrin and malathion. The results revealed that the residues of deltamethrin and malathion were lower than the standard level announced by European Union regulation and only three samples contained permethrin higher than Europe standard level.


Modeling the network dynamics of pulse-coupled neurons.
We derive a mean-field approximation for the macroscopic dynamics of large networks of pulse-coupled theta neurons in order to study the effects of different network degree distributions and degree correlations (assortativity). Using the ansatz of Ott and Antonsen [Chaos 18, 037113 (2008)], we obtain a reduced system of ordinary differential equations describing the mean-field dynamics, with significantly lower dimensionality compared with the complete set of dynamical equations for the system. We find that, for sufficiently large networks and degrees, the dynamical behavior of the reduced system agrees well with that of the full network. This dimensional reduction allows for an efficient characterization of system phase transitions and attractors. For networks with tightly peaked degree distributions, the macroscopic behavior closely resembles that of fully connected networks previously studied by others. In contrast, networks with highly skewed degree distributions exhibit different macroscopic dynamics due to the emergence of degree dependent behavior of different oscillators. For nonassortative networks (i.e., networks without degree correlations), we observe the presence of a synchronously firing phase that can be suppressed by the presence of either assortativity or disassortativity in the network. We show that the results derived here can be used to analyze the effects of network topology on macroscopic behavior in neuronal networks in a computationally efficient fashion.


Effects of nicotine on the concentration of native and cryptic Met- and Leu-enkephalin in peripheral tissues.
The distribution of the native pentapeptides, Met- and Leu-enkephalin, and their cryptic forms (larger enkephalin-containing peptides) in adrenal medulla, spleen, lung, salivary gland, vas deferens, heart, duodenum and jejunum were determined by radioimmunoassay. The proportion of total Met- and Leu-enkephalin represented by native pentapeptide varied markedly among these tissues. Also, the distribution of native and cryptic Met-enkephalin was distinct from that of Leu-enkephalin. Repeated short-term administration of nicotine, 0.1 mg/kg i.p. six times at 30 min intervals, produced significant changes in native and cryptic Met-enkephalin in adrenal medulla, jejunum, vas deferens, spleen and heart. This regimen of nicotine also affected the concentration of Leu-enkephalin in adrenal medulla, jejunum and spleen.


Biomechanical evaluation of variable angle locking systems. A micro-CT analysis.
Formerly poor bone stock and periprosthetic fractures used to jeopardize monaxial constructs. Polyaxial locking screws have substantially supported those particular fixation constructs. However, those systems rely on complex alignment between the screw head and the plate hole. This study aimed to investigate the mechanical properties of several polyaxial systems and to correlate these parameters with the screw head and the plate hole engagement. Polyaxial locking systems were tested with screws inserted into the corresponding plates at various angles (0°, 5°, 10°, 15°). A micro-CT scan of the plate-hole and screw-head interface with the quantification of average thread engagement was performed before destructive tests. The screw-plate interface of each system was tested in a cantilever bending setup. Representative screws and plates were also examined by SEM. The standard insertion at 0° sustained the greatest maximum bending strength in all analyzed systems. Point-loading thread-in and cut-in screws inserted off-axis showed a significant reduction in bending strength (p<0.001) (p=0.041) (p<0.001). In contrast, locking cap screws maintained similar bending strength with disregard to the angle of insertion (p<0.4849). A micro-CT analysis confirmed that the average thread engagement of point-loading thread-in, cut-in and locking-cap screws was significantly reduced when placed off-axis (p=0.005) (p<0.001) (p=0.002) (p<0.001). The locking-cap mechanisms maintained the highest average thread engagement among all analyzed systems. The mechanical performance of polyaxial locking plates usually comes at the price of reduced bending strength. Surgeons should limit polyaxial insertions depending on the particular system's characteristics.


The kinetics of the Cl-pH equilibration in human red blood cells.
If erythrocytes were transferred into solutions of different ionic composition, they changed the inner pH and chloride concentration until reaching a new quasi-equilibrium state (C-State). Electrochemical measurements were performed to follow the kinetics of this adaption and to answer the question whether the time constant of unidirectional chloride flux or time constant of chloride net flux is responsible for this process. It was found that the kinetics depend strongly on the kind and the concentration of the buffer system used. In unbuffered solutions, a new Cl-pH-equilibrium is reached very fast and proceeds by the Cl-/HCO-3-exchange. If Tris or phosphate buffer were used, this process had a time constant of about 10(-3) S-1 and was mainly realised by a Cl-/OH-exchange or Cl-H+-cotransport. If the suspension contained phosphate, an overshoot of pH took place. The reason for this behavior is the additional exchange of Cl- for HPO2-(4) + H+.


Fusion of Multiple Person Re-id Methods With Model and Data-Aware Abilities.
Person re-identification (person re-id) has attracted rapidly increasing attention in computer vision and pattern recognition research community in recent years. With the goal of providing match ranking results between each query person image and the gallery ones, the person re-id technique has been widely explored and a large number of person re-id methods have been developed. As these algorithms leverage different kinds of prior assumptions, image features, distance matching functions, et al., each of them has its own strengths and weaknesses. Inspired by these facts, this paper proposes a novel person re-id method based on the idea of inferring superior fusion results from a variety of previous base person re-id algorithms using different methodologies or features. To achieve this goal, we propose a novel framework which mainly consists of two steps: 1) a number of existing person re-id methods are implemented, and the ranking results are obtained in the test datasets. and 2) the robust fusion strategy is applied to obtain better re-ranked matching results by simultaneously considering the recognition abilities of various base re-id methods and the difficulties of different gallery person images to be correctly recognized under the generative model of labels, abilities, and difficulties framework. Comprehensive experiments show the effectiveness of our proposed method, and we have received state-of-the-art results on recent popular person re-id datasets.


Recent and ongoing clinical trials for treating colorectal cancer.
Colorectal cancer is one of the most common cancers worldwide. Through well-designed clinical trials, advances have been made in the treatment of localised and advanced colorectal cancer. It has been established that 6 months of 5-fluorouracil-based chemotherapy will improve overall survival in patients with stage III colon cancer. The role of adjuvant chemotherapy in stage II colon cancer remains an unresolved issue. Recent studies have demonstrated an improved survival with the addition of irinotecan to 5-fluorouracil and leucovorin for the treatment of advanced colorectal cancer. Immunotherapy, molecular targeted therapy and liver-directed therapy, in addition to new chemotherapy combinations, are all being evaluated for the treatment of localised and advanced colorectal cancer. Ongoing and proposed studies are incorporating the identification of genetic and molecular abnormalities, which may provide prognostic information as well as direct treatment decisions.


[Activity and acceptability of indalpine in a double-blind study versus placebo].
In this double-bind randomized study involving 35 depressed female inpatients, Indalpine proved significantly superior to placebo on all the criteria used: Hamilton scales for depression and anxiety, clinician's vectorial ratings. Its rapid onset of action was further confirmed by the rapid appearance of significance relative to placebo: as early as the third day of treatment, that is, during the optimum placebo effect period. The results are all more valuable if one considers the magnitude of the placebo effect obtained with daily infusions of isotonic sodium chloride-dextros solution, the possible adjunction of a benzodiazepine and the availability of placebo tablets as an adjunct to the infusions upon request. Acceptabilité was found to be good, especially at the cardiovascular and cholinergic levels.


Non-adiabatic dynamics investigation of the radiationless decay mechanism of trans-urocanic acid in the S2 state.
The trans-urocanic acid, a UV chromophore in the epidermis of human skin, was found to exhibit a wavelength dependent isomerization property. The isomerization quantum yield to cis-urocanic is greatest when being excited to the S1 state, whereas exciting the molecule to the S2 state causes almost no isomerization. The comparative photochemical behavior of the trans-urocanic on the S1 and S2 states continues to be the subject of intense research effort. This study is concerned with the unique photo-behavior of this interesting molecule on the S2 state. Combining the on-the-fly surface hopping dynamics simulations and static electronic structure calculations, three decay channels were observed following excitation to the S2 state. An overwhelming majority of the molecules decay to the S1 state through a planar or pucker characterized minimum energy conical intersection (MECI), and then decay to the ground state along a relaxation coordinate driven by a pucker deformation of the ring. A very small fraction of molecules decay to the S1 state by a MECI characterized by a twisting motion around the CC double bond, which continues to drive the molecule to deactivate to the ground state. The latter channel is related with the photoisomerization process, whereas the former one will only generate the original trans-form products. The present work provides a novel S2 state decay mechanism of this molecule, which offers useful information to explain the wavelength dependent isomerization behavior.


Cytotoxic Activity of Crude Extracts as well as of Pure Components from Jatropha Species, Plants Used Extensively in African Traditional Medicine.
Extracts from Jatropha curcas, a plant used in African traditional medicine for various diseases, were tested for cytotoxic activity. The root extracts strongly reduced cell growth of tumor cells in vitro, a result consistent with the knowledge of the application of these plant extracts in traditional medicine, especially to cure/ameliorate cancer. A selection of pure diterpenoids existing in extracts from Jatropha species and isolated from J. curcas, for example, curcusone C, curcusone D, multidione, 15-epi-4Z-jatrogrossidentadion, 4Z-jatrogrossidentadion, 4E-jatrogrossidentadion, 2-hydroxyisojatrogrossidion, and 2-epi-hydroxyisojatrogrossidion, were likewise tested, and they also showed strong cytotoxic activity. It turned out that these extracts are highly active against L5178y mouse lymphoma cells and HeLa human cervix carcinoma cells, while they cause none or only very low activity against neuronal cell, for example, PC12. These data underscore that extracts from J. curcas or pure secondary metabolites from the plant are promising candidates to be anticancer drug, combined with low neuroactive effects.


pen repeat sequences are GGN clusters and encode a glycine-rich domain in a Drosophila cDNA homologous to the rat helix destabilizing protein.
Several cDNA clones that contain the pen repeat have been isolated and sequenced; pen consists of clusters of GGN triplets, where N can be any nucleotide. Some of the pen repeat sequences are found within long open reading frames in which they encode oligoglycine stretches. For one of the clones, the deduced amino acid sequence of the entire open reading frame, especially in the region preceding the glycine-rich domain, shows strong homology to the rat helix destabilizing protein [Cobianchi, F., SenGupta, D. N., Zmudzka, B. Z. & Wilson, S. H. (1986) J. Biol. Chem. 261, 3536-3543]. The rat protein and homologs in other organisms are single-stranded nucleic acid binding proteins, some of which are major components of heterogeneous nuclear ribonucleoprotein particles. We suggest that we have cloned a cDNA encoding a Drosophila single-stranded nucleic acid binding protein.


Toxicological information conducted by Polish Poison Information Centres based on selected cases of acute intoxication.
The paper presents relatively diversified answers provided by Polish Poison Control Centres concerning the diagnosis and the treatment of the three standard acute poisonings. This diversity resulted from the lack of standardized, compatible, reliable and up-dated system of information. There is an urgent need to establish the national network of RPCC in Poland. The up-dated source of information and unified system of collecting data should be introduced as soon as possible.


[New and established indications for phototherapy with narrowband UVB].
Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320 nm (UV-B) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310-315 nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UV-B phototherapy, the number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UV-B phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed.


Processing Enhances Coix Seed Prolamins Structure and Releases Functional Peptides after Digestion: In Silico and In Vitro Studies.
Dipeptidyl peptidase-IV (DPP-IV) is a key target for the treatment of type 2 diabetes mellitus. It is possible that peptides that precisely regulate DPP-IV could be released from coix seed prolamins (CSP), but whether this happens has not yet been investigated. We performed the in silico digestion of CSP and predicted the bioactivity, absorption, transport, toxicity, and allergenicity of the resulting peptides. The simulation predicted that 47 non-toxic bioactive peptides would be released. After screening these, we found that 64.58% of them could possess DPP-IV inhibitory activity. The effect of thermal processing on the amino acid composition and structural properties of CSP was determined, and the DPP-IV inhibitory activity of its digestion-derived peptides was also assessed. The results showed that processing could change the flavour of coix seed and the supply of amino acids. After processing, the spatial conformation of CSP changed from ordered to disordered, and the peptide content and the DPP-IV inhibitory activity of its digestion products significantly increased by 19.89-30.91% and 36.84-42.02%, respectively. These results support the hypothesis that processing can change the protein structure and increase the probability that bioactive peptides will be released. They also have important implications for the development of bioactive peptides and the intensive processing of coix seeds.


Testing a Polygenic Risk Score for Morphological Microglial Activation in Alzheimer's Disease and Aging.
Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer's disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. We sought to determine whether a PRS for microglial activation (PRSmic) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. First, PRSmic were calculated and optimized in a calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 450), with resampling. Second, predictive performance of optimal PRSmic was assessed in two independent, population-based cohorts (total n = 212,237). Finally, we explored associations of PRSmic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. Our PRSmic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance in either external cohort. Some nominal associations were found in ADNI, but with inconsistent effect directions. While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.


Retrospective tracking of young obese children back to birth in Japan: special attention to the relationship with parental obesity.
Childhood obesity is tracked to adulthood at a high rate. However, longitudinal studies of obesity in early childhood remain limited. This study aimed at tracking young obese children back to birth in comparison with normal-weight children, and investigating the relationship with parental obesity. A total of 2,678 (1,353 boys) young children attending kindergarten or nursery school in Nara Prefecture, Japan, were enrolled. The present heights and weights of children and parents were obtained by a questionnaire, and children's heights and weights at birth, 1.5, and 3.5 years were obtained from mother-child health notebooks. Using body mass index (BMI), child and parental obesity were defined as >=90th percentile based on the reference values for Japanese children and >=25 (kg/m²), respectively. The overall prevalence of obesity at birth was 10.2%, and decreased to 5.6% at 5 years. In the retrospective tracking, obese children at 5 years exhibited significantly higher weight Z-scores and BMI percentiles consistently from birth than in normal-weight children. The increased velocity of weight gain as judged by their Z-score during three periods; birth-1.5, 1.5-3.5, and 3.5-5 years were significantly associated with an increased risk for the obesity at 5 years of age. Only maternal obesity was found to be associated with daughters' obesity in the analysis of association of parents-children obesity. It is important to manage body weight from early infancy for reducing the occurrence of obesity at 5 years. Where there is maternal obesity, greater attention may be required, especially for daughters.


Neuropharmacology of paroxetine.
Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with some neuropharmacologic properties unique among this class of compounds. The findings of early in vitro studies demonstrated the potency of paroxetine at inhibiting 5-HT uptake in rat synaptosomes. Paroxetine also has been shown to be a potent and selective inhibitor of the human serotonin transporter (SERT) and has recently been demonstrated to have moderate affinity for the norepinephrine transporter (NET). Because of the affinity and in vitro selectivity of this SSRI, tritiated paroxetine is now widely used as a marker for SERT in laboratory settings, and its use has advanced our understanding of neurotransmitter function in the brain and periphery. The in vivo pharmacologic properties of paroxetine are well characterized, especially following acute administration. However, the pharmacologic effects of chronically administered paroxetine remain an active area of study. Paroxetine administration in laboratory animals has been shown to be associated with decreased SERT density and function, maintenance of normal firing rates and release of 5-HT, and increased activation of postsynaptic 5-HT receptors. Using a novel ex vivo assay, we have demonstrated that paroxetine exhibits dose-related inhibition of the NET in patients treated for depression. At usual clinical doses (ie, 20 mg/d), paroxetine is a potent and selective inhibitor of the SERT; however, at higher doses (ie, 40 mg/d), paroxetine can exhibit marked NET inhibition. The application of these findings of in vivo NET inhibition by paroxetine in the treatment of mood and anxiety disorders will be informed by further clinical studies.


Temperature-sensitive nonsense mutations in essential genes of Escherichia coli.
Cells containing nonsense mutations in essential genes have been isolated in a strain of Escherichia coli that carried the su4(ts) gene which specifies a temperature-sensitive tyrosine transfer ribonucleic acid. Such cells are unable to form colonies at temperatures which inactivate this suppressor transfer ribonucleic acid. A screening procedure for the identification of mutants that carry temperature-sensitive nonsense mutations in essential genes is described, and certain properties of two such mutants are reported.


Gender moderates the association between acute alcohol intoxication and facial emotion recognition in a naturalistic field study setting.
Alcohol intoxication is associated with significant negative social consequences. Social information processing theory provides a framework for understanding how the accurate decoding and interpretation of social cues are critical for effective social responding. Acute intoxication has the potential to disrupt facial emotion recognition. If alcohol impairs the processing and interpretation of emotional cues, then the resultant behavioral responses may be less effective. The current study tested the association between alcohol intoxication and facial emotion recognition in a naturalistic field study of intoxicated participants. 114 participants (59.4% men; Mage = 24.2 years) who had been consuming alcohol were recruited in the downtown area of a mid-size town surrounded by several drinking establishments in the mid-southern United States. Participants were shown images depicting 5 facial displays of emotions (happy, sad, anger, disgust, and no emotion) portrayed by 1 male and 1 female actor per emotion and breath alcohol concentration (BrAC) was measured by the field breathalyzer test (M = 0.078%, SD = 0.052). BrAC was significantly negatively associated with emotion recognition accuracy when controlling for average alcohol use, B = -.35, t = -2.08, p < 0.05, F(3, 110) = 5.28, p < 0.01, R2 = 0.13. A significant BrAC × gender interaction was revealed, B = -0.39, t = -2.07, p = 0.04, ΔR2 = 0.033, p = 0.04, such that men (but not women) displayed a significant negative association between BrAC and emotion recognition accuracy. Acute intoxication was associated with impaired facial emotion recognition, particularly for men, in a field study context. Findings support and extend some previous experimental laboratory-based research and suggest that intoxication can impair the decoding stage of social information processing.


QSAR modeling of in vitro inhibition of cytochrome P450 3A4.
We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.


Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells.
In this study, we investigated the antitumor activity of Silymarin in a mouse model of colon cancer xenograft of Lewis lung cancer (LLC) cells. Silymarin significantly suppressed tumor growth and induced apoptosis of cells in tumor tissues at a dose of 25 and 50mg/kg. Silymarin treatment enhanced the infiltration and function of CD8(+) T cells. In the meantime, Silymarin decreased the level of IL-10 while elevated the level of IL-2 and IFN-γ in the serum of tumor-bearing mice. Finally, Silymarin reduced the proportion of myeloid-derived suppressor cells (MDSC) in the tumor tissue and also the mRNA expressions of inducible nitric oxide synthases-2 (iNOS2), arginase-1 (Arg-1) and MMP9, which indicated that the function of MDSC in tumor tissues were suppressed. Altogether, our data here showed that Silymarin inhibited the MDSC and promoted the infiltration and function of CD8(+) T cells thus suppressed the growth of LLC xenografts, which provides evidence for the possible use of Silymarin against lung cancer.


Intersectional social identities and loneliness: Evidence from a municipality in Switzerland.
We examined the extent to which intersectional social identities combine to shape risks of loneliness and identified the specific social clusters that are most at risk of loneliness for more precise and targeted interventions to reduce loneliness in a Swiss municipality. Based on data collected using participatory action research, we used the novel multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) to estimate the predictive power of intersectional social attributes on risk of loneliness. We found that 56% of the between-strata variance was captured by intersectional interaction but was not explained by the additive effect of social identities. We also found that nationality and education had the strongest predictive power for loneliness. Interventions to reduce loneliness may benefit from understanding the resident population's intersectional identities given that individuals with the same combinations of social identities face a common set of social exposures relating to loneliness.


[A concept analysis of successful weaning from mechanical ventilation].
The process of being weaned from mechanical ventilation is a stressful transition for critically ill patients who are taken off ventilation assistance and regain spontaneous breathing. Degree of weaning success is being increasingly used as an outcome indicator in clinical practice and lay literature. However, "successful weaning" remains a largely undefined concept in nursing practice. Following the concept analysis framework of Walker and Avant (1995), any such analysis that targets development of an operational definition of successful weaning should focus on two distinct sets of indicators, namely objective physiological and subjective psychological. Listing defining attributes and developing a model case will accurately reflect underlying relationships between weaning concepts.


Normative values of cervical sagittal alignment according to global spine balance: based on 126 asymptomatic Chinese young adults.
To explore the normal distribution of cervical sagittal alignment and the relationship between cervical alignment and global spine balance in asymptomatic young adults. A total of 67 males and 59 females aged from 18 to 30 years old were recruited from 11/2011 to 12/2014. The C0-C2 angle, disk angles from C2-C3 to C6-C7, vertebral angles from C3 to C7, T1 slope, thoracic kyphosis (TK), lumbar lordosis, pelvic incidence, sacral slope, C2-C7 sagittal vertical axis (SVA), center of gravity of head to C7 SVA (CGH-C7SVA), C7-S1SVA were measured and statistically analyzed. The Roussouly classification was utilized. Mean value of C0-C7 was 26.0° ± 12.8°, composed of 15.2° ± 6.7° for C0-C2, 9.1° ± 12.1° for sum of disk angles from C2-C3 to C6-C7, and 1.4° ± 10.2° for sum of vertebral angles from C3 to C7. C2-C7SVA (18.6 mm ± 7.9 mm) and CGH-C7SVA (22.9 mm ± 12.3 mm) were offset ideally by C7-S1SVA (-21.6 mm ± 31.0 mm). Significant difference was found between cervical alignment of different Roussouly types (p < 0.01). There was significant correlation between cervical alignment and T1 slope (p < 0.01), TK (p < 0.01). There was significant correlation between adjacent segmental angles from T1 slope up to C0-C2 angle (p < 0.05). Normative values of each vertebral angle and disk angle were established. The cervical lordosis occurred mainly at C0-C2 and disk levels, which was influenced by parameters of other parts of the spine, such as T1 slope, TK and the Roussouly classification. There was significant correlation between adjacent disk angles. Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.


Genetic regulation of cold-induced albinism in the maize inbred line A661.
In spite of multiple studies elucidating the regulatory pathways controlling chlorophyll biosynthesis and photosynthetic activity, little is known about the molecular mechanism regulating cold-induced chlorosis in higher plants. Herein the characterization of the maize inbred line A661 which shows a cold-induced albino phenotype is reported. The data show that exposure of seedlings to low temperatures during early leaf biogenesis led to chlorophyll losses in this inbred. A661 shows a high plasticity, recovering resting levels of photosynthesis activity when exposed to optimal temperatures. Biochemical and transcriptome data indicate that at suboptimal temperatures chlorophyll could not be fully accommodated in the photosynthetic antenna in A661, remaining free in the chloroplast. The accumulation of free chlorophyll activates the expression of an early light inducible protein (elip) gene which binds chlorophyll to avoid cross-reactions that could lead to the generation of harmful reactive oxygen species. Higher levels of the elip transcript were observed in plants showing a cold-induced albino phenotype. Forward genetic analysis reveals that a gene located on the short arm of chromosome 2 regulates this protective mechanism.


High resolution proteome/peptidome analysis of body fluids by capillary electrophoresis coupled with MS.
All organisms contain thousands of proteins and peptides in their body fluids. A deeper insight into the functional relevance of these polypeptides under different physiological and pathophysiological conditions and the discovery of specific peptide biomarkers would greatly enhance both diagnosis and therapy of specific diseases. Proteomic methods can provide means to accomplish this grand medical vision. In this review, we will focus on the potential use of proteome analysis for clinical applications, such as disease diagnosis and assessment of response to therapy. We focus on CE coupled with MS (CE-MS) and review in detail different aspects of CE-MS coupling and the results obtained using CE-MS analysis of clinically relevant samples. We also discuss clinical applications of the technology for the diagnosis of renal diseases, urogenital cancer, and arteriosclerosis as well as monitoring the responses to therapeutic interventions.


Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796).
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH(2) interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degrees C translating into K(d) values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.


Indica rice (Oryza sativa, BR29 and IR64).
Rice is the world's most important food crop. Indica-type rice provides the staple food for more than half of the world population. To satisfy the growing demand of the ever-increasing population, more sustained production of indica-type rice is needed. In addition, because of the high per capita consumption of indica rice, improvement of any traits including its nutritive value may have a significant positive health outcome for the rice-consuming population. Rice yield productivity is greatly affected by different biotic stresses, like diseases and insect pests, and abiotic stresses like drought, cold, and salinity. Attempts to improve resistance in rice to these stresses by conventional breeding through introgression of traits have limited success owing to a lack of resistance germplasm in the wild relatives. Gene transfer technology with genes from other sources can be used to make rice plants resistant or tolerant to insect pests, diseases, and different environmental stresses. For improving the nutritional value of the edible endosperm part of the rice, genes for increasing iron, beta-carotene, or better quality protein can be introduced in rice plants by genetic engineering. Different crops have been transformed using various gene transfer methods, such as protoplast transformation, biolistic, and Agrobacterium-mediated transformation. This chapter describes the Agrobacterium-mediated transformation protocol for indica-type rice. The selectable marker genes used are hygromycin phosphotransferase (hpt), neomycin phosphotransferase (nptII), or phosphomannose isomerase (pmi), and, accordingly, the selection agents are hygromycin, kanamycin (G418), or mannose, respectively.


Deletion 6q is not a characteristic marker of nodal lymphoplasmacytic lymphoma.
Lymphoplasmacytic lymphoma (LPL) is a small B-cell neoplasm with plasmacytic differentiation that does not fulfill the criteria for any other type of B-cell leukemia or lymphoma. In many cases, LPL is associated with Waldenström macroglobulinemia (WM), although WM may also be associated with other types of lymphoma. Recent studies have demonstrated that del(6q) is the most common structural abnormality in patients with bone marrow-based LPL. It is unknown whether del(6q) might also be associated with nodal LPL. We, therefore, examined 10 well-characterized LPL involving lymph nodes or other extramedullary tissues for del(6q) using paraffin section interphase fluorescence in situ hybridization (FISH). Dual-color FISH was performed using a chromosome 6 centromere probe (CEP6) and a probe for 6q21 (RP11-91C23). The latter probe has previously been reported as deleted in up to 63% of cases of bone marrow-based LPL. In contrast, no nuclei containing a del(6q) pattern were identified in any case of extramedullary LPL examined in this study, and 89-98.5% of nuclei contained a normal signal pattern. These results indicate that del(6q) is at least uncommon in nodal LPL, and cannot be employed as a diagnostic marker to identify this type of lymphoma. Furthermore, these findings suggest that nodal LPL and bone marrow-based cases of LPL may be associated with different cytogenetic findings.


Aspirin does not inhibit human megakaryocyte thromboxane synthesis in vivo.
Cyclooxygenase activity in human platelets reappears after ingestion of aspirin as a function of the platelet production rate. In different studies the activity reappeared without delay or with an interval of at least 48 h after stopping the drug. Because inhibition of megakaryocyte cyclooxygenase is the sole likely explanation for a delay we determined thromboxane B2 in human megakaryocytes obtained under local anaesthesia. We found that aspirin does not inhibit human megakaryocytes in vivo but does so in vitro. Therefore, it does not seem likely that there is actually a delay in platelet cyclooxygenase resurgence after aspirin intake. In order to suppress platelet cyclooxygenase constantly, aspirin should be given once or twice a day and not once or twice a week.


Possible Mechanisms by which Stefin B could Regulate Proteostasis and Oxidative Stress.
Human stefin B is a protease inhibitor from the family of cystatins. It was reported that it forms oligomers in cells. We have shown that it has a role in cell's response to misfolded proteins. We also have shown that its oligomers bind amyloid-beta (Aβ). Here, we discuss ways, how stefin B could reduce build-up of protein aggregates by other proteins and consequently reduces ROS and, how this might be connected to autophagy. When overexpressed, stefin B forms protein aggregates itself and these protein aggregates induce autophagy. Similarly, cystatin C was shown to bind Aβ and to induce autophagy. It is also suggested how more knowledge about the role of stefin B in a cell's response to misfolded proteins could be used to modulate progressive myoclonus epilepsy of type 1 EPM1 disease.


False-positive beta-galactosidase staining in osteoclasts by endogenous enzyme: studies in neonatal and month-old wild-type mice.
Escherichia coli beta-galactosidase (beta-gal), encoded by the lacZ gene, has become an essential tool in studies of gene expression and function in higher eukaryotes. lac-Z is widely used as a marker gene to detect expression of transgenes or Cre recombinase driven by tissue-specific promoters. The timing and location of promoter activity is easily visualized in whole embryos or specific tissues using the cleavable, chromogenic substrate, 5-bromo-4-chloro-3-indolyl-D-galactopyranoside (X-gal). The tissue specificity of promoters in transgenic constructs is routinely tested by using a promoter of choice to drive lacZ. Alternatively, the targeted expression of Cre recombinase to perform in vivo recombination of loxP sites can be visualized by beta-gal staining in mice carrying a Cre-activated lacZ transgene, such as the ROSA26 strain. In the course of our investigations, we examined beta-gal activity in bone tissue from genetically normal mice using standard detection methodology and found very high endogenous activity in bone-resorbing osteoclasts. This was true in frozen, paraffin, and glycol methacrylate sections. X-gal staining colocalized with the osteoclast marker, tartrate-resistant acid phosphatase (TRAP). beta-gal activity was present in osteoclasts in long bones, in the mandible, and in both neonatal and more mature animals. We present this brief article as a caution to those testing genetic models of skeletal gene expression using beta-gal as a marker gene.


The cerebral microcirculation in ischemia and hypoxemia. The Arisztid G. B. Kovách Memorial Lecture.
The cerebral capillary circulation exhibits heterogenous perfusion and undergoes characteristic changes in the distribution of RBC flow in response to systemic physiological stimuli. Hypoxemia, hypercapnia and hypotension increase the homogeneity of capillary perfusion, which is thought to preserve or enhance transcapillary exchange. Redistribution of capillary RBC flow between nutritive capillaries and preferential channels may contribute to this response. Selective changes in capillary flow may be brought about by non-smooth muscle-based contractile or blood-borne mechanisms. Isovolemic hemodilution anemia increases RBC velocity and supply rate with no decrease in capillary hematocrit. The effect of cerebral ischemia on microvascular patency depends on the severity and time course of the insult and whether the injury is global or focal. Capillary plugging is not observed following transient forebrain ischemia in the rat cerebral cortex but may contribute to tissue injury prior to reperfusion and during prolonged and severe ischemia. In the future, a better understanding of the functional architecture of the cerebral capillary network and its significance in the adaptation to altered circulatory conditions will continue to be an important goal of research. More work will have to be done to (i) substantiate the postulated physiological regulation of cerebral capillary flow, (ii) determine the cellular mechanism of integration of flow-dependent and neuronal activity-dependent signals, and (iii) identify the principal mediators, their cellular sources and molecular targets. The final answer to these questions will in a large part depend on our ability to directly, i.e. microscopically, visualize microvascular, neuronal and molecular phenomena as they occur in the brain in a spatially and temporally distributed manner.


Association of minimal change nephrotic syndrome (MCNS) with HLA-B8 an B13.
HLA antigens of 45 children with idiopathic nephrotic syndrome were typed for 26 phenotypic specificities. A significant association of MCNS with HLA-B 8 and B 13 was found. There was also a significantly increased frequency of the antigen combination HLA-A 1/B 8 (most presumably the haplo-type). The association with HLA-B 8 provides further evidence of an important role of immune mechanisms in the pathogenesis of MCNS.


Epilithonimonas ginsengisoli sp. nov., isolated from soil of a ginseng field.
A novel Gram-staining-negative, rod-shaped bacterium, designated DCY78(T), was isolated from soil of a ginseng field in Yeon-cheon province (38° 04' 00″ N 126° 57' 00″ E), Republic of Korea. The phylogenetic analysis based on 16S rRNA gene sequences showed that strain DCY78(T) belonged to the genus Epilithonimonas and was most closely related to Epilithonimonas lactis DSM 19921(T) (98.5 % sequence similarity) and Epilithonimonas tenax DSM 16811(T) (97.8 %). Growth occurred at 10-30 °C with an optimum temperature of 28 °C. The pH range for growth was pH 5.5-8.0. The major polar lipids were found to be phosphatidylethanolamine three unidentified amino lipids and one unidentified polar lipid. The only predominant quinone was MK-6. The major polyamines were sym-homospermidine and spermidine. The major fatty acids were summed feature 3 (comprising C16 : 1ω6c and/or C16 : 1ω7c), iso-C15 : 0 and iso-C17 : 0 3-OH. The DNA G+C content was 37.9 mol%. On the basis of the phenotypic and genotypic analysis, the isolate is classified as representative of a novel species in the genus Epilithonimonas, for which the name Epilithonimonas ginsengisoli is proposed. The type strain is DCY78(T) ( = KCTC 32174(T) = JCM 19896(T)).


The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.
Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.


[Development of the personalized finite element model of the adolescent idiopathic scoliosis and its significance].
This study was aimed to develop the personalized finite element model (FEM) of spine of a scoliotic adolescent. We derived the data of spine of a scoliotic adolescent using spiral computed tomography. Then by using a series of computer aided design (CAD) software, the patient-specific 3D finite element model of spine of a scoliotic adolescent was developed. Results show the 3-D FEM of spine of AIS adolescent was established according to patient-specific geometric parameters. The model had an appearance similar an reality. We concluded that the way in this study is an exact and effective one to develop the FEM of spine of scoliotic adolescent. It is possible to analyze and research the biomechanical behavior of the scoliotic spine using the personalized FEM.


Item-based versus subscale-based mappings from the SF-36 to a preference-based quality of life measure.
Algorithms for mapping descriptive measures of health status into preference-based measures are now widely available and their application in economic evaluation is increasingly commonplace. Existing algorithms make use of scale, subscale, or item scores on descriptive measures. Item-based algorithms entail fewer restrictions than their scale or subscale-based equivalents but are subject to problems in estimation and application. The objective of the present study is to quantify any loss of predictive validity associated with using subscale or scale scores (rather than item scores) to derive conversion algorithms. Multiple linear regression methods to derive item-based, subscale-based, and scale-based algorithms for mapping SF-36 data into Assessment of Quality of Life (AQoL) utility scores in a stratified sample of persons aged more than 16 years and resident in Victoria, Australia. The theoretical consistency and predictive validity of competing algorithms is evaluated against criteria reflecting the intended use of predicted utility scores. Three mappings were suitable for between-group comparisons. There was no discernible increase in error associated with a move from the item-based mapping to either the subscale- or scale-based mapping. Our results do not support the hypothesis that fewer restrictions on functional form necessarily result in a lower magnitude of error when predicting between-group differences. Rather, it appears that the subscale-based mapping offers a good compromise--requiring fewer restrictions on the form of the relationship between SF-36 responses and the AQoL utility score than the scale-based mapping and permitting a more efficient use of SF-36 data than the item-based mapping.


The evaluation of Healthy Families Arizona: a multisite home visitation program.
Healthy Families Arizona is a broadly implemented home visitation program aimed at preventing child abuse and neglect, improving child health and development, and promoting positive parent/child interaction. The program began as a pilot in two sites in 1991 and by 2004 had grown to 48 sites located in urban, rural, and tribal regions of the state. The unique administrative structure of the program and collaboration between evaluation and quality assurance have helped overcome many of the problems familiar to home visitation programs. This paper describes how a systematic focus to improve processes and outcomes has positioned the program for a randomized longitudinal study. Key components of the program are described and evaluation results are presented.


Towards Canine Rabies Elimination in KwaZulu-Natal, South Africa: Assessment of Health Economic Data.
Rabies remains a significant problem throughout much of the developing world. An estimated 69 000 people die annually from exposure to rabies. Most of these deaths are the result of being bitten by a rabid dog. Mass vaccination campaigns targeting dogs have been implemented around the world in an attempt to control or eliminate canine rabies. We analysed the vaccination and cost data for a campaign in the KwaZulu-Natal province of South Africa; we found that the cost per dog vaccinated to be $6.61 for mass campaigns and $5.41 for local campaigns. We also estimated the cost of human post-exposure prophylaxis (PEP). The cost of PEP is approximately $64.50 on average per patient, and $333 on average for the 9% of patients who receive RIG. We also found that the districts that vaccinated the most dogs per capita experienced the highest rates of human treatment and thus had the highest PEP costs.


Enhanced gastric stability of esomeprazole by molecular interaction and modulation of microenvironmental pH with alkalizers in solid dispersion.
Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pHM) was measured to evaluate the effect of the alkalizer on the pHM of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer-containing SD and the enteric-coated reference tablet Nexium® were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pHM values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pHM values decreased in the following order: MgO, Na2CO3, Ca(OH)2, and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium® and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method.