Health-related quality of life evaluated by tumor node metastasis staging system in patients with hepatocellular carcinoma.
To investigate and evaluate the change in health-related quality of life (HRQoL) by tumor node metastasis (TNM) staging system in patients with hepatocellular carcinoma (HCC). A total of 140 patients diagnosed with HCC between June 2008 and April 2009 in our department were enrolled to this study. One hundred and thirty-five (96.5%) patients had liver cirrhosis secondary to hepatitis B virus (HBV) infection, 73 (54.07%) of them being HBV DNA positive; the other etiologies of liver cirrhosis were alcoholic liver disease (1.4%), hepatitis C (1.4%) or cryptogenic (0.7%). All subjects were fully aware of their diagnosis and provided informed consent. HRQoL was assessed before treatment using the functional assessment of cancer therapy-hepatobiliary (FACT-Hep) questionnaire. Descriptive statistics were used to evaluate demographics and disease-specific characteristics of the patients. One-way analysis of variance and independent samples t tests were used to compare the overall FACT-Hep scores and clinically distinct TNM stages. Scores for all FACT-Hep items were analyzed by frequency analyses. The mean scores obtained from the FACT-Hep in different Child-Pugh classes were also evaluated. The mean FACT-Hep scores were reduced significantly from TNM Stage I to Stage II, Stage IIIA, Stage IIIB group (687 ± 39.69 vs 547 ± 42.57 vs 387 ± 51.24 vs 177 ± 71.44, P = 0.001). Regarding the physical and emotional well-being subscales, scores decreased gradually from Stage I to Stage IIIB (P = 0.002 vs Stage I; P = 0.032 vs Stage II; P = 0.033 vs Stage IIIA). Mean FACT-Hep scores varied by Child-Pugh class, especially in the subscales of physical well-being, functional well-being and the hepatobiliary cancer (P = 0.001 vs Stage I; P = 0.036 vs Stage II; P = 0.032 vs Stage IIIA). For the social and family well-being subscale, only Stage IIIB scores were significantly lower as compared with Stage I scores (P = 0.035). For the subscales of functional well-being and hepatobiliary cancer, there were significant differences for Stages IIΙ, IIIA and IIIB (P = 0.002 vs Stage I). HRQoL of patients with HCC worsens gradually with progression of TNM stages. The most impaired subscales of HRQoL, as measured by FACT-Hep, were physical and emotional well-being.


Exposures to conditioned flavours with different hedonic values induce contrasted behavioural and brain responses in pigs.
This study investigated the behavioural and brain responses towards conditioned flavours with different hedonic values in juvenile pigs. Twelve 30-kg pigs were given four three-day conditioning sessions: they received three different flavoured meals paired with intraduodenal (i.d.) infusions of 15% glucose (F(Glu)), lithium chloride (F(LiCl)), or saline (control treatment, F(NaCl)). One and five weeks later, the animals were subjected to three two-choice feeding tests without reinforcement to check the acquisition of a conditioned flavour preference or aversion. In between, the anaesthetised pigs were subjected to three (18)FDG PET brain imaging coupled with an olfactogustatory stimulation with the conditioned flavours. During conditioning, the pigs spent more time lying inactive, and investigated their environment less after the F(LiCl) than the F(NaCl) or F(Glu) meals. During the two-choice tests performed one and five weeks later, the F(NaCl) and F(Glu) foods were significantly preferred over the F(LICl) food even in the absence of i.d. infusions. Surprisingly, the F(NaCl) food was also preferred over the F(Glu) food during the first test only, suggesting that, while LiCl i.d. infusions led to a strong flavour aversion, glucose infusions failed to induce flavour preference. As for brain imaging results, exposure to aversive or less preferred flavours triggered global deactivation of the prefrontal cortex, specific activation of the posterior cingulate cortex, as well as asymmetric brain responses in the basal nuclei and the temporal gyrus. In conclusion, postingestive visceral stimuli can modulate the flavour/food hedonism and further feeding choices. Exposure to flavours with different hedonic values induced metabolism differences in neural circuits known to be involved in humans in the characterization of food palatability, feeding motivation, reward expectation, and more generally in the regulation of food intake.


[The effects and mechanisms of berberine on proliferation of papillary thyroid cancer K1 cells induced by high glucose].
Objective: To study the effect and mechanisms of berberine (BBR) on the proliferation of papillary thyroid cancer K1 cells induced by high glucose. Methods: K1 cells were cultured under 5.5 mmol/L or 25 mmol/L glucose condition with or without different concentration of BBR (0, 10, 40 and 80 μmol/L) for 24 hours. The proliferations of K1 cells in each condition were detected by MTT. Western blot was used to measure the expression of nuclear factor erythroid 2-related factor 2(Nrf2), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt) and phosphorylated-Akt (p-Akt). The distribution pattern of Nrf2 in K1 cells was determined using immunofluorescent staining. Results: Compared with 5.5 mmol/L condition, the proliferation rate [(126.64±5.41) % vs (87.31±3.67)%], expression levels of PI3K (0.425±0.019 vs 0.272±0.039), p-Akt/Akt (0.446±0.021 vs 0.168±0.035) and Nrf2 (0.597±0.014 vs 0.308±0.026), and Nrf2 distribution (93.0% vs 23.1%) in nuclear of K 1 cells under 25 mmol/L condition were significantly elevated, respectively (all P<0.01). Addition of BBR in 25 mmol/L condition dose dependently (10, 40, 80 μmol/L) lowered the proliferation rate of K1 cells [(111.76±4.10)%, (70.03±2.18)%, (32.41±3.76)% vs (126.64±5.41)%, all P<0.05], and suppressed the expression of PI3K, p-Akt/Akt, Nrf2, and Nrf2 nuclear distribution (P<0.05). Conclusions: BBR dose dependently inhibited the proliferation of high glucose-induced K1 cells. This effect was associated with the suppression on of PI3K/Akt signaling activation, Nrf2 expression and its nuclear translocation.


IL-12B Polymorphisms Are Associated with the Presence of Premature Coronary Artery Disease and with Cardiovascular Risk Factors: The Genetics of Atherosclerotic Disease Mexican Study.
The aim of this study was to evaluate the association of the IL-12B polymorphisms with the presence of premature coronary artery disease (pCAD) and with cardiovascular risk factors. The study included 2163 individuals (1133 patients with pCAD and 1030 healthy controls). Seven IL-12B polymorphisms (rs1363670, rs3212220, rs3212227, rs6887695, rs1433048, rs2853694, and rs1368439) were determined by TaqMan assays. The associations were evaluated by logistic regression using inheritance models adjusted for confounding variables. The rs1363670 was associated with a low risk of pCAD (odds ratio [OR] 0.718, pdominant = 0.034; OR 0.701, pheterozygote = 0.024; OR 0.702, pcodominant1 = 0.025). The association of the polymorphisms with cardiovascular risk factors was evaluated independently in each group. In controls, the rs3212227, rs3212220, and rs6887695 polymorphisms were associated with subcutaneous abdominal fat > p75, whereas the rs6887695 was associated with a high risk of central obesity. In pCAD patients, the rs2853694 was associated with a low risk of insulin resistance; and association of rs3212227 and rs3212220 with a low risk of metabolic syndrome was found, and the rs6887695 polymorphism was nominally associated with a high risk of hyperuricemia. In conclusion, the IL-12B rs1363670 polymorphism was associated with a low risk of pCAD, and in both pCAD patients and healthy controls, some IL-12B polymorphisms were associated with cardiovascular risk factors.


[Assassination of Henri IV, mental disorders and criminal responsibility].
On 14th May 1610, François Ravaillac, a delusional mystic, assassinated King Henri IV. Under the Ancien Regime, regicide was considered as a supreme act of patricide and received the ultimate punishment even if the perpetrator showed obvious signs of insanity. What would the situation be today? A study of this notorious historical episode provides a reflection on the way dangerousness linked to mental disorders has been viewed and treated over the last four centuries.


Evaluation of pre-existent immunity in patients with primary breast cancer: molecular and cellular assays to quantify antigen-specific T lymphocytes in peripheral blood mononuclear cells.
Breast cancers are known to frequently (over)express several well-characterized tumor-associated antigens (TAAs) such as carcinoembryonic antigen, MUC-1, Her-2/neu, and cancer/testis antigens such as NY-ESO-1, SSX-2, and members of the MAGE family. Whereas in melanoma patients, the detection of pre-existing T cell responses to tumor-associated differentiation antigens was a rationale to initiate several vaccination strategies, little is known thus far concerning tumor-specific immunity in breast cancer patients. The objectives of our study were (a) to modify and compare different immunodiagnostic T cell assays with regard to their suitability for clinical applications and (b) to determine endogenous TAA-specific T cell immunity of breast cancer patients at the time point of primary diagnosis. Using MUC-1- and Her-2/neu-derived HLA-A*0201-restricted peptides as model antigens, we analyzed antigen-dependent IFN-gamma release of T cells by enzyme-linked immunospot (ELISpot) assay, intracellular cytokine flow cytometry (CytoSpot), and quantitative real-time PCR. As an assay independent of T cell function, we performed tetramer staining. In our hands, the quantitative real-time PCR method is most sensitive and a feasible screening test to perform an "immunological staging" of cancer patients. By doing this, we detected in 7 of 13 (54%) of HLA-A*0201(+) breast cancer patients a pre-existent specific cellular immune response to at least one of the investigated TAAs (MUC-1, Her-2/neu, carcinoembryonic antigen, NY-ESO-1, and SSX-2). Four of 21 patients (19%) were found to have a significant Her-2/neu-specific T cell response as defined by a stimulation index >/==" BORDER="0"> 2 (range, 10-88). Although the clinical relevance of endogenous TAA-specific immunity remains unclear, our findings suggest that patients with primary breast cancer can mount a T cell immune response to their tumor that might be beneficially enhanced by TAA-dependent vaccination strategies in the adjuvant situation.


Development of a Rapid and Efficient RPA-CRISPR/Cas12a Assay for Mycoplasma pneumoniae Detection.
Mycoplasma pneumoniae (MP) is a one of most common pathogen in causing respiratory infection in children and adolescents. Rapid and efficient diagnostic methods are crucial for control and treatment of MP infections. Herein, we present an operationally simple, rapid and efficient molecular method for MP identification, which eliminates expensive instruments and specialized personnel. The method combines recombinase polymerase amplification (RPA) with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins (Cas) 12a-based detection, with an optimal procedure less than 1 h from sample to result including DNA extraction (25 min), RPA reaction (39°C for 15-20 min), CRISPR/Cas12a detection (37°C for 10 min) and visual detection by naked eyes (2 min). This diagnostic method shows high sensitivity (two copies per reaction) and no cross-reactivity against other common pathogenic bacteria. Preliminary evaluation using 201 clinical samples shows sensitivity of 99.1% (107/108), specificity of 100% (93/93) and consistency of 99.5% (200/201), compared with real-time PCR method. The above data demonstrate that our developed method is reliable for rapid diagnosis of MP. In conclusion, the RPA-CRISPR/Cas12a has a great potential to be as a useful tool for reliable and quick diagnosis of MP infection, especially in primary hospitals with limited conditions.


The Earth's Mantle: Evidence of Non-Newtonian Flow.
Recent information from experimentally deformed dunite coupled with a reanalysis of data on the Fennoscandian postglacial rebound suggest that the rheological behavior of the upper mantle is distinctly non-Newtonian, and that the shear strain rate is proportional to the shear stress raised to about the third power.


Decomposition dynamic of higher plant pigments by HPLC analysis.
The fate of the litter of dominant vegetation(willows and reeds) is one of the aspects studied in the frame of the project "Onderzoek Milieu Effecten Sigmaplan". One of the questions to be considered is how long the litter stays within the estuary. In this paper, the time the leaf litter (Salix triandra and Phragmites australis) stayed in the Schelde estuary was studied by using plant pigment as biomarkers with HPLC application. After analyzing the original data from the incubation experiment described by Dubuison and Geers (1999), the decomposition dynamics patterns of pigments were analyzed and described, and these decomposition dynamics patterns were used as calibration patterns. By using Spearman Rank Order Correlation, the calibration patterns of the pigments which were significant (p < 0.05) were grouped. In this way, several groups of the calibration patterns of pigment decomposition were achieved. The presence or absence of these groups of pigments (whether they can be detected or not from HPLC) was shown to be useful in determining the time the litter has stayed in the water. Combining data of DW and POC, more precise timing can be obtained.


Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase.
Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon.


Association Between Vascular Cell Adhesion Molecule 1 and Atrial Fibrillation.
Accumulating evidence links inflammation and atrial fibrillation (AF). To assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population. The Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline in 1990. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016. Levels of 13 inflammation markers. Incident AF over a 20-year follow-up period in the Bruneck Study. Of the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM-1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-κB ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age- and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age- and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001). Levels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores.


Modified Monoterpenes from Biotransformation of (-)-Isopiperitenone by Suspension Cell Culture of Mentha piperita
The biotransformation of (-)-(4R)-isopiperitenone (1) by suspension cell culture of Mentha piperita yielded three new hydroxylated derivatives, 4-6, and two new epoxidized derivatives, 7 and 8. (-)-7-Hydroxyisopiperitenone (2) and its glucoside were previously isolated from the culture. The structures of 4-8 were elucidated using spectral methods, and their absolute stereochemistry was established by NMR experiments and correlation with compounds of known configuration.


Acknowledging tissue donation: Human cadaveric specimens in musculoskeletal research.
Human cadaveric specimens are an important resource for research, particularly in biomechanical studies, but their use also raises ethical questions and cannot simply be taken for granted. It was asked how much information authors publishing musculoskeletal research actually give about such specimens and about how they were acquired. The aim was to formulate recommendations on how this reporting might be improved. Relevant articles published between 2009 and 2012 in four North American or European journals were scanned for information regarding the characteristics of the human specimens used, their institutional source and the ethical or legal context of their acquisition. While the majority of articles report biological characteristics of specimens (sex, age at death, preservation method), only 40% of articles refer to body donation, only 23% report the institution that provided specimens, and only 17% refer to some kind of formalized approval of their research. There were regional and journal-to-journal differences. No standard for reporting studies involving human specimens could be detected. It is suggested that such a standard be developed by researchers and editors. Information on the source of specimens and on the ethical or legal basis should be regularly reported to acknowledge this unique research resource and to preserve the good relationship between researchers and the communities, that provide the required specimens by body donation and upon which researchers depend.


Identification of nitrated proteins in the normal rat brain using a proteomics approach.
The nitration of tyrosine has been suggested to play a role in the pathogenesis of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In the present study, we identified four targets of protein nitration, T-complex polypeptide 1 alpha subunit (TCP-1), neurofilament L (NFL), glial fibrillary acidic protein (GFAP) and clathrin heavy chain (CHC), in the normal rat cortex using a proteomics approach. There have been no reports on these proteins being identified by proteomics as nitrated forms in the brain. For further study, we have to investigate alterations in these nitrated proteins during aging and in neurodegenerative disorders.


The trans-kingdom identification of negative regulators of pathogen hypervirulence.
Modern society and global ecosystems are increasingly under threat from pathogens, which cause a plethora of human, animal, invertebrate and plant diseases. Of increasing concern is the trans-kingdom tendency for increased pathogen virulence that is beginning to emerge in natural, clinical and agricultural settings. The study of pathogenicity has revealed multiple examples of convergently evolved virulence mechanisms. Originally described as rare, but increasingly common, are interactions where a single gene deletion in a pathogenic species causes hypervirulence. This review utilised the pathogen-host interaction database (www.PHI-base.org) to identify 112 hypervirulent mutations from 37 pathogen species, and subsequently interrogates the trans-kingdom, conserved, molecular, biochemical and cellular themes that cause hypervirulence. This study investigates 22 animal and 15 plant pathogens including 17 bacterial and 17 fungal species. Finally, the evolutionary significance and trans-kingdom requirement for negative regulators of hypervirulence and the implication of pathogen hypervirulence and emerging infectious diseases on society are discussed.


Immunohistochemical analysis of myosin heavy chain expression in laryngeal muscles of the rabbit, cat, and baboon.
We studied myosin heavy chain (MyHC) expression and fiber type distribution in laryngeal muscles in the rabbit, cat, and baboon using immunohistochemistry with highly MyHC-specific antibodies. Two types of variation in MyHC expression were found: between muscles of different function within species and within specific muscles between species. Within species, thyroarytenoid (Ta), an adductor, had faster MyHCs and fiber type profiles than the abductor, posterior cricoarytenoid (PCA), which expressed faster MyHCs than the vocal fold tensor, cricothyroid (CT). Between species, laryngeal muscles generally expressed faster MyHCs in small animals than in larger ones: extraocular (EO) MyHC was expressed in the Ta and PCA of the rabbit but not in the cat and baboon, whereas 2B MyHC was expressed in these muscles of the cat but not of the baboon. The CT expressed only MyHC isoforms and fiber types found in the limb muscles of the same species. These results are discussed in light of the hypothesis that the between-species variations in laryngeal muscle fiber types are evolutionary adaptations in response to changes in body mass and respiratory frequency. Within-species variations in fiber types ensure that protective closure of the glottis is always faster than movements regulating airflow during respiration.


Serological profiles after consecutive experimental infections of pigs with European H1N1, H3N2, and H1N2 swine influenza viruses.
Swine influenza viruses (SIVs) of H1N1, H3N2, and H1N2 subtypes, with antigenically different hemagglutinins, are currently cocirculating in pigs in Europe. This study aimed to determine whether the hemagglutination inhibition (HI) test, which is the primary serological test for SIV, is sufficiently specific to discriminate between infections with the three subtypes. In experiment 1, pigs were consecutively inoculated with European H1N1, H3N2, and H1N2 SIVs by the intranasal route, or with the respective subtypes only. In a second experiment, a commercial, inactivated H1N1- and H3N2- based SIV vaccine was administered once to pigs previously infected with one to three SIV subtypes or to influenza-naive pigs. Sequential serum samples were examined in HI and virus-neutralizing (VN) tests to the three strains used for pig inoculations. Of the 160 sera collected after infection with one or two SIV subtypes, only 8 showed cross-reactive antibodies to the remaining subtype(s) in the HI test, and 11 in the VN test. Consecutive inoculations with H1N1 and H1N2 or vice versa were followed by a significant rise in preexisting antibody titers to the first subtype after the second inoculation. When dually infection-immune pigs were inoculated with the third, remaining SIV subtype, nasal virus excretion was undetectable or reduced and the serological response was absent to moderate. A single vaccination of infection-immune pigs resulted in a dramatic rise in HI and VN antibody titers to any of the previously encountered subtypes, whereas SIV-naive pigs barely seroconverted. Most important, pigs previously infected with H1N1 but not with H1N2 developed crossreactive antibodies to H1N2 after the vaccination. In conclusion, the HI test remains adequate for the differential diagnosis of infections with H1N1, H3N2, and H1N2 in European swine populations if it is properly used and if the SIV vaccination status is taken into account.


The Impact of a Newly Established Multidisciplinary Team on the Interventional Treatment of Patients With Emphysema.
The emphysema interventional treatment involves mainly lung volume reduction surgery (LVRS) and endobronchial valve (EBV) implantation. Few institutes discuss these cases at a dedicated emphysema multidisciplinary team (MDT) meeting. To investigate the impact of a newly established dedicated emphysema MDT meeting on the interventional treatment of such patients. During a study period of 4 years, the outcome of 44 patients who underwent intervention according to the proposal of the emphysema MDT (group A) was compared with the outcome of 44 propensity score matched patients (group B) treated without the emphysema MDT proposal. More LVRS and less EBV insertions were performed in group A (P = .009). In group B, the interventions were performed sooner than in group A (P = .003). Postoperative overall morbidity and length of in-hospital stay were similar in the 2 groups (P = .918 and .758, respectively). Improvement of breathing ability was reported in more patients from group A (P = .012). In group B, the total number of re-interventions was higher (P = .001) and the time to re-intervention had the tendency to be less (P = .069). Survival was similar between the 2 groups (P = .884). Intervention without discussion at the MDT and EBV as initial intervention was an independent predictor of re-intervention. Interventional treatment for patients with chronic obstructive pulmonary disease (COPD) after discussion at a dedicated MDT involved more LVRS performed, required fewer interventions for their disease, and had longer re-intervention-free intervals and better breathing improvement.


Coarse-grained protein-protein stiffnesses and dynamics from all-atom simulations.
Large protein assemblies, such as virus capsids, may be coarse-grained as a set of rigid units linked by generalized (rotational and stretching) harmonic springs. We present an ab initio method to obtain the elastic parameters and overdamped dynamics for these springs from all-atom molecular-dynamics simulations of one pair of units at a time. The computed relaxation times of this pair give a consistency check for the simulation, and we can also find the corrective force needed to null systematic drifts. As a first application we predict the stiffness of an HIV capsid layer and the relaxation time for its breathing mode.


Secondary organic aerosol in residences: predicting its fraction of fine particle mass and determinants of formation strength.
Indoor secondary organic aerosol (SOA) formation may contribute to particle concentrations within residences, but little systematic work has investigated its magnitude or the determinants of its formation. This work uses a time-averaged modeling approach to predict the indoor SOA mass formed in residences due to the oxidation of 66 reactive organic compounds by ozone or the hydroxyl radical, parameterizing SOA formation with the aerosol mass fraction. Other organic and inorganic aerosols owing to outdoor and indoor sources were also predicted. Model inputs were represented as distributions within a Monte Carlo analysis, so that result distributions and sensitivity of results to inputs could be quantified, using a dataset developed from the study of Relationships between Indoor, Outdoor and Personal Air and other sources. SOA comprised a large amount of indoor organic and total fine particles for a subset of the results (e.g., >47% of indoor organic and >30% of fine aerosol for 10% of the modeled cases), but was often a small fraction. The sensitivity analysis revealed that SOA formation is driven by high terpene emission rates (particularly by d-limonene) and outdoor ozone, along with low air exchange and ozone and particle deposition rates. This study predicts that indoor SOA formation can be a substantial fraction of indoor aerosols in residences, for certain combinations of building and reactant parameters. The model herein can predict SOA for risk analyses or be used to design experiments to study indoor SOA formation. The terpene, d-limonene, contributes by far the most to formation, and eliminating this particular compound indoors would be impactful on indoor aerosol concentrations.


Imaging of VEGF receptor kinase inhibitor-induced antiangiogenic effects in drug-resistant human adenocarcinoma model.
Small molecule vascular endothelial growth factor (VEGF) receptor tyrosinase kinase inhibitors (VEGFR-TKIs) show great promise in inducing antiangiogenic responses in tumors. We investigated whether antiangiogenic tumor responses induced by an experimental VEGFR-TKI (AG013925; Pfizer Global Research and Development) could be reported by magnetic resonance imaging (MRI) during the initial phase of treatment. We used MRI and superparamagnetic nanoparticles for measuring relative vascular volume fraction (rVVF) in a drug-resistant colon carcinoma model. Athymic mice harboring MV522 xenografts were treated with VEGFR-TKI (25 mg/kg, p.o., with a 12-hour interval in between treatments) and were imaged after three consecutive treatments. Relative tumor blood volume fractions were calculated using deltaR2* maps that were scaled by the known VVF value of an in-plane skeletal muscle (1.9%). There was a pronounced and statistically significant (P < .001) decrease of tumor rVVF in treated animals (0.95 +/- 0.24%; mean +/- SEM, n = 66 slices, eight mice) compared to mice that received a placebo (2.91 +/- 0.24%; mean +/- SEM, n = 66 slices, nine mice). Tumor histology confirmed a three-fold decrease of vascular density and a concomitant increase of apoptotic cell index. Hence, we demonstrated that: 1) the VEGFR-TKI resulted in antiangiogenic effects that were manifested by a decrease or rVVF; and 2) iron oxide nanoparticles and steady-state MRI enable an early detection of tumor response to antiangiogenic therapies.


New 20 m Progressive Shuttle Test Protocol and Equation for Predicting the Maximal Oxygen Uptake of Korean Adolescents Aged 13-18 Years.
Background: Although several equations for predicting VO2max in children and adolescents have been reported, the validity of application of these equations to the Korean population has not been verified. The purpose of study was to develop and validate regression models to estimate maximal oxygen uptake (VO2max) using a newly developed 20 m progressive shuttle test (20 m PST) protocol in Korean male (n = 80, 15.3 ± 1.86 years) and female (n = 81, 15.5 ± 1.73 years) adolescents aged 13-18 years. Methods: The modified 20 m PST was performed and the VO2max was assessed in a sample of 161 participants. The participants underwent a treadmill test (TT) in the laboratory and the modified 20 m PST in a gymnasium. For the validation study, the participants performed the TT with a stationary metabolic cart and the 20 m PST with a portable metabolic cart once. In addition, they performed the 20 m PST two more times to establish test-retest reliability. Results: The mean VO2max (49.6 ± 8.7 mL·kg-1·min-1) measured with the potable metabolic cart was significantly higher than that measured in the graded exercise test with the stationary metabolic cart (46.6 ± 8.9 mL·kg-1·min-1, p < 0.001) using the new 20 m PST protocol. The standard error of the estimate (SEE) between these two measurements was 1.35 mL·kg-1·min-1. However, the VO2max derived from the newly developed equation was 46.7 ± 7.3 mL·kg-1·min-1 (p > 0.05) and the SEE was 2.90 mL·kg-1·min-1. The test and retest trials of the 20 m PST yielded comparable results (laps, r = 0.96; last speed, r = 0.93). Conclusions: Our data suggest that the new 20 m PST protocol is valid and reliable and that the equation developed in this study provides a valid estimate of VO2max in Korean male and female adolescents aged 13-18 years.


The motivating impact of informing women smokers of a link between smoking and cervical cancer: the role of coherence.
This research assessed the role of having a coherent explanation of the link between smoking and cervical cancer in motivating women to stop smoking. In the 1st study, women were given a leaflet with either a detailed or a minimal explanation of the link or no leaflet. The leaflets were similarly effective at providing a coherent explanation. In a cross-sectional analysis, having a coherent explanation moderated the relationship between perceived vulnerability and intention: Higher perceived vulnerability to cervical cancer was associated with greater intention to quit smoking only amongst women with a more coherent explanation of the link between smoking and cervical cancer. This finding was replicated in a 2nd study. These results are consistent with H. Leventhal et al.'s (1997) self-regulatory model, which suggests that motivation to change behavior depends not only on perceiving a threat but also on having a coherent model linking the behavior with the threat.


Pipette-tip solid-phase extraction based on deep eutectic solvent modified graphene for the determination of sulfamerazine in river water.
A green and novel deep eutectic solvent modified graphene was prepared and used as a neutral adsorbent for the rapid determination of sulfamerazine in a river water sample by pipette-tip solid-phase extraction. Compared with conventional graphene, deep eutectic solvent modified graphene can change the surface of graphene with wrinkled structure and higher selective extraction ability. The properties of deep eutectic solvent modified graphene and graphene were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Static adsorption showed deep eutectic solvent modified graphene had a higher adsorption ability (18.62 mg/g) than graphene. Under the optimum conditions, factors such as kinds of washing solvents and elution solvents and volume of elution solvent were evaluated. The limits of detection and quantification were 0.01 and 0.03 μg/mL, respectively. The method recoveries of sulfamerazine were in the range of 91.01-96.82% with associated intraday relative standard deviations ranging from 1.63 to 3.46% and interday relative standard deviations ranging from 0.68 to 3.84%. Deep eutectic solvent modified graphene showed satisfactory results (recovery was 95.38%) and potential for rapid purification of sulfamerazine in river water sample in combination with the pipette-tip solid-phase extraction method.


Toward Medical Documentation That Enhances Situational Awareness Learning.
The purpose of writing medical notes in a computer system goes beyond documentation for medical-legal purposes or billing. The structure of documentation is a checklist that serves as a cognitive aid and a potential index to retrieve information for learning from the record. For the past 50 years, one of the primary organizing structures for physicians' clinical documentation have been the SOAP note (Subjective, Objective, Assessment, Plan). The cognitive check list is well-suited to differential diagnosis but may not support detection of changes in systems and/or learning from cases. We describe an alternative cognitive checklist called the OODA Loop (Observe, Orient, Decide, Act. Through incorporation of projections of anticipated course events with and without treatment and by making "Decisions" an explicit category of documentation in the medical record in the context of a variable temporal cycle for observations, OODA may enhance opportunities to learn from clinical care.


Circadian rhythm disruption with high-fat diet impairs glycemic control and bone quality.
Biological functions, including glycemic control and bone metabolism, are highly influenced by the body's internal clock. Circadian rhythms are biological rhythms that run with a period close to 24 hours and receive input from environmental stimuli, such as the light/dark cycle. We investigated the effects of circadian rhythm disruption (CRD), through alteration of the light/dark schedule, on glycemic control and bone quality of mice. Ten-week-old male mice (C57/BL6, n = 48) were given a low-fat diet (LFD) or a high-fat diet (HFD) and kept on a dayshift or altered schedule (RSS3) for 22 weeks. Mice were divided into four experimental groups (n = 12/group): Dayshift/LFD, Dayshift/HFD, RSS3/LFD, and RSS3/HFD. CRD in growing mice fed a HFD resulted in a diabetic state, with a 36.2% increase in fasting glucose levels compared to the Dayshift/LFD group. Micro-CT scans of femora revealed a reduction in inner and outer surface expansion for mice on a HFD and altered light schedule. Cancellous bone demonstrated deterioration of bone quality as trabecular number and thickness decreased while trabecular separation increased. While HFD increased cortical bone mineral density, its combination with CRD reduced this phenomenon. The growth of mineral crystals, determined by small angle X-ray scattering, showed HFD led to smaller crystals. Considering modifications of the organic matrix, regardless of diet, CRD exacerbated the accumulation of fluorescent advanced glycation end-products (fAGEs) in collagen. Strength testing of tibiae showed that CRD mitigated the higher strength in the HFD group and increased brittleness indicated by lower post-yield deflection and work-to-fracture. Consistent with accumulation of fAGEs, various measures of toughness were lowered with CRD, but combination of CRD with HFD protected against this decrease. Differences between strength and toughness results represent different contributions of structural and material properties of bone to energy dissipation. Collectively, these results demonstrate that combination of CRD with HFD impairs glycemic control and have complex effects on bone quality.


Biomarker discovery based on BBHA and AdaboostM1 on microarray data for cancer classification.
In this paper, a new approach based on Binary Black Hole Algorithm (BBHA) and Adaptive Boosting version Ml (AdaboostM1) is proposed for finding genes that can classify the group of cancers correctly. In this approach, BBHA is used to perform gene selection and AdaboostM1 with 10-fold cross validation is adopted as the classifier. Also, to find the relation between the biomarkers for biological point of view, decision tree algorithm (C4.5) is utilized. The proposed approach is tested on three benchmark microarrays. The experimental results show that our proposed method can select the most informative gene subsets by reducing the dimension of the data set and improve classification accuracy as compared to several recent studies.


Delta hepatitis virus infection in China.
To assess the prevalence, epidemiological features and prognostic implications of hepatitis D (Delta) in Sichuan Province, The People's Republic of China, 649 sera (515 from HBsAg positive patients and 134 from HBsAg negative subjects) were tested by radioimmunoassay (RIA) for antibody to the hepatitis D virus (anti-HD). Forty-seven sera (7.2%) showed some degree of reactivity. Serial dilutions of these sera indicated that prozoning was not responsible for the equivocal results. Thirty-four of the 47 sera were submitted under code to a second laboratory for independent analysis. According to those results anti-HD antibodies were detected in four of these sera. The overall prevalence of anti-HD in the HBsAg positive patients therefore was 0.8% (4/515). On the basis of clinical, biochemical and histological data 427 HBsAg positive sera were further divided into acute Type B hepatitis, chronic Type B hepatitis, healthy carrier state and hepatocellular carcinoma (HCC) subgroups. Two of 65 (3.1%) anti-HD positive sera belonged to the acute Type B hepatitis group; one of 104 (0.9%), the chronic Type B hepatitis group and one of 246 (0.4%), the healthy carrier group. No antibody was detected in sera from 12 HBsAg positive HCC patients. All HBsAg negative patients were negative for anti-HD antibody. The results of this study indicate that despite a high prevalence of hepatitis B virus infection, positive serology for delta virus is uncommon in Sichuan Province, The People's Republic of China.


Outcome of meningomyelocele/lipomeningomyelocele in children of northern India.
To evaluate the clinical profile, associated anomalies and surgical outcome of children with meningomyelocele (MMC)/lipomeningomyelocele. Out of a total of 181 cases of spinal dysraphism treated at our Institute between 1996 and 2004, 102 (56.35%) cases of MMC/lipomeningomyelocele were analyzed retrospectively and prospectively. The clinical profile and radiological findings of these children were recorded. Craniospinal MRI was the essential investigation and was done as a management protocol at our Institute for these children. Eighty-two out of 102 (80.3%) cases had pure MMC/lipomeningomyelocele and 20/102 (19.6%) had associated split cord malformation (SCM; complex spina bifida). All these children underwent surgery for their primary and associated malformations as indicated. They were clinically assessed over a mean follow-up period of 3.6 years ranging from 1.5 months to 8 years. No urodynamic or evoked potential studies were done to assess the sphincteric outcome following surgery. Forty-six (45.1%) of children with MMC had other associated tethering lesions, including the presence of SCM. Craniospinal axis screening remained an important tool to understand the associated tethering lesions and malformations. Only 58.8% of children had hydrocephalus; thus the incidence was much lower compared with reports from the western literature (80-96%). 63.3% of children with overt hydrocephalus required shunt surgery prior to the definitive surgery; however, 23.3% of cases required a shunt after the MMC has been closed. Improvement in clinical profile following microneurosurgery was observed in 42.8% of cases with motor involvement, 46.8% of cases with sensory dysfunction and 39.5% of cases with sphincteric involvement. Motor improvement was seen in 43.6% of cases of pure MMC/lipomeningomyelocele as compared to only 40.0% of cases of complex spina bifida. Sensory improvement was also better in pure MMC/lipomeningomyelocele group being seen in 48.0% of cases as compared to only 42.9% of cases of complex spina bifida. Presence of SCM with MMC is referred to as complex spina bifida and is seen in a significant proportion (19.6%) of all cases of MMC. Thorough assessment of the craniospinal imaging needs to be done to look for the presence of multiple tethering lesions which could be present in the same case. Not all children with spinal dysraphism with hydrocephalus required shunt surgery or CSF diversion but a constant and vigilant follow up could avoid it in 13.3% of cases. Improvement in motor and sensory dysfunction was better in the pure MMC/lipomeningomyelocele group than in the complex spina bifida group. Improvement in sphincteric dysfunction, although seen in significant cases, was less compared with improvement in motor and sensory dysfunction. This probably represents a lack of definitive objective criteria for urodynamic improvement and a lack of proper rehabilitation. Electromyographic studies and uroflowmetry are required to asses the true sphincteric outcome following surgery.


Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells.
Transfer of tumor antigen-specific T-cell receptors (TCRs) into human T cells aims at redirecting their cytotoxicity toward tumors. Efficacy and safety may be affected by pairing of natural and introduced TCRalpha/beta chains potentially leading to autoimmunity. We hypothesized that a novel single-chain (sc)TCR framework relying on the coexpression of the TCRalpha constant alpha (Calpha) domain would prevent undesired pairing while preserving structural and functional similarity to a fully assembled double-chain (dc)TCR/CD3 complex. We confirmed this hypothesis for a murine p53-specific scTCR. Substantial effector function was observed only in the presence of a murine Calpha domain preceded by a TCRalpha signal peptide for shuttling to the cell membrane. The generalization to a human gp100-specific TCR required the murinization of both C domains. Structural and functional T-cell avidities of an accessory disulfide-linked scTCR gp100/Calpha were higher than those of a dcTCR. Antigen-dependent phosphorylation of the proximal effector zeta-chain-associated protein kinase 70 at tyrosine 319 was not impaired, reflecting its molecular integrity in signaling. In melanoma-engrafted nonobese diabetic/severe combined immunodeficient mice, adoptive transfer of scTCR gp100/Calpha transduced T cells conferred superior delay in tumor growth among primary and long-term secondary tumor challenges. We conclude that the novel scTCR constitutes a reliable means to immunotherapeutically target hematologic malignancies.


Effects of Neonicotinoids and Crop Rotation for Managing Wireworms in Wheat Crops.
Soil-dwelling insects are severe pests in many agroecosystems. These pests have cryptic life cycles, making sampling difficult and damage hard to anticipate. The management of soil insects is therefore often based on preventative insecticides applied at planting or cultural practices. Wireworms, the subterranean larvae of click beetles (Coleoptera: Elateridae), have re-emerged as problematic pests in cereal crops in the Pacific Northwestern United States. Here, we evaluated two management strategies for wireworms in long-term field experiments: 1) treating spring wheat seed with the neonicotinoid thiamethoxam and 2) replacing continuous spring wheat with a summer fallow and winter wheat rotation. Separate experiments were conducted for two wireworm species--Limonius californicus (Mannerheim) and Limonius infuscatus (Motschulsky). In the experiment with L. californicus, spring wheat yields and economic returns increased by 24-30% with neonicotinoid treatments. In contrast, in the experiment with L. infuscatus, spring wheat yields and economic returns did not increase with neonicotinoids despite an 80% reduction in wireworms. Thus, the usefulness of seed-applied neonicotinoids differed based on the wireworm species present. In experiments with both species, we detected significantly fewer wireworms with a no-till summer fallow and winter wheat rotation compared with continuous spring wheat. This suggests that switching from continuous spring wheat to a winter wheat and summer fallow rotation may aid in wireworm management. More generally, our results show that integrated management of soil-dwelling pests such as wireworms may require both preventative insecticide treatments and cultural practices.


Hydrolysis of butteroil by immobilized lipase using a hollow-fiber reactor: part III. Multiresponse kinetic studies.
A lipase from Aspergillus niger immobilized by adsorption on microporous, polypropylene hollow fibers was used to effect the continuous hydrolysis of the glycerides of butter oil at 40 degrees C and pH 7.0. The effluent concentrations of 10 different free fatty acid products were measured by high-performance liquid chromatography (HPLC). Multiresponse nonlinear regression methods were used to fit the data to a multisubstrate rate expression derived from a Ping Pong Bi Bi mechanism in which the rate-controlling step is deacylation of the lipase. Thermal deactivation of the enzyme was also included in the mathematical model of reactor performance. A postulated normal distribution of v(max) with respect to the chain length of the fatty acid (with an additive correction for the degree of unsaturation) was tested for statistical significance. The model is useful for predicting the free fatty acid profile of the lipolyzed butteroil product over a wide range of flow rates.


A simple green route to prepare stable silver nanoparticles with pear juice and a new selective colorimetric method for detection of cysteine.
In this work, a new cost-effective, rapid and simple method for the preparation of stable silver nanoparticles (AgNPs) was developed, which can be completed within 15 minutes at room temperature by oxidizing the reductants in pear juice with AgNO3. Compared with the most used citrate-capped AgNPs, the as-prepared AgNPs showed high stability, good biocompatibility and enhanced antibacterial activity. Based on the formation of Ag-S covalent bonds between cysteine and AgNPs as well as the electrostatic interaction of COO(-) and NH4(+) between cysteine molecules, which selectively lead to the aggregation of the as-prepared AgNPs and give a specific yellow-to-red colour change, a new selective colorimetric method for detection of cysteine was proposed with the as-prepared AgNPs by coupling the decrease of the characteristic localized surface plasmon resonance (LSPR) absorption at 406 nm of the as-prepared AgNPs and the increase of the new aggregation-induced band at 530 nm. The ratio of the absorbance at 530 nm to 406 nm (A530/A406) was found to be linearly dependent on the cysteine concentrations in the range of 5.0 × 10(-7) to 1.0 × 10(-5) M with a limit of detection of 6.8 × 10(-8) M.


LALF32-51 -E7, a HPV-16 therapeutic vaccine candidate, forms protein body-like structures when expressed in Nicotiana benthamiana leaves.
High-risk human papillomaviruses (HPVs) cause cervical cancer, and while there are good prophylactic vaccines on the market, these are ineffective against established infections, creating a clear need for therapeutic vaccines. The HPV E7 protein is one of the essential oncoproteins for the onset and maintenance of malignancy and is therefore an ideal therapeutic vaccine target. We fused the HPV-16 E7 protein to the Limulus polyphemus antilipopolysaccharide factor (LALF32-51 ), a small hydrophobic peptide that can penetrate cell membranes and that has immunomodulatory properties. LALF32-51 -E7 was transiently expressed in Nicotiana benthamiana, and we previously determined that it accumulated better when targeted to chloroplasts compared to being localized in the cytoplasm. Subsequently, we aimed to prove whether LALF32-51 -E7 was indeed associated with the chloroplasts by determining its subcellular localization. The LALF32-51 -E7 gene was fused to one encoding enhanced GFP to generate a LG fusion protein, and localization was determined by confocal laser scanning microscopy and transmission electron microscopy (TEM). The fluorescence observed from chloroplast-targeted LG was distinctively different from that of the cytoplasmic LG. Small spherical structures resembling protein bodies (PBs) were seen that clearly localized with the chloroplasts. Larger but less abundant PB-like structures were also seen for the cytoplasmic LG. PB-like structure formation was confirmed for both LG and LALF32-51 -E7 by TEM. LALF32-51 -E7 was indeed targeted to the chloroplasts by the chloroplast transit peptide used in this study, and it formed aggregated PB-like structures. This study could open a new avenue for the use of LALF32-51 as a PB-inducing peptide.


Microbial Iron(II) Oxidation in Littoral Freshwater Lake Sediment: The Potential for Competition between Phototrophic vs. Nitrate-Reducing Iron(II)-Oxidizers.
The distribution of neutrophilic microbial iron oxidation is mainly determined by local gradients of oxygen, light, nitrate and ferrous iron. In the anoxic top part of littoral freshwater lake sediment, nitrate-reducing and phototrophic Fe(II)-oxidizers compete for the same e(-) donor; reduced iron. It is not yet understood how these microbes co-exist in the sediment and what role they play in the Fe cycle. We show that both metabolic types of anaerobic Fe(II)-oxidizing microorganisms are present in the same sediment layer directly beneath the oxic-anoxic sediment interface. The photoferrotrophic most probable number counted 3.4·10(5) cells·g(-1) and the autotrophic and mixotrophic nitrate-reducing Fe(II)-oxidizers totaled 1.8·10(4) and 4.5·10(4) cells·g(-1) dry weight sediment, respectively. To distinguish between the two microbial Fe(II) oxidation processes and assess their individual contribution to the sedimentary Fe cycle, littoral lake sediment was incubated in microcosm experiments. Nitrate-reducing Fe(II)-oxidizing bacteria exhibited a higher maximum Fe(II) oxidation rate per cell, in both pure cultures and microcosms, than photoferrotrophs. In microcosms, photoferrotrophs instantly started oxidizing Fe(II), whilst nitrate-reducing Fe(II)-oxidizers showed a significant lag-phase during which they probably use organics as e(-) donor before initiating Fe(II) oxidation. This suggests that they will be outcompeted by phototrophic Fe(II)-oxidizers during optimal light conditions; as phototrophs deplete Fe(II) before nitrate-reducing Fe(II)-oxidizers start Fe(II) oxidation. Thus, the co-existence of the two anaerobic Fe(II)-oxidizers may be possible due to a niche space separation in time by the day-night cycle, where nitrate-reducing Fe(II)-oxidizers oxidize Fe(II) during darkness and phototrophs play a dominant role in Fe(II) oxidation during daylight. Furthermore, metabolic flexibility of Fe(II)-oxidizing microbes may play a paramount role in the conservation of the sedimentary Fe cycle.


Thermophilic Enzyme or Mesophilic Enzyme with Enhanced Thermostability: Can We Draw a Line?
Aminoglycoside nucleotidyltransferase 4' (ANT) is a homodimeric enzyme that modifies the C4'-OH site of aminoglycoside antibiotics by nucleotidylation. A few single- and double-residue mutants of this enzyme (T130K, D80Y, and D80Y/T130K) from Bacillus stearothermophilus show increased thermostability. This article investigates how such residue replacements, which are distant from the active site and monomer-monomer interface, result in various changes of the thermostability of the enzyme. In this work, we show that the thermodynamic properties of enzyme-ligand complexes and protein dynamics may be indicators of a thermophilic behavior. Our data suggests that one of the single-site mutants of ANT, D80Y, may be a thermophilic protein and the other thermostable mutant, T130K, is actually a more heat-stable variant of the mesophilic wild type (WT) with a higher Tm. Our data also suggest that T130K and D80Y adopt different global dynamics strategies to achieve different levels of thermostability enhancement and that the differences between the properties of the species can be described in terms of global dynamics rather than in terms of specific structural features. Thermophilicity of the D80Y comes at the cost of less favorable thermodynamic parameters for ligand binding relative to WT. On the other hand, the T130K species exhibits the same affinity to ligands and the same thermodynamic parameters of complex formation as the WT enzyme. These observations suggest that a quantitative characterization of ligand binding and protein dynamics can be used to differentiate thermophilic proteins from their simply more heat-stable mesophilic counterparts.


A case of diabetes, deafness, cardiomyopathy, and central sleep apnea: novel mitochondrial DNA polymorphisms.
We describe a case of diabetes mellitus complicated by neurosensory hearing loss, cardiomyopathy, and sleep apnea syndrome. A 48-year-old man who was admitted for treatment of a lacerated tendon of the right shoulder was also found to require preoperative control of diabetes, a condition that had been diagnosed 4 years earlier. The family pedigree suggested maternal inheritance of diabetes. The patient also had neurosensory hearing loss and the central type of sleep apnea syndrome. His myocardium was hypertrophic and the ultrastructural analysis showed morphologically abnormal mitochondria. On the basis of the apparent characteristic manifestations, we speculated that he had a mitochondrial disease. To elucidate the responsible mutation of mitochondrial DNA, we sequenced the patient's entire mitochondrial DNA derived from blood leukocytes and found 40 sequence variants. Three of those, 5466 A/G, 7912 G/A, and 10601 T/C, have not yet been reported. Nine of the 40 variants were accompanied by an amino acid replacement, including 5466 A/G. Although we could not determine the most significant mutation, the variants of mitochondrial DNA may have been associated with this patient's unusually variable clinical manifestations.


The effect of human recombinant GM-CSF on the myelopoiesis in a long-term bone marrow culture (LTBMC).
The long-term bone marrow culture (LTBMC) allows continuous self-renewal of a myeloid precursor population from an adherent stromal cell layer. We investigated the effect of human recombinant GM-CSF (100 ng/ml) on the in vitro hemopoiesis in a LTBMC. After a culture period of 14 days we observed a 2.3-fold increase in the total number of non-adherent cells in the cultures containing GM-CSF. Whereas the total cell number in the cultures without GM-CSF decreased after 28 days, proliferation continued in the cultures with GM-CSF. During the first 14 days there was a slight decrease of the number of CFU-GM in the cultures with GM-CSF. Thereafter no significant difference in the numbers of committed progenitors present in two culture systems could be observed.


Fetal and neonatal rat pancreas in organ culture: age-related effects of corticosterone on the acinar cell component.
Fetal rat pancreas (ages 16 to 22 days postcoitum) and neonatal pancreas (4 days postnatal) were grown in organ culture for four days. The medium consisted of chick embryo extract and rooster serum either with or without the addition of corticosterone (3 X 10(-5) M). Acinar cell differentiation was assessed using quantitative light microscopic linear scanning of tissue sections and enzymatic analysis of amylase in the culture media and in the explants. In the younger fetal tissue of 16 and 18 days postcoitum exocrine differentiation continued in vitro. The effect of corticosterone was an enhancement of the degree of in vitro differentiation. Even with corticosterone, however, the degree of differentiation in vitro was less than that observed during a similar period in vivo. In differentiated pancreas (20- and 22-day fetal neonatal) the acinar pancreas degenerated under control conditions and a selective growth of the endocrine pancreas was observed. The addition of corticosterone to the media resulted in a maintenance of the differentiated state of the acini except in 22-day fetal tissue in which the acini were not preserved. The differences between these results and the work of other investigators and the possible in vivo role of adrenocorticosteroids in exocrine pancreatic differentiation is discussed.


Central nervous system toxicity attributable to epidural ropivacaine hydrochloride.
Ropivacaine, a new local anaesthetic agent, has been demonstrated to have less potential than bupivacaine for central nervous system toxicity on the basis of human and animal studies. We report a case of a convulsion secondary to presumed inadvertent intravascular injection of 20 mg of ropivacaine in a 44 kg patient during an epidural for chronic pain. There were minimal signs of cardiovascular toxicity.


A series of M(II)Cu(II)3 stars (M = Mn, Ni, Cu, Zn) exhibiting unusual magnetic properties.
The work in this report describes the syntheses, electrospray ionization mass spectromtery, structures, and experimental and density functional theoretical (DFT) magnetic properties of four tetrametallic stars of composition [M(II)(Cu(II)L)3](ClO4)2 (1, M = Mn; 2, M = Ni; 3, M = Cu; 4, M = Zn) derived from a single-compartment Schiff base ligand, N,N'-bis(salicylidene)-1,4-butanediamine (H2L), which is the [2 + 1] condensation product of salicylaldehyde and 1,4-diaminobutane. The central metal ion (Mn(II), Ni(II), Cu(II), or Zn(II)) is linked with two μ2-phenoxo bridges of each of the three [Cu(II)L] moieties, and thus the central metal ion is encapsulated in between three [Cu(II)L] units. The title compounds are rare or sole examples of stars having these metal-ion combinations. In the cases of 1, 3, and 4, the four metal ions form a centered isosceles triangle, while the four metal ions in 2 form a centered equilateral triangle. Both the variable-temperature magnetic susceptibility and variable-field magnetization (at 2-10 K) of 1-3 have been measured and simulated contemporaneously. While the Mn(II)Cu(II)3 compound 1 exhibits ferromagnetic interaction with J = 1.02 cm(-1), the Ni(II)Cu(II)3 compound 2 and Cu(II)Cu(II)3 compound 3 exhibit antiferromagnetic interaction with J = -3.53 and -35.5 cm(-1), respectively. Variable-temperature magnetic susceptibility data of the Zn(II)Cu(II)3 compound 4 indicate very weak antiferromagnetic interaction of -1.4 cm(-1), as expected. On the basis of known correlations, the magnetic properties of 1-3 are unusual; it seems that ferromagnetic interaction in 1 and weak/moderate antiferromagnetic interaction in 2 and 3 are possibly related to the distorted coordination environment of the peripheral copper(II) centers (intermediate between square-planar and tetrahedral). DFT calculations have been done to elucidate the magnetic properties. The DFT-computed J values are quantitatively (for 1) or qualitatively (for 2 and 3) matched well with the experimental values. Spin densities and magnetic orbitals (natural bond orbitals) correspond well with the trend of observed/computed magnetic exchange interactions.


Hand hygiene management among nurses: collective health challenges.
To describe the determining factors in hand hygiene management among nurses and identify associated collective health challenges. Cross-sectional descriptive study. Data were collected using a questionnaire that was applied in four internal medicine units of a hospital of reference in Portugal. The sample was composed of 50 nurses aged 26 to 55 years (mean age of 34.88 years); 80% were women, 58% had a Bachelor's degree, and had 5-30 years of nursing practice (X̄ =11.94;±5.92). The vast majority of nurses (90%) reported complying with the existing recommendations on hand hygiene in pre-established moments. However, none of the nurses were able to identify all the moments for hand hygiene using water and soap or alcohol-based handrub. This study shows that continuous training, adequate materials/structures in the units, and redesigned administration/supervision practices are determining factors to achieve higher levels of adherence to hand hygiene among nurses, as well as increased quality and safety in care delivery, which is a current collective health challenge.


Comparison of the structure and musculature of male terminalia in the tribe Cidariini Duponchel (Lepidoptera: Geometridae: Larentiinae) once again throws into doubt a sister relationship with the Xanthorhoini.
The structure and musculature of the male terminalia are described and illustrated in 11 genera of the tribe Cidariini (Lepidoptera, Geometridae, Larentiinae) from the Holarctic and Oriental regions. Nine genital muscles were identified: m1, m2(10), m3(2), m4, m5(7), m6(5), m7(6), m8(3) and m21. Variation in the insertion of the muscles m1, m3(2), m4, m5(7), m6(5) and m8(3) on the sclerites in several generic groups of the tribe Cidariini is discussed, revealing that the Thera species group does not share some apparently cidariine characters. A comparative analysis of the musculature in the tribes Cidariini and Xanthorhoini questions the sister relationship of these tribes that was suggested by earlier studies. The application of the terms 'anellus lobes' and 'labides' is discussed.


Cyclosporin A inhibits the replication of diverse coronaviruses.
Low micromolar, non-cytotoxic concentrations of cyclosporin A (CsA) strongly affected the replication of severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus 229E and mouse hepatitis virus in cell culture, as was evident from the strong inhibition of GFP reporter gene expression and a reduction of up to 4 logs in progeny titres. Upon high-multiplicity infection, CsA treatment rendered SARS-CoV RNA and protein synthesis almost undetectable, suggesting an early block in replication. siRNA-mediated knockdown of the expression of the prominent CsA targets cyclophilin A and B did not affect SARS-CoV replication, suggesting either that these specific cyclophilin family members are dispensable or that the reduced expression levels suffice to support replication.


m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease.
Accumulating evidence links m6A modification with immune infiltration. However, the correlation and mechanism by which m6A modification promotes intestinal immune infiltration in inflammatory bowel disease (IBD) is unknown. Here, genomic information from IBD tissues was integrated to evaluate disease-related m6A modification, and the correlation between the m6A modification pattern and the immune microenvironment in the intestinal mucosa was explored. Next, we identified hub genes from the key modules of the m6Acluster and analyzed the correlation among the hub genes, immune infiltration, and therapy. We found that IGF2BP1 and IGF2BP2 expression was decreased in Crohn's disease (CD) tissues and that IGF2BP2 was decreased in ulcerative colitis (UC) tissues compared with normal tissues (P < 0.05). m6Acluster2, containing higher expressions of IL15, IL16, and IL18, was enriched in M0 macrophage, M1 macrophage, native B cells, memory B cells, and m6Acluster1 with high expression of IL8 and was enriched in resting dendritic and plasma cells (P < 0.05). Furthermore, we reveal that expression of m6A phenotype-related hub genes (i.e., NUP37, SNRPG, H2AFZ) was increased with a high abundance of M1 macrophages, M0 macrophages, and naive B cells in IBD (P < 0.01). Immune checkpoint expression in the genecluster1 with higher expression of hub genes was increased. The anti-TNF therapeutic response of patients in genecluster1 was more significant, and the therapeutic effect of CD was better than that of UC. These findings indicate that m6A modification may affect immune infiltration and therapeutic response in IBD. Assessing the expression of m6A phenotype-related hub genes might guide the choice of IBD drugs and improve the prediction of therapeutic response to anti-TNF therapy.


Irregularities in genetic variation and mutation rates with environmental stresses.
The appearance of new mutations is determined by the equilibrium between DNA error formation and repair. In bacteria like Escherichia coli, stresses are thought shift this balance towards increased mutagenesis. Recent findings, however, suggest a very uneven relationship between stress and mutations. Only a subset of stressful environments increase the net rate of mutation and different forms of nutritional stress (such as oxygen, carbon or phosphorus limitations) result in markedly different mutation rates after similar reductions in growth rate. Moreover, different stresses result in altered mutational spectra, with some increasing transposition and others increasing indel formation. Single-base substitution rates are lower with some stresses than in unstressed bacteria. Indeed, changes to the mix of mutations with stress are more widespread than a marked increase in net mutation rate. Much remains to be learned on how environments have unique mutational signatures and why some stresses are more mutagenic than others. Even beyond stress-induced genetic variation, the fundamental unresolved question in the stress-mutation relationship is the adaptive value of different types of mutations and mutation rates; is transposition, for example, more advantageous under anaerobic conditions? It remains to be investigated whether stress-specific genetic variation impacts on evolvability differentially in distinct environments.


Phosphorylation of maize eukaryotic translation initiation factor on Ser2 by catalytic subunit CK2.
Alignment of eukaryotic translation initiation factor 5A (eIF5A) sequences has shown, for plants, in contrast to most other eukaryotes, the presence of N-terminal serine residue (Ser2) which could be phosphorylated by CK2. Using point directed mutagenesis, we demonstrate here that in recombinant maize ZmeIF5Awt Ser2 is exclusively phosphorylated by catalytic subunit of CK2 (CK2α), whereas its mutated variant Ser2Ala is not phosphorylated. To shed light on the physiological significance of this Ser2 phosphorylation, transient expression of fluorescence-labeled proteins was performed in maize protoplast. Wild-type ZmeIF5A was distributed evenly between nucleus and cytoplasm, but the replacement of Ser2 by aspartic acid, which mimics the phosphorylated serine, influences its intracellular localization. We postulate that phosphorylation of Ser2 in maize eIF5A, and most probably in other plant cells, plays a role in specific regulation of nuclear export of eIF5A-bound mRNAs.


Noise suppression and spectral decomposition for state-dependent noise in the presence of a stationary fluctuating input.
It recently has been shown that the observed noise amplitude of an intrinsically noisy system may be reduced by causing the underlying state to fluctuate [Phys. Rev. Lett. 86, 950 (2001)]]. This paper extends the previous theory by considering the full power spectrum of the output signal, interpreting noise reduction in terms of the low-frequency end of the spectrum as well as the integrated spectrum. Our treatment accounts for arbitrarily sized fluctuations and deals with both continuous and discretely sampled observations. We show that noise suppression is possible if and only if the stationary average of the intensity of state-dependent noise decreases. We apply our analysis to an example involving saturable electrical conduction discussed in the original paper by Vilar and Rubí.


Isothiocyanates are important as haptens in contact allergy to chloroprene rubber.
Contact allergy to chloroprene rubber products is well known. Thiourea compounds are considered the cause of allergy. Diethylthiourea commonly occurs in this type of product and can decompose to the sensitizer ethyl isothiocyanate. To investigate the clinical importance of degradation products and metabolites from organic thioureas in contact allergy to chloroprene rubber with a focus on isothiocyanates and isocyanates. Patients with contact allergy to diphenylthiourea were patch tested with phenyl isothiocyanate and phenyl isocyanate. Patients with known contact allergy to diethylthiourea were retested with diethylthiourea, while chemical analyses of their chloroprene rubber products were performed. The stability of diethylthiourea, diphenylthiourea and dibutylthiourea in patch-test preparations was investigated. Liquid chromatography/mass spectrometry and solid-phase microextraction/gas chromatography were used for determination of organic thioureas and isothiocyanates. All patients allergic to diphenylthiourea reacted to phenyl isothiocyanate, two of eight reacted to phenyl isocyanate and six of eight reacted to diphenylthiourea. Four patients allergic to diethylthiourea reacted at retest; diethylthiourea was detected in all chloroprene rubber samples, with levels of 2-1200 nmol cm-2 . At 35 °C, ethyl isothiocyanate was emitted from all samples. Patch-test preparations of diethylthiourea, diphenylthiourea and dibutylthiourea all emitted the corresponding isothiocyanate, with diethylthiourea showing the highest rate of isothiocyanate emission. Thiourea compounds are degraded to isothiocyanates, which are generally strong or extreme sensitizers, thus acting as prehaptens. This process occurs in both chloroprene rubber products and patch-test preparations. Positive reactions to phenyl isocyanate indicate cutaneous metabolism, as the only known source of exposure to phenyl isocyanate is through bioactivation of diphenylthiourea.


Can incident reporting improve safety? Healthcare practitioners' views of the effectiveness of incident reporting.
Recent critiques of incident reporting suggest that its role in managing safety has been over emphasized. The objective of this study was to examine the perceived effectiveness of incident reporting in improving safety in mental health and acute hospital settings by asking staff about their perceptions and experiences. Qualitative research design using documentary analysis and semi-structured interviews. Two large teaching hospitals in London; one providing acute and the other mental healthcare. Sixty-two healthcare practitioners with experience of reporting and analysing incidents. Incident reporting was perceived as having a positive effect on safety, not only by leading to changes in care processes but also by changing staff attitudes and knowledge. Staff discussed examples of both instrumental and conceptual uses of the knowledge generated by incident reports. There are difficulties in using incident reports to improve safety in healthcare at all stages of the incident reporting process. Differences in the risks encountered and the organizational systems developed in the two hospitals to review reported incidents could be linked to the differences we found in attitudes to incident reporting between the two hospitals. Incident reporting can be a powerful tool for developing and maintaining an awareness of risks in healthcare practice. Using incident reports to improve care is challenging and the study highlighted the complexities involved and the difficulties faced by staff in learning from incident data.


Oral Health Status of Patients with Lysosomal Storage Diseases in Poland.
Patients with lysosomal storage diseases (LSDs) suffer from physical and mental disabilities, which together with poor access to professional care may lead to impaired oral health. This cross-sectional case-control study characterized the status of oral health in patients with LSDs in Poland. Thirty-six children and young adults with various forms of LSDs were examined. The data were compared with those from age- and sex-matched healthy controls. Exemplary cases were presented to highlight typical problems in oral care associated with LSDs. When possible, saliva was collected and analyzed for total protein, inflammatory mediators, and antioxidant status. Generally, patients with LSDs had significantly higher prevalence of caries, inferior gingival status, and inadequate oral hygiene. The severity of oral health impairment in mucopolysaccaridoses, the most common LSD in Poland, was similar to that seen in patients with mannosidoses or Pompe disease. Saliva could be collected only from few less handicapped patients. In MPS, it did not appear to differ significantly from the controls, but in patients with Pompe disease it contained lower concentrations of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1), but higher levels of tumor necrosis factor receptors 1 and 2 (TNF-R1, TNF-R2) and myeloperoxidase (MPO). In conclusion, Polish patients with LSDs have an inadequate level of oral hygiene and substantially deteriorated oral health.


Simplest kinetic schemes for biochemical oscillators.
The topological structure of the simplest critical fragments in biochemical systems has been characterized. The conditions are considered where the critical fragments induce oscillations of the concentrations of the system participants. To illustrate, three biochemical systems (transport of ions through a membrane, protein phosphorylation, and two-substrate reaction) are discussed. The kinetic schemes of these systems contain one of the discovered critical fragments. Relaxation oscillations of the concentrations of the system participants were demonstrated using the numerical integration method.


NUBIScan, an in silico approach for prediction of nuclear receptor response elements.
Nuclear receptors (NRs) are transcription factors activated by a multitude of hormones, other endogenous substances, and exogenous molecules. These proteins modulate the regulation of target genes by contacting their promoter or enhancer sequences at specific recognition sites. The identification of these response elements is the first step toward detailed insight into the regulatory mechanisms affecting a gene. We have developed NUBIScan, a computer algorithm to predict DNA recognition sites for NRs in the regulatory regions of genes. The algorithm is based on weighted nucleotide distribution matrices and combines scores from both half-sites necessary for NR dimer binding. It provides more specific identification of functional sites than previous in silico approaches, as evidenced by scanning published regulatory regions of drug-inducible genes and comparing the obtained predictions with experimental results. In prospective analyses, NUBIScan consistently identified new functional NR binding sites in sets of large sequences, which had eluded previous analyses. This is exemplified by the detailed functional analysis of the flanking region of two genes. This approach therefore facilitates the selection of likely sites of gene regulation for subsequent experimental analysis.


High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells.
Progression of castration-resistant tumors is frequent in prostate cancer. Current systemic treatments for castration-resistant prostate cancer only produce modest increases in survival time and self-renewing Tumor-Initiating Cells (TICs) are suspected to play an important role in resistance to these treatments. However it remains unclear whether the same TICs display both chemo-resistance and self-renewing abilities throughout progression from early stage lesions to late, castration resistant tumors. Here, we found that treatment of mice bearing LNCaP-derived xenograft tumors with cytotoxic (docetaxel) and anti-androgen (flutamide) compounds enriched for cells that express TROP2, a putative TIC marker. Consistent with a tumor-initiating role, TROP2high cells from androgen-sensitive prostate cancer cell lines displayed an enhanced ability to re-grow in culture following treatment with taxane-based chemotherapy with or without androgen blockade. TROP2 down-regulation in these cells reduced their ability to recur after treatment with docetaxel, in the presence or absence of flutamide. Accordingly, in silico analysis of published clinical data revealed that prostate cancer patients with poor prognosis exhibit significantly elevated TROP2 expression level compared to low-risk patients, particularly in the case of patients diagnosed with early stage tumors. In contrast, in androgen-independent prostate cancer cell lines, TROP2high cells did not exhibit a differential treatment response but were characterized by their high self-renewal ability. Based on these findings we propose that high TROP2 expression identifies distinct cell sub-populations in androgen-sensitive and androgen-independent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.


Neglected Proximal Tibiofibular Joint Dislocation Treated With a Cortical Button Suspension Device: A Case Report.
Proximal tibiofibular joint dislocation is a rare knee injury. Hence, its diagnosis is often missed. Herein, we have reported a case of posterior lateral proximal tibiofibular joint dislocation that was initially missed because it was associated with a fibula diaphyseal fracture. Our patient was a 23-year-old male with a complaint of left lateral knee pain and a history of fall from a motorcycle. He was treated with a cortical button suspension device. The patient reported no symptoms or complications at the one-year follow-up. Proximal tibiofibular joint dislocation is easily neglected if not considered as a diagnosis during clinical assessment. Half of these cases present with symptoms such as chronic pain and peroneal nerve palsy that require surgical treatment. A detailed physical examination and close review of imaging findings are important to establish a definitive diagnosis. A cortical bone button suspension device could be the appropriate treatment for cases requiring surgical management.


Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine.
Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design. Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment. Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment. The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.


Partition function zeros of the square-lattice Ising model with nearest- and next-nearest-neighbor interactions.
The distributions of the partition function zeros in the complex a=e2betaJ1 plane of the square-lattice Ising model with nearest-neighbor (J1) and next-nearest-neighbor (J2) interactions are investigated as a function of R=J2/J1. Starting from the well-known two-circle distribution of the zeros a=+/-1+sqrt[2]eitheta for R=0 , finally the partition function zeros lie on the unit circle a=eitheta for R=infinity . Between these two ends, the changes in the zero distributions are described. Using the partition function zeros, the critical point ac(R) and the thermal scaling exponent yt(R) are estimated for the Ising ferromagnet (equivalently, antiferromagnet) and superantiferromagnet. For the special case of R=1/2 , the possible implications of the zero distributions are also discussed.


Oligomer Model of PB1 Domain of p62/SQSTM1 Based on Crystal Structure of Homo-Dimer and Calculation of Helical Characteristics.
Autophagy is an important process for protein recycling. Oligomerization of p62/SQSTM1 is an essential step in this process and is achieved in two steps. Phox and Bem1p (PB1) domains can oligomerize through both basic and acidic surfaces in each molecule. The ZZ-type zinc finger (ZZ) domain binds to target proteins and promotes higheroligomerization of p62. This mechanism is an important step in routing target proteins to the autophagosome. Here, we determined the crystal structure of the PB1 homo-dimer and modeled the p62 PB1 oligomers. These oligomer models were represented by a cylindrical helix and were compared with the previously determined electron microscopic map of a PB1 oligomer. To accurately compare, we mathematically calculated the lead length and radius of the helical oligomers. Our PB1 oligomer model fits the electron microscopy map and is both bendable and stretchable as a flexible helical filament.


Jasmine flower extract lowers prolactin.
Antipsychotic drugs frequently cause amenorrhoea and galactorrhoea. Jasmine flowers used topically were as effective as oral Bromocriptine in suppressing puerperal lactation. This study aims to evaluate the efficacy and safety of intranasal jasmine flower extract (JFE) to reduce prolactin levels of patients on stable doses of antipsychotic drugs. This is a randomized, double blind, crossover clinical trial. An aqueous-ethanol extract of jasmine flowers was prepared and used as nasal drops. A decrease in serum prolactin of ≥25 ng/mL was considered a significant response. Ten out of 35 women had a significant drop in the serum prolactin while on the JFE. The non-responders to JFE were on higher doses of antipsychotic drugs. The main side effect was a transient and mild burning sensation in the nose. A cost analysis favoured JFE over dopamine agonists. JFE contains a prolactin-lowering substance which needs further characterisation.


[Intensive glycemia control in the first day of the acute cerebral blood flow disturbance in patients with diabetes mellitus type 2].
Forty-seven patients with cerebral stroke and diabetes mellitus type 2 were included in the study. To maintain the target values of glycemia on the level 7.8-10.2 mmol/l, patients of the main group received the continuous intravenous infusion of insulin and patients of the control group received frequent (every 3h) subcutaneous injections of insulin during the first 24 h after the acute cerebral blood flow disturbance. The results obtained have shown that continuous intravenous insulin infusion reduces the risk of hypoglycemia, accelerates positive neurologic dynamics, reduces terms of hospitalization and decreases mortality in patients with diabetes mellitus type 2.


Asymmetric Synthesis of Chiral Acyclic Purine Nucleosides Containing a Hemiaminal Ester Moiety via Three-Component Dynamic Kinetic Resolution.
An efficient route to construct chiral acyclic purine nucleosides containing a hemiaminal ester moiety is reported via three-component dynamic kinetic resolution of purines, aldehydes, and acid anhydrides. The procedure provides diverse chiral acyclic purine nucleoside analogues in a regioselective manner with good yields (up to 93% yield) and excellent enantioselectivities (up to 95% ee). Furthermore, the chiral (acyloxyalkyl)-5-fluorouracil could also be generated as a potential prodrug of 5-fluorouracil.


Application of Nursing Interventions Classification (NIC) in a cardiovascular critical care unit.
The nursing profession is moving toward developing a standardized language. Benefits of such a language are outlined. Nursing Interventions Classification (NIC) (Iowa Intervention Project, 1992), a standardized language for nursing interventions, has been recently developed by the Iowa Intervention Project. This article describes how NIC was incorporated into a nursing care plan in a tertiary acute care facility. Teaching strategies, which include aspects of adult learning theory and motivational theory, are discussed. Utilization of creativity and variability in the planning and implementation of a unit based inservice program were the most beneficial strategies used.


Clinging on to alpine life: Investigating factors driving the uphill range contraction and population decline of a mountain breeding bird.
Climate change and anthropogenic nitrogen deposition are widely regarded as important drivers of environmental change in alpine habitats. However, due to the difficulties working in high-elevation mountain systems, the impacts of these drivers on alpine breeding species have rarely been investigated. The Eurasian dotterel (Charadrius morinellus) is a migratory wader, which has been the subject of uniquely long-term and spatially widespread monitoring effort in Scotland, where it breeds in alpine areas in dwindling numbers. Here we analyse data sets spanning three decades, to investigate whether key potential drivers of environmental change in Scottish mountains (snow lie, elevated summer temperatures and nitrogen deposition) have contributed to the population decline of dotterel. We also consider the role of rainfall on the species' wintering grounds in North Africa. We found that dotterel declines-in both density and site occupancy of breeding males-primarily occurred on low and intermediate elevation sites. High-elevation sites mostly continued to be occupied, but males occurred at lower densities in years following snow-rich winters, suggesting that high-elevation snow cover displaced dotterel to lower sites. Wintering ground rainfall was positively associated with densities of breeding males two springs later. Dotterel densities were reduced at low and intermediate sites where nitrogen deposition was greatest, but not at high-elevation sites. While climatic factors explained variation in breeding density between years, they did not seem to explain the species' uphill retreat and decline. We cannot rule out the possibility that dotterel have increasingly settled on higher sites previously unavailable due to extensive snow cover, while changes associated with nitrogen deposition may also have rendered lower lying sites less suitable for breeding. Causes of population and range changes in mountain-breeding species are thus liable to be complex, involving multiple anthropogenic drivers of environmental change acting widely across annual and migratory life cycles.


Flexible dynamic quantitative phase imaging based on division of focal plane polarization imaging technique.
This paper proposes a flexible and accurate dynamic quantitative phase imaging (QPI) method using single-shot transport of intensity equation (TIE) phase retrieval achieved by division of focal plane (DoFP) polarization imaging technique. By exploiting the polarization property of the liquid crystal spatial light modulator (LC-SLM), two intensity images of different defocus distances contained in orthogonal polarization directions can be generated simultaneously. Then, with the help of the DoFP polarization imaging, these images can be captured with single exposure, enabling accurate dynamic QPI by solving the TIE. In addition, our approach gains great flexibility in defocus distance adjustment by adjusting the pattern loaded on the LC-SLM. Experiments on microlens array, phase plate, and living human gastric cancer cells demonstrate the accuracy, flexibility, and dynamic measurement performance for various objects. The proposed method provides a simple, flexible, and accurate approach for real-time QPI without sacrificing the field of view.


Determination of the interfacial characteristics of a series of bolaamphiphilic poly(fluorooxetane) surfactants through molecular dynamics simulation.
Constant surface tension (NgammaT) and constant volume (NVT) molecular dynamics simulations have been conducted on a series of bolaamphiphilic alpha,varpi-(diammonium disulfato)poly(fluorooxetane)s and on a typical "long-chain" anionic fluorosurfactant used to improve the flow-and-leveling characteristics of aqueous coatings, to compare their behavior at a water/air interface. Recent research has shown that the poly(fluorooxetane) surfactants considered in this paper could serve as an effective substitute for traditional fluorosurfactants used in flow-and-leveling applications.(1) From molecular dynamics simulation, we have determined the saturated interfacial area per surfactant, interfacial area per surfactant as a function of surface tension, density profiles, the degree of hydration for various atoms in each surfactant, the degree of counterion binding, and order parameters. Our results for saturated interfacial area per surfactant molecule are greater than what has been obtained by other researchers through parametric fitting of interfacial area from experimental surface tension data using the Davies isotherm. Possible explanations for this difference are discussed. The low interfacial areas occupied by each poly(fluorooxetane) at the water/air interface are the result of their ability to adopt a "looped" conformation, in which the carbon and oxygen backbone of each surfactant and the attached perfluoroalkyl chains are forced into the air phase. A geometrically defined penetration parameter was calculated from the density profiles, which reveals that each poly(fluorooxetane) surfactant is more effective at separating the air and water phases than the "long-chain" anionic fluorosurfactant. The degree of hydration measured for different atoms in poly(fluorooxetane) during simulation confirms that a "looped" conformation is adopted in which the surfactant backbone and the perfluoroalkyl chains are lifted away from the water surface. Calculation of order parameters revealed a much lower degree of ordering for the perfluoroalkyl side chains in each bolaamphiphile than in the "long chain" anionic fluorosurfactant. When viewed in the context of the penetration parameter analysis, the density profiles and hydration data suggest why each poly(fluorooxetane) is capable of significantly reducing surface tension when other fluorosurfactants with similarly short perfluoroalkyl moieties provide inadequate surface tension reduction for practical flow-and-leveling applications.


Secretion of a lysophospholipase D activity by adipocytes: involvement in lysophosphatidic acid synthesis.
The aim of the present work was to depict the metabolic pathways involved in extracellular production of lysophosphatidic acid (LPA) by adipocytes. LPA was followed by quantifying the accumulation of LPA in the incubation medium (conditioned medium, CM) of 3T3F442A adipocytes or human adipose tissue explants using a radioenzymatic assay. Surprisingly, after separation from the cells, the amount of LPA present in CM could be significantly increased by further incubation at 37 degrees C. This suggested the presence of a LPA-synthesizing activity (LPA-SA) in CM. LPA-SA appeared as a soluble activity which was inhibited by divalent ion chelators EDTA and phenanthrolin. The effect of EDTA was preferentially reverted by CoCl2, as described for a lysophospholipase D (lyso-PLD) activity previously identified in rat plasma. LPA concentration could also be increased by treatment with a bacterial PLD, demonstrating the presence of PLD-sensitive LPA precursors (mainly lysophosphatidylcholine) in adipocyte CM. LPA-SA could be increased by the addition of exogenous lysophosphatidylcholine, lysophosphatidylglycerol, or lyso-platelet activating factor, demonstrating that LPA-SA resulted from the action of a lyso-PLD. LPA-SA was not inhibited, but rather activated, by primary alcohol (ethanol and 1-butanol), suggesting that adipocyte lyso-PLD was not a classical PLD. Finally, LPA-SA was found to be weaker in CM of undifferentiated adipocyte (preadipocytes) compared with CM of differentiated adipocytes. In conclusion, our results reveal the existence of a secreted lyso-PLD activity regulated during adipocyte-differentiation and involved in extra cellular production of synthesis of LPA by adipocytes.


Trigonelline, An Alkaloid From Leonurus japonicus Houtt., Suppresses Mast Cell Activation and OVA-Induced Allergic Asthma.
Trigonelline, one of the active compounds from Leonurus japonicus Houtt., has been proven to have pharmacological value in diabetes, the central nervous system and cardiovascular diseases. Recent studies have shown that it may also be beneficial in controlling inflammation. However, the mechanism of the antiallergic effects of trigonelline has not been well studied. As the key effector cells participating in the development of allergies, mast cells have been linked to the pathogenesis of asthma for ages. In this study, we demonstrated the inhibitory effect of trigonelline on activated bone marrow-derived mast cells (BMMCs) and verified its anti-inflammatory properties using an ovalbumin (OVA)-induced asthma model. Trigonelline suppressed BMMC degranulation and decreased the production of the cytokines, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) in a dose-dependent manner. The potent mechanism is mainly through the suppression of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Trigonelline can alleviate pathological damage in lung tissue and reduce the levels of serum immunoglobulin E (IgE) and T helper 2 (Th2) cytokines. RNA-seq results revealed the HIF-1α to be a potential target for the allergic reaction. Taken together, our study demonstrated that trigonelline can inhibit allergic inflammation in vitro and in vivo, which may provide a basis for novel anti-inflammatory drug development.


The complete mitochondrial genome of the butterfly Herona marathus (Lepidoptera: Nymphalidae).
The complete mitochondrial genome (mitogenome) of Herona marathus was sequenced and analyzed in the study. The mitogenome is 15 487 bp in size, including 37 genes and a putative control region. Thirteen protein-coding genes (PCGs) all start with a typical ATN codon, expect that COI gene uses CGA as its initial codon. Majority of the 13 PCGs have a complete termination codon (TAA or TAG) except for COII and ND4 have a single T-- residue. All tRNAs have typical clover-leaf secondary structure, except for tRNASer(AGN), in which the dihydrouridine (DHU) arm is a simple loop. Bayesian analyses support the monophyly of butterflies and recover high supports for the following family level relationships: (Papilionidae + Hesperioidea + (Pieridae + Lycaenidae + (Danaidae + Nymphalidae))).