Efficacy of a new full face mask for noninvasive positive pressure ventilation.
Previous studies have shown that noninvasive positive pressure ventilation (NPPV) improves gas exchange in acute and chronic respiratory failure. However, some patients are unable to tolerate NPPV due to air leaks around the mask, facial discomfort, and claustrophobia. A new mask that covers the entire face (Total, Respironics, Monroeville, Pa), attempts to overcome these obstacles. We studied the efficacy of NPPV via the Total face mask (TFM) in nine patients with chronic respiratory failure. In three patients, respiratory failure was due to chronic obstructive lung disease, and in six patients, it was secondary to restrictive disorders. None of the patients were previously able to tolerate NPPV via nasal (N) or nasal-oral (NO) masks. At baseline, all patients had impaired gas exchange with low PaO2/FIO2 (241 +/- 14), elevated PaCO2 (79 +/- 5 mm Hg), and poor functional status (1.89 +/- 1.45, on a scale of 1 to 7). After NPPV in the hospital for 7.1 +/- 1.5 h per night for 22 +/- 26 days, the PaCO2 fell to 59 +/- 3 mm Hg, and the PaO2/FIO2 rose to 304 +/- 27. Following nocturnal NPPV via the TFM for 6.7 +/- 1.5 h a night 6 +/- 5 weeks after hospital discharge, sustained improvements in PaCO2 (58 +/- 3 mm Hg, p < 0.05), PaO2/FIO2 (304 +/- 18), and functional status (5.38 +/- 1.06, p < 0.05) were observed. In four patients, measurements of respiratory rate, tidal volume, minute ventilation, dyspnea, discomfort with the face mask, and mask and mouth leaks were made during 30-min sessions of NPPV applied at constant levels via all three masks (N, NO, TFM). Discomfort with the face mask (0.38 +/- 0.18 vs 1.44 +/- 0.34 vs 2.38 +/- 0.32, p < 0.05) and mask leaks (0.44 +/- 0.18 vs 1.89 +/- 0.39 vs 1.89 +/- 0.35, p < 0.05) were least during NPPV via TFM compared with the N or NO masks, respectively. Moreover, expired tidal volume was highest (804 +/- 10 vs 498 +/- 9 vs 537 +/- 13 ml, p < 0.05) and PaCO2 lowest (51 +/- 2 vs 57 +/- 2 vs 58 +/- 3, p < 0.05) during NPPV via the TFM compared with N or NO masks. We conclude that NPPV delivered via a Total mask ensures a comfortable, stable patient-mask interface and improves gas exchange in selected patients intolerant of more conventional N or NO masks.


Characterization and classification of zebrafish brain morphology mutants.
The mechanisms by which the vertebrate brain achieves its three-dimensional structure are clearly complex, requiring the functions of many genes. Using the zebrafish as a model, we have begun to define genes required for brain morphogenesis, including brain ventricle formation, by studying 16 mutants previously identified as having embryonic brain morphology defects. We report the phenotypic characterization of these mutants at several timepoints, using brain ventricle dye injection, imaging, and immunohistochemistry with neuronal markers. Most of these mutants display early phenotypes, affecting initial brain shaping, whereas others show later phenotypes, affecting brain ventricle expansion. In the early phenotype group, we further define four phenotypic classes and corresponding functions required for brain morphogenesis. Although we did not use known genotypes for this classification, basing it solely on phenotypes, many mutants with defects in functionally related genes clustered in a single class. In particular, Class 1 mutants show midline separation defects, corresponding to epithelial junction defects; Class 2 mutants show reduced brain ventricle size; Class 3 mutants show midbrain-hindbrain abnormalities, corresponding to basement membrane defects; and Class 4 mutants show absence of ventricle lumen inflation, corresponding to defective ion pumping. Later brain ventricle expansion requires the extracellular matrix, cardiovascular circulation, and transcription/splicing-dependent events. We suggest that these mutants define processes likely to be used during brain morphogenesis throughout the vertebrates. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.


[Study on the prevention of deep venous thrombosis in surgery].
In a survey of the use of methods for prevention of postoperative deep venous thrombosis (DVT) performed in French speaking Switzerland, a questionnaire was sent to 380 surgeons and 316 answers (83%) were received. Systematic prevention is performed by 75% of the surgeons; it is performed by 89% of orthopedic surgeons, 66% of abdominal surgeons and 76% of obstetricians. Low dose heparin is use dy 75% of general and orthopedic surgeons and by 50% of the obstetricians. 40% of the surgeons believe that preventive methods cause untoward side effects. Only 55% of orthopedic surgeons believe in the effectiveness of the prevention they are using. Prevention of DVT is more systematically carried on in Switzerland than in other Western countries, especially in high risk surgery. However, surgeons are aware of the imperfection of this prevention.


Treatment-emergent and trajectory-based peripheral gene expression markers of antidepressant response.
Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.


The Role of Home Gardens in Promoting Biodiversity and Food Security.
Plant genetic resources provide the basis for sustainable agricultural production, adaptation to climate change, and economic development. Many present crop plants are endangered due to extreme environmental conditions induced by climate change or due to the use of a limited selection of plant materials. Changing environmental conditions are a challenge for plant production and food security, emphasizing the urgent need for access to a wider range of plant genetic resources than what are utilized today, for breeding novel crop varieties capable of resilience and adaptation to climate change and other environmental challenges. Besides large-scale agricultural production, it is important to recognize that home gardens have been an integral component of family farming and local food systems for centuries. It is remarkable how home gardens have allowed the adaptation and domestication of plants to extreme or specific ecological conditions, thus contributing to the diversification of cultivated plants. Home gardens can help in reducing hunger and malnutrition and improve food security. In addition, they provide opportunities to broaden the base of cultivated plant materials by harboring underutilized crop plants and crop wild relative species. Crop wild relatives contain a wide range of genetic diversity not available in cultivated crops. Although the importance of home gardens in conserving plant genetic resources is well recognized, there is a risk that local genetic diversity will be lost if traditional plant materials are replaced by high-yielding modern cultivars. This paper provides an overview of home gardens and their present role and future potential in conserving and utilizing plant genetic resources and enhancing food and nutritional security under global challenges.


Somatic cell origin of teratocarcinomas.
Malignant teratocarcinomas arise from developmentally totipotent normal stem cells. Whether the targets are embryonal somatic cells or germinal cells has long been a matter of controversy. Past experiments on teratocarcinoma induction by ectopic grafting of early rodent embryos or fetal germinal ridges have remained ambiguous because embryos ordinarily soon form germ cells, and parthenogenetic germ cells form "embryos." In order to interrupt the developmental cycle at its most telling point, day 6 (egg-cylinder stage) mouse embryos of genetically sterile types were grafted; in such grafts, only a terminal residue of totipotent embryonal somatic ("ectoderm") cells is available, and subsequent germ cell development is severely impaired. One graft series, from S1(J)/+ matings, comprised 25% S1(J)/S1(J) presumptive sterile embryos; these grafts formed tumors containing embryonal carcinoma cells as often (47%) as did control +/+ grafts (41%) on the same genetic background. In another series, from W/+ matings, tumors of the sterile W/W genotype were individually identified by means of a closely linked marker, phosphoglucomutase (PGM, EC 184.108.40.206; Pgm-1 locus), coding for electrophoretic enzyme variants and incorporated into the stock. Four tumors were obtained (out of 16) that had the PGM-1D phenotype diagnostic for W/W, and that also contained embryonal carcinoma cells. Therefore, the malignancy arises here in susceptible somatic embryonal stem cells at the terminal stage of their capacity for totipotency. Other teratocarcinomas-whether induced or spontaneous-of ostensible germ-cell origin by parthenogenesis may also depend upon development of the same somatic target cells before neoplastic conversion can occur. A general model based on these experiments is proposed for all malignancies: Malignant transformation of a particular kind of normal stem cell may be possible only when that stem cell has progressed to the threshold of further differentiation.


Cardiogenic shock.
Despite advances in treatment, the mortality rate of patients who develop cardiogenic shock after an acute myocardial infarction remains unacceptably high. This article presents an overview of cardiogenic shock--incidence, epidemiology, predisposing factors, pathophysiology, and management, both medical and surgical.


Bacteriological study of amniotic fluid during labor.
Amniotic fluid from 207 women in labor was analysed at the time of artificial rupture of membranes or by amniocentesis. The following organisms were identified in concentrations of more than 1 000/ml: Staphylococcus aureus (1), Propionibacterium (1), E. coli (1), group B Streptococci (3), Lactobacilli (16). The 6 patient-carriers of pathogens became infected as did 4 of their babies. Leukocyte counts and LDH levels performed on amniotic fluid did not correlate with the appearance of symptoms of infection. Quantitative bacteriology of amniotic fluid seems to be of value in identifying patients at high risk of developing endometritis and/or neonatal sepsis.


Validation of manometric microrespirometers for measuring oxygen consumption in small arthropods.
Scientists have used numerous techniques to measure organismal metabolic rate, including assays of oxygen (O2) consumption and carbon dioxide (CO2) production. Relatively few studies have directly compared estimates of metabolic rate on the same groups of animals as determined by different assay methods. This study directly compared measures of the metabolic rate of three lines of Drosophila simulans as determined either from direct measures of CO2 production using infrared gas analysis (IRGA), or from estimates of O2 consumption based on manometeric techniques. Determinations of metabolic rate of the same cohorts of flies using these two methods produced results that often differed widely. Typically metabolic rate as determined by the manometric method was significantly greater than that determined by CO2 output. These differences are difficult to explain by simple biotic or abiotic factor(s). Because of the idiosyncratic nature of these differences it is not possible to use a simple factor to convert from metabolic rate measurements done using manometric techniques to those expected from direct measures of CO2 output or O2 consumption. Although manometric devices are simple to construct and use, measurements of metabolic rate made with this method can vary significantly from measurements made by directly assaying CO2 production or O2 consumption.


The sequence of the Saccharomyces cerevisiae gene PHO2 codes for a regulatory protein with unusual aminoacid composition.
A new centromere vector for the construction of a Saccharomyces cerevisiae gene library, allowing direct selection for DNA insert, will be described. From that library the gene for the regulatory protein PHO2 involved in PHO5 induction has been cloned by complementation of a pho2 mutation. The complementing activity was shown to be located on a 3.6 kb HindIII fragment. This fragment was used to evict the genomic copy and with appropriate genetic crosses we proved, that the cloned gene is PHO2. The DNA sequence of PHO2 was determined. Analysis of the sequence data uncovered striking homology regions with PHO4, another protein necessary for the induction of PHO5. The relevance of the observed homology will be discussed.


Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA).
R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.


Occupational exposure to metals and solvents and the risk of motor neuron disease. A case-control study.
Previous studies based on recalled occupational histories have implicated metal and solvent exposure in the etiology of motor neuron disease (MND). We have used death certificates held in pension fund archives and linked unbiased historical occupational records to investigate the effects of occupational exposure to metals or solvents on the risk of death from MND in 22 cases and 206 controls from 22,526 past employees of a major UK engineering company. We found no evidence of increased risk of death from MND in individuals who had worked with either metals (adjusted odds ratio=0.88, 95% CI 0.35-2.22) or solvents (odds ratio=1.12, 95% CI 0.45-2.78), and no relation between disease risk and either duration or intensity of exposure. We conclude that metal and solvent exposures are unlikely to be involved in the etiology of MND.


Assessment Of Preanalytical Blood Sampling Errors In Clinical Settings.
Blood sampling is one of the common procedures done in every ward for disease diagnosis and prognosis. Daily hundreds of samples are collected from different wards but lack of appropriate knowledge of blood sampling by paramedical staff and accidental errors make the samples inappropriate for testing. Thus the need to avoid these errors for better results still remains. We carried out this research with an aim to determine the common errors during blood sampling; find factors responsible and propose ways to reduce these errors. A cross sectional descriptive study was carried out at the Military and Combined Military Hospital Rawalpindi during February and March 2014. A Venous Blood Sampling questionnaire (VBSQ) was filled by the staff on voluntary basis in front of the researchers. The staff was briefed on the purpose of the survey before filling the questionnaire. Sample size was 228. Results were analysed using SPSS-21. When asked in the questionnaire, around 61.6% of the paramedical staff stated that they cleaned the vein by moving the alcohol swab from inward to outwards while 20.8% of the staff reported that they felt the vein after disinfection. On contrary to WHO guidelines, 89.6% identified that they had a habit of placing blood in the test tube by holding it in the other hand, which should actually be done after inserting it into the stand. Although 86% thought that they had ample knowledge regarding the blood sampling process but they didn't practice it properly. Pre analytical blood sampling errors are common in our setup. Eighty six percent participants though thought that they had adequate knowledge regarding blood sampling, but most of them were not adhering to standard protocols. There is a need of continued education and refresher courses.


Male germ cell expression of murine beta 4-galactosyltransferase. A 796-base pair genomic region, containing two cAMP-responsive element (CRE)-like elements, mediates male germ cell-specific expression in transgenic mice.
In murine somatic cells, transcription of the single gene encoding beta 4-galactosyltransferase results in two transcripts of 4.1 and 3.9 kilobases (kb), as a consequence of the use of two transcriptional start sites that are located on exon one separated by 200 base pairs (bp). In early male germ cell development, spermatogonia use only the 4.1-kb start site to yield a transcript that is identical to its somatic cell counterpart. As these cells enter meiosis, there is a switch from the use of this somatic cell start site to the exclusive use, beginning in pachytene spermatocytes, of a male germ cell-specific start site. Germ cell-specific transcripts are distinguished from their somatic counterparts by an additional approximately 560 nucleotides of 5'-untranslated sequence that is located immediately upstream and contiguous with the transcriptional start site defined for the 4.1-kb mRNA (Harduin-Lepers, A., Shaper, N.L., Mahoney, J.A., and Shaper, J.H. (1992) Glycobiology 2, 361-368). This observation predicts the use of a different upstream male germ cell-specific promoter. In this study we show that a 796-bp fragment containing 543 bp of genomic sequence upstream of the germ cell specific transcriptional start site and 253 bp of flanking downstream sequence, directs expression of the reporter gene, beta-galactosidase, exclusively to the pachytene spermatocytes and round spermatids of transgenic mice. This pattern of cell type-specific expression of the transgene is comparable with that of the endogenous beta 4-galactosyltransferase gene.


Campylobacteremia in stage IV gliosarcoma with bevacizumab treatment.
Primary campylobacter enteritis with secondary bacteremia was diagnosed in an immunocompromised patient with stage IV gliosarcoma. She developed mild diarrhea followed by systemic symptoms with transient generalized weakness and fever. She was treated with azithromycin and had a full recovery and without relapse through 2 months of follow-up. Her diagnosis was confirmed by a positive stool culture for Campylobacter sp. and blood culture for Campylobacter jejuni/coli.


Soluble angiogenesis factors in sera of Egyptian patients with hepatitis C virus infection: correlation with disease severity.
Hepatitis C virus (HCV) infection causes chronic hepatitis, which gradually progresses to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC). Angiogenesis plays a major role in chronic inflammation and may have prognostic value in disease progression. This study was designed to evaluate vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and tumor necrosis factor-alpha (TNF-alpha) as prognostic factors of disease progression in Egyptian patients with different stages of HCV-related cirrhosis and HCC. VEGF, PDGF, and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) in 82 HCV-infected patients (20 mild, 20 moderate, and 20 severe cirrhosis patients, and 22 HCC patients), and 20 healthy controls. Our results showed comparable increases in VEGF and PDGF levels in those with increasing clinical stages of disease, with maximal production seen in HCC patients. A gradual elevation of TNF-alpha levels was seen also in HCV-infected patients at different stages of disease and HCC. A statistically significantly positive correlation between serum levels of VEGF, PDGF, and TNF-alpha, and grade of disease was recorded. Thus assessment of these parameters in those with different stages of disease may be helpful in choosing the best treatment strategy, and indicate that anti-angiogenic therapy may be useful.


Model simulations of the adsorption of statherin to solid surfaces: Effects of surface charge and hydrophobicity.
The structural properties of the salivary protein statherin upon adsorption have been examined using a coarse-grained model and Monte Carlo simulation. A simple model system with focus on electrostatic interactions and short-ranged attractions among the uncharged amino acids has been used. To mimic hydrophobically modified surfaces, an extra short-ranged interaction was implemented between the amino acids and the surface. It has been shown that the adsorption and the thickness of the adsorbed layer are determined by (i) the affinity for the surface, i.e., denser layer with an extrashort-ranged potential, and (ii) the distribution of the charges along the chain. If all the amino acids have a high affinity for the surface, the protein adsorbs in a train conformation, if the surface is negatively charged the protein adsorbs in a tail-train conformation, whereas if the surface is positively charged the protein adsorbs in a loop conformation. The latter gives rise to a more confined adsorbed layer.


Use of CUSUM and Shewhart charts to monitor regional trends of birth defect reports in New York State.
Cumulative sum (CUSUM) charts were originally developed for industrial quality control, but may be adapted for the surveillance of health outcome data, such as birth defects. The reported prevalence of birth defects can vary due to differences in case ascertainment, surveillance practices, or true changes in prevalence. We examined the utility of CUSUM and Shewhart charts for detect-ing changes in prevalence of two different birth defect groups. We chose obstructive renal defects because we expected an increase in reporting due to improved diagnosis. We chose oral clefts for comparison because we expected reporting to be unaffected by changes in diagnostic technologies. Data from the New York State Congenital Malformations Registry from 1992-1999 were analyzed using self-starting binomial CUSUM and Shewhart charts for four regions of New York State. CUSUM charts show that reports of obstructive urinary defects have increased from 1992-1999 in all regions of New York State. Reports of oral clefts increased only on Long Island. The CUSUM method proved useful for identifying changes in birth defect reporting and was able to detect the expected increases in obstructive renal defects. The apparent increase is likely due to improvements in diagnostic imaging techniques. In contrast, we only detected an increase in oral clefts on Long Island, which may be related to under report-ing of cases in the earlier years. CUSUM charts are useful in detecting small, sustained increases in prevalences over time while Shewhart charts are easier to interpret and can detect large sharp increases.


"Missing Tooth" Multidomain Peptide Nanofibers for Delivery of Small Molecule Drugs.
The clinical administration of many small molecule hydrophobic drugs is challenged by the insolubility of these drugs under physiological conditions. Because of this, the development of biocompatible scaffolds capable of effectively delivering hydrophobic drug molecules is of particular interest. Multidomain peptides (MDPs) provide biocompatible hydrogel scaffolds that are injectable and space-conforming, allowing for in situ delivery of a variety of drugs. Here we demonstrate that through manipulation of peptide primary sequence, a molecular cavity can be incorporated into the hydrophobic core of these peptide nanofibers allowing for encapsulation and delivery of small molecule drugs with poor water solubility. Using SN-38, daunorubicin, diflunisal, etodolac, levofloxacin, and norfloxacin, we demonstrate drug encapsulation and release from multidomain peptide fibers. Steady-state fluorescence and drug release studies show that hydrogels loaded with SN-38, diflunisal, and etodolac exhibit prolonged drug release profiles due to intrafibrillar drug encapsulation. This study establishes multidomain peptides as promising carriers for localized in situ delivery of small molecule drugs with poor water solubility.


Distinguishing Signatures of Multipathway Conformational Transitions.
The folding and binding of biomolecules into functional conformations are thought to be commonly mediated by multiple pathways rather than a unique route. Yet even in experiments where one can "see" individual conformational transitions, their stochastic nature generally precludes one from determining whether the transitions occurred through one or multiple pathways. We establish model-free, observable signatures in the response of macromolecules to force that unambiguously identify multiple pathways-even when the pathways themselves cannot be resolved. The unified analytical description reveals that, through multiple pathways, the response of molecules to external forces can be shaped in diverse ways, resulting in a rich design space for a tailored biological function already at the single-molecule level.


Humans can navigate complex graph structures acquired during latent learning.
Humans appear to represent many forms of knowledge in associative networks whose nodes are multiply connected, including sensory, spatial, and semantic. Recent work has shown that explicitly augmenting artificial agents with such graph-structured representations endows them with more human-like capabilities of compositionality and transfer learning. An open question is how humans acquire these representations. Previously, it has been shown that humans can learn to navigate graph-structured conceptual spaces on the basis of direct experience with trajectories that intentionally draw the network contours (Schapiro, Kustner, & Turk-Browne, 2012; Schapiro, Turk-Browne, Botvinick, & Norman, 2016), or through direct experience with rewards that covary with the underlying associative distance (Wu, Schulz, Speekenbrink, Nelson, & Meder, 2018). Here, we provide initial evidence that this capability is more general, extending to learning to reason about shortest-path distances across a graph structure acquired across disjoint experiences with randomized edges of the graph - a form of latent learning. In other words, we show that humans can infer graph structures, assembling them from disordered experiences. We further show that the degree to which individuals learn to reason correctly and with reference to the structure of the graph corresponds to their propensity, in a separate task, to use model-based reinforcement learning to achieve rewards. This connection suggests that the correct acquisition of graph-structured relationships is a central ability underlying forward planning and reasoning, and may be a core computation across the many domains in which graph-based reasoning is advantageous.


Cellular effects of industrial metal nanoparticles and hydrophilic carbon black dispersion.
The effects of five types of metal nanoparticles, gold (Au), silver (Ag), platinum (Pt), Au-polyvinylpyrrolidone (PVP) colloid, and Pt-PVP colloid, and two types of hydrophilic carbon black on cell behavior were examined. Stable nanoparticle dispersions were prepared and applied to the culture medium of human keratinocyte (HaCaT) and human lung carcinoma (A549) cells for 6 and 24 hr. Then, the mitochondrial activity (MTT assay) and the induction of cellular oxidative stress were examined. The exposure to Au and Ag decreased mitochondrial activity. The exposure to Pt nanoparticles induced an increase in the intracellular reactive oxygen species (ROS) level. In contrast, Au-PVP, Pt-PVP, and hydrophilic carbon black did not exhibit any effects. The observed increase in the ROS level induced by the Pt nanoparticles in this study contradicted our previous findings, in which Pt did not produce chemically reactive molecules. Some nanoparticle dispersions included chemicals as the dispersant, which is used in industrial applications. In some cases, the dispersing agent may have caused some cellular effects. Adsorption of agents on the surface of the nanoparticles may be an important factor here. Hence, the cellular effects of industrial nanoparticles should be evaluated carefully.


Three-Component Synthesis of Isoquinoline Derivatives by a Relay Catalysis with a Single Rhodium(III) Catalyst.
A rhodium(III)-catalyzed one-pot three-component reaction of N-methoxybenzamide, α-diazoester, and alkyne was developed, providing an alternative way to synthesize isoquinoline derivatives. Mechanistically, it is a relay catalysis, and the reaction occurred via successive O-alkylation and C-H activation processes, both of which were promoted by the same catalyst.


ESTIMATION OF GENE FLOW FROM F-STATISTICS.
We present theory clarifying the general behavior of FST -based and GST -based estimators of gene flow, and confirm these predictions with simulations. In particular, we use the correlation of genes within groups within populations to define an estimator. The theoretical value of the correlation doe not depend on the number of groups in a population, and properties of the estimated correlation do not depend on the number of groups sampled or the number of individuals sampled per group. This invariance is in contrast to properties of GST . For a complete census of a population, bias and variance considerations would suggest the use of the GST -based estimator of gene flow, but lack of knowledge of population size or group number in practice suggests preference be given to the correlation-based estimator. We acknowledge that these estimators require that several conditions of a population-genetic model be met, since they do not make use of direct observations on the flow of genes. Our results differ from some of those based on simulation in a series of recent papers by M. Slatkin.


Ovarian activity and reproductive performance of dairy cows fed different amounts of phosphorus.
Fifty-four multiparous Holsteins were utilized to determine the effect of dietary P on ovarian activity and reproductive performance. Cows were assigned at calving to diets containing 0.35 or 0.47% P. Ovarian activity was monitored 3 times weekly by ultrasonography, beginning 10 d after parturition until the end of a 60-d voluntary waiting period. After this period, cows were synchronized and bred using the Ovsynch protocol. During wk 2 of lactation, the number of small (3 to 5 mm in diameter) and large (>9 mm) follicles was similar between groups, but the number of medium (6 to 9 mm) follicles was lower for 0.35% P than for 0.47% P (1.2 vs. 1.9). Dietary P did not affect the number of days to first postpartum ovulation or the diameter of dominant and ovulating follicles. The multiple ovulation rate and the proportion of cows that were anovulatory or developed follicular cysts did not differ between groups. Dietary P amount did not influence corpus luteum development or blood progesterone concentration during the voluntary waiting period. The first service conception rate and pregnancy loss from 30 to 60 d after breeding were not affected. The overall pregnancy rate during the first 200 d of lactation (60.9 and 60.0%) and the number of services per pregnancy (2.1 and 1.9) did not differ between groups. Serum inorganic P was elevated from 6 to 7 mg/dL during the first 3 mo postpartum as dietary P was increased. Fecal P content measured during the first 16 wk of lactation averaged 0.63 and 0.89%, 29% lower for the 0.35% P group. Mean milk yield during the first 40 wk of lactation did not differ, averaging 40.5 and 39.0 kg/d for the 0.35 and 0.47% P groups, respectively. Overall, varying dietary P from 0.35 to 0.47% did not affect postpartum ovarian activity, reproductive performance, or milk production.


Prefrontal acetylcholine release controls cue detection on multiple timescales.
Cholinergic neurons originating from the basal forebrain innervate the entire cortical mantle. Choline-sensitive microelectrodes were used to measure the synaptic release of cortical acetylcholine (ACh) at a subsecond resolution in rats performing a task involving the detection of cues. Cues that were detected, defined behaviorally, evoked transient increases in cholinergic activity (at the scale of seconds) in the medial prefrontal cortex (mPFC), but not in a nonassociational control region (motor cortex). In trials involving missed cues, cholinergic transients were not observed. Cholinergic deafferentation of the mPFC, but not motor cortex, impaired cue detection. Furthermore, decreases and increases in precue cholinergic activity predicted subsequent cue detection or misses, respectively. Finally, cue-evoked cholinergic transients were superimposed over slower (at the timescale of minutes) changes in cholinergic activity. Cortical cholinergic neurotransmission is regulated on multiple timescales to mediate the detection of behaviorally significant cues and to support cognitive performance.


Household economic strategies and nutritional anthropometry of women in American Samoa and highland Bolivia.
This study compares findings from research projects involving different genetic, environmental, and cultural contexts: a study of lifestyle and health from American Samoa (ASLS) and the Bolivian project. Reproduction and Ecology in Provincia Aroma (REPA). This paper presents analyses of varying economic strategies and their association with nutritional status indicators in each population. The ASLS sample includes 66 Samoan women and the REPA sample includes 210 Aymara women. Principle components analysis of household economic resources within each sample extracted two significant factors: one represents modernizing influences including education and occupational status, and the other represents ethnographically salient traditional economic behavior. The traditional pattern includes adding household members in Samoa and selling agricultural products in Bolivia. This analysis places each woman along two continua, traditional and modern, based on her household mobilization of economic resources, permitting an understanding of the patterns underlying household economic behavior that is not possible in univariate analyses of socioeconomic variables. For the Bolivian women the strategy involving more education and higher occupational status was associated with higher measures of several nutritional status indicators, including body mass index, arm muscle area, and peripheral skinfolds. But among the Samoan women, where substantial obesity was the norm, there were no significant differences in anthropometric measurements based on economic strategies. These data argue for the importance of directly measuring the potential consequences of variation in household economic strategies rather than merely inferring such, and of assessing ethnographically relevant aspects of household economic production rather than limiting analyses to non-context-specific economic indicators such as income. This focus on household strategy is likely to be fruitful especially where economic and nutritional conditions are marginal. The findings from Bolivia also support efforts in developing countries to improve girls' education, and thereby occupational prospects, as a means to improve their health status as women.


Engagement with fact-checked posts on Reddit.
Contested factual claims shared online are of increasing interest to scholars and the public. Characterizing temporal patterns of sharing and engagement with such information, as well as the effect of sharing associated fact-checks, can help us understand the online political news environment more fully. Here, we investigate differential engagement with fact-checked posts shared online via Reddit from 2016 to 2018. The data comprise ∼29,000 conversations, ∼849,000 users, and ∼9.8 million comments. We classified the veracity of the posts being discussed as true, mixed, or false using three fact-checking organizations. Regardless of veracity, fact-checked posts had larger and longer lasting conversations than claims that were not fact-checked. Among those that were fact-checked, posts rated as false were discussed less and for shorter periods of time than claims that were rated as true. We also observe that fact-checks of posts rated as false tend to happen more quickly than fact-checks of posts rated as true. Finally, we observe that thread deletion and removal are systematically related to the presence of a fact-check and the veracity of the fact-check, but when deletion and removal are combined the differences are minimal. Theoretical and practical implications of the findings are discussed.


DNA microarray stochastic model.
A stochastic model of the DNA microarray image pixels is presented. The model includes spot pixel intensity distribution, interpixel correlations and the intensity distribution of background noise. The data is indicative of a small exponential additive noise process and a larger Gaussian fluctuation that scales with spot intensity. Correlations are observed among pixels in the spot and between test and control images. The correlated fluctuations may be attributed to variations across each spot in the amount of DNA placed on the spot during the array fabrication process. The model may be used in gene expression estimation algorithm development, both to test new algorithms through simulation and to develop optimum algorithms. The model should also be easily adapted to new array based technologies in proteomics.


Bioinspired mechano-photonic artificial synapse based on graphene/MoS2 heterostructure.
Developing multifunctional and diversified artificial neural systems to integrate multimodal plasticity, memory, and supervised learning functions is an important task toward the emulation of neuromorphic computation. Here, we present a bioinspired mechano-photonic artificial synapse with synergistic mechanical and optical plasticity. The artificial synapse is composed of an optoelectronic transistor based on graphene/MoS2 heterostructure and an integrated triboelectric nanogenerator. By controlling the charge transfer/exchange in the heterostructure with triboelectric potential, the optoelectronic synaptic behaviors can be readily modulated, including postsynaptic photocurrents, persistent photoconductivity, and photosensitivity. The photonic synaptic plasticity is elaborately investigated under the synergistic effect of mechanical displacement and the light pulses embodying different spatiotemporal information. Furthermore, artificial neural networks are simulated to demonstrate the improved image recognition accuracy up to 92% assisted with mechanical plasticization. The mechano-photonic artificial synapse is highly promising for implementing mixed-modal interaction, emulating complex biological nervous system, and promoting the development of interactive artificial intelligence.


Aquaporin-dependent water permeation at the mouse ocular surface: in vivo microfluorimetric measurements in cornea and conjunctiva.
Fluorescence methods were developed to quantify membrane and tissue water permeabilities at the ocular surface and to compare water transport in wild-type mice versus transgenic mice lacking each of the water channels, aquaporin (AQP)-1, -3, and -5, normally expressed in cornea or conjunctiva. Membrane water permeabilities (P(f)(mem)) of calcein-stained surface epithelial cells were measured from the kinetics of fluorescence quenching in response to rapid (<0.2 seconds) changes in extraocular fluid osmolarity. Tissue water permeabilities (P(f)(tiss)) across intact cornea and conjunctiva--the relevant parameters describing water movement into the hyperosmolar tear film in vivo--were determined by a dye-dilution method from the fluorescence of Texas red-dextran in an anisosmolar solution in a microchamber at the ocular surface. Osmotic equilibration occurred with an exponential time constant (tau) of 1.3 +/- 0.2 seconds (P(f)(mem) = 0.045 cm/s) in calcein-loaded corneal epithelial cells of wild-type mice, slowing 2.1 +/- 0.4-fold in AQP5-deficient mice; tau was 2.4 +/- 0.1 seconds in conjunctiva (P(f)(mem) = 0.025 cm/s), slowing 3.6 +/- 0.7-fold in AQP3-deficient mice. In dye-dilution experiments, P(f)(tiss) of cornea was 0.0017 cm/s and decreased by greater than fivefold in AQP5-deficient mice. P(f)(tiss) in AQP5-null mice was restored to 0.0015 cm/s after removal of the epithelium. P(f)(tiss) of conjunctiva was 0.0011 cm/s and was not sensitive to AQP3 deletion. These results define for the first time the water-transporting properties of the two principal ocular surface barriers in vivo. The permeability data were incorporated into a mathematical model of tear film osmolarity, providing insights into the pathophysiology of dry eye disorders.


Tracking change in dysphonia: a case study.
This longitudinal case study of a woman with nodules examines the relationship between clinical and acoustic measures of change. Relative changes in voice quality, vocal fold condition, and patient symptoms were compared to measures of mean fundamental frequency (MFF), jitter, and fundamental frequency range (FFR). Seven assessments were performed over a 2-year period. The findings indicated that voice quality judgments tended to relate to changes in degree of vocal fold pathology and patient report of vocal function. However, acoustic measures of MFF, FFR, and jitter did not relate to measures of clinical change. The discussion focuses on explanations for the acoustic findings, the need for using connected speech samples for perceptual and acoustic analysis, and a suggestion for future study.


["Six-step strategy" for effective compounds in Chinese medicinal prescriptions based on in vitro-in vivo integration and its application in research on component-based Chinese medicine].
The discovery and identification of effective components are pivotal in the research on Chinese medicinal prescriptions. Given two basic conditions for effective components in Chinese medicinal prescriptions, i.e., active structure and a certain level of drug exposure in the body(including the intestine), a "six-step strategy" for the effective compounds in Chinese medicinal prescriptions based on in vitro-in vivo integration(SSS for short) has been proposed and established, as well as the key technologies. SSS contains qualitative and quantitative analyses of components in five steps, including those in Chinese medicinal extract, intestinal contents, portal vein blood, liver, and peripheral blood. The components(prototype components and metabolites) with a certain exposure level(including in the intestine) and those with large differences between in vitro content and in vivo exposure or in exposure among various parts in the body are selected as the minority prioritized candidates. The sixth step is to screen the pharmacological activity of candidate components specifically extracted from Chinese medicinal materials or artificially synthesized. SSS can significantly narrow the screening range, enhance the hit rate, and speed up the identification of effective components specifically targeting indications. Based on the effective components identified by the SSS, the "upstream" can be linked(mechanism research based on the effective components with clear structures) and the "downstream" can be combined(development of innovative component-based Chinese medicine with definite pharmacodynamic composition). In this study, the concept of component-based Chinese medicine and specific applications of SSS in the development of component-based Chinese medicine are also introduced.


Use of chitosan in compressed tablets of diclofenac sodium: inhibition of drug release in an acidic environment.
The purpose of this study was to evaluate the potential utility of chitosan (I) in inhibiting diclofenac sodium (II) release in the gastric environment from a directly compressible tablet formulation. I, subjected to depolymerization to improve its microcrystallinity and subsequent compressibility, was then used to prepare tablets of II. A full-factorial design was employed to evaluate the effects of degree of N-deacetylation of I, and the pH and ionic strengths, mu, of the dissolution media on drug release. Directly compressible tablets were prepared from admixtures of 25 mg of II, 174 mg of I of various degrees of N-deacetylation (74, 87, and 92%), and 1 mg of magnesium stearate. The in vitro dissolution studies were performed using aqueous buffers (pHs 1.2, 3.8, and 6.8, and mu of approximately 1.0 and 0.1). The slopes of logarithmically transformed cumulative percent released-time curves (from t = 0 to t = 5 hr) were compared. Analyses of variance performed using SAS indicated that the degree of N-deacetylation of chitosan significantly affected drug release at pHs 1.2 and 6.8 (p < 0.0001). An increase in the pH of the dissolution medium resulted in an increase in drug release (p < 0.0001). The ionic strength of the dissolution medium did not significantly affect drug release at any of the pHs studied (p > 0.198). Besides the poor aqueous solubility of II, the two factors possibly affecting the drug release in the acidic environment were (a) the formation of a rate-limiting chitosan gel barrier; and (b) the ionic interaction of II with ionized amino groups of I.


Do postmenopausal women with thickened endometrium on trans-vaginal ultrasound in the absence of vaginal bleeding need hysteroscopic assessment? A Pilot Study.
We aimed to determine the incidence of endometrial cancer in a cohort of postmenopausal women with thickened endometrium but no bleeding referred for hysteroscopy and determine the risk estimate of cancer using a cut-off of > 11 mm. This retrospective study of asymptomatic postmenopausal women with thickened endometrium on trans-vaginal scan referred for hysteroscopy was performed using data from 2008 to 2010. In total 63 women were identified. 2 cases of endometrial cancer were identified with an incidence of 3.17%. 22 cases had endometrial thickness (ET) > 11 mm of which 2 were malignant giving a risk estimate for endometrial cancer of 9.1%. 61 women had benign pathology, 40.98% had atrophic endometrium and 59.02% had benign polyp. In conclusion, the incidence of endometrial cancer in postmenopausal women with thickened endometrium on transvaginal scan without vaginal bleeding is low and ET of 11 mm or more seems realistic to use as a cut-off for referral for hysteroscopy.


The effect of selective brain cooling on intracerebral temperature during craniotomy.
In this study we investigated the effect of topical application of cool irrigation fluid on brain tissue temperature during craniotomy. Eight patients were given a standard general anaesthetic for craniotomy. Distal oesophageal and nasopharyngeal temperatures were measured continuously and systemic normothermia was maintained. A sterile needle temperature probe was inserted 18 mm into the cerebrum to measure brain temperature. Brain temperatures were recorded for five minutes while the brain was irrigated with 1000 ml of normal saline at a temperature of 30 degrees C. Measurement continued until the brain temperature returned to baseline. The mean maximum decrease in cerebralparenchymal temperaturefollowing irrigation was 1.6 +/- 0.5 degrees C (P<0.01). The average time to return to baseline temperature after cessation of irrigation was 5.3 +/- 1.5 minutes. Cooling the brain has a marked protective effect after brain injury, but systemic hypothermia can produce significant harmful effects. This study demonstrates that the use of cool irrigation fluid during neurosurgery is a simple and effective method of cooling the brain whilst minimizing the use of systemic hypothermia.


Systematic review and meta-analysis identify significant relationships between clinical anxiety and lower urinary tract symptoms.
Lower urinary tract symptoms (LUTS), such as voiding symptoms, overactive bladder, and interstitial cystitis, and anxiety disorders are often comorbid conditions in patients. However, the existing evidence regarding the rates and nature of the co-occurrence of these conditions has not been systematically evaluated. The aim of this study was to examine these relationships. We conducted a systematic review and meta-analysis to examine the relationship between LUTS and anxiety. We searched for articles published from January 1990 to July 2019 in PubMed, CENTRAL, PsycINFO, and Google Scholar. Outcomes were anxiety-related disorders and symptoms (clinically significant anxiety) and LUTS. We performed random-effects meta-analyses, inspected funnel plots, and applied the Egger's test to evaluate publication bias. We followed PRISMA guidelines and recorded our protocol on PROSPERO (ID = CRD42019118607). We identified 814 articles, of which 94 fulfilled inclusion criteria, and 23 had sufficient data for meta-analysis. The odds ratio (OR) for clinically significant anxiety among individuals with LUTS was 2.87 (95% CI: 2.38,3.46, p < .001). The OR for LUTS among individuals with clinically significant anxiety was 2.87 (95% CI: 1.07,7.74, p < .001), although very few studies examined this relationship. A large value of I2 index suggests high heterogeneity between studies. The results demonstrate a significant association between clinically significant anxiety and LUTS in both females and males. There were limited studies on younger individuals and on individuals ascertained for clinically significant anxiety, which should motivate further study in these areas. Understanding the co-occurrence of these conditions will lead to better prevention and interventions to ameliorate the progression of the symptoms and improve the quality of life. A thorough assessment of anxiety may provide more optimal care for LUTS patients.


2,5-Dimethylphenacyl carbamate: a photoremovable protecting group for amines and amino acids.
2,5-Dimethylphenacyl (DMP) carbamates (1a-c) released the corresponding free amines or amino acids in high chemical yields, albeit with quantum yields Phi of only 0.04-0.09, upon irradiation in either aprotic or protic solvents. The photoreaction proceeded principally from the triplet excited state via the E-photoenol. The lifetimes of the triplet enol and the E- and Z-enols in the ground state were determined by laser flash photolysis. The primary photoinitiated transformation liberated a carbamic acid derivative, which subsequently decarboxylated to the amino group-containing compound. Exhaustive irradiation of a DMP-protected aniline (1a) in acetonitrile did not provide aniline in quantitative chemical yields, because it was involved in reductive cleavage of the starting material as an electron donor, thereby decreasing the overall deprotection yield (86%). Phenylalanine methyl ester, liberated from 1c, was, however, obtained in excellent chemical yield (97%). It was also found that the carbamates, while thermally stable, released amines with higher quantum yields in acidic methanol solutions. The DMP chromophore is proposed as an excellent photoremovable protecting group for amino acids and, under specific conditions, for amines in organic synthesis and biochemistry.


Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments.
Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.


Transcriptional activation of heat-shock genes in eukaryotes.
Prokaryotes and eukaryotes respond to thermal or various chemical stresses by the rapid induction of a group of genes collectively referred to as the heat shock genes. In eucaryotes, the expression of these genes is primarily regulated at the transcriptional level. The early observations that transfected heat shock genes were inducible in heterologous systems suggested the existence of common regulatory elements in these ubiquitous genes. Sequence analysis of cloned Drosophila heat shock genes revealed a conserved 14 base pair (bp) inverted repeat, which is essential for heat induction. This regulatory sequence, referred to as the heat shock element (HSE), is found in multiple imperfect copies upstream of the TATA box of all heat shock genes. While studies in heterologous systems indicated that a single copy of HSE was sufficient for inducibility, further analysis in homologous assays suggests that multiple HSE can act in a cooperative way and that the efficiency of transcriptional activation is related, within limits, to the number of HSE. Comparative analysis of heat shock genes reveals that HSE can be positioned at different distances from the TATA box in either orientation, a behavior reminiscent of enhancer elements. However, the presence of HSE does not necessarily confer heat inducibility, as shown by their presence in the constitutively expressed but non-heat-inducible homologous cognate genes. Footprinting and nuclease mapping have been used to show that a protein factor (HSTF: heat shock transcription factor) binds to the HSE element, activating heat shock gene transcription in a dose-dependent manner. The recent progress in the isolation and characterization of HSTF in Drosophila, yeast, and human cells is reviewed. Finally, different models suggested to account for the positive regulation of heat shock genes by the HSTF are presented.


Production of interferon in mixed leukocyte cultures from two individuals.
No detectable interferon (IFN) was produced when purified leukocytes from individual blood donors were incubated without induction at 10(7) cells/ml at 37 degrees C. Mixing the leukocytes from two donors resulted in the production of IFN that was predominantly IFN-gamma but contained also some IFN-alpha/beta. The titers varied greatly depending on the combination of the two individuals. The amount of IFN produced did not bear a clear correlation to the HLA A, B, or DQ antigenic differences between the two individuals. A difference in one or two DR alleles was not always a sufficient stimulus for abundant IFN production, but more numerous antigenic DR differences tended to increase the IFN response.


Induction of CD8+ CTL recognizing mycobacterial peptides.
Mycobacterium tuberculosis is the single, most important cause of morbidity attributable to a single infectious organism. CD8+ T cells play an important role in anti-tuberculous immune responses in both mice and humans. Data concerning the identity of mycobacterial antigens recognized by CD8+ T cells is limited; consequently, few CTL epitopes have been characterized. The authors identified allele-specific (H-2b and d) MHC class I binding motifs in six prominent M. tuberculosis protein antigens (the 19 and 38 kDa lipoglycoproteins and the 10, 16, 65 and 70 kDa stress proteins). These predicted epitopes were tested for MHC binding as well as their ability to elicit peptide-specific CTL following in vivo priming. The authors were able to identify eight previously undescribed mycobacterial CTL epitopes by using spleen cells from peptide-immunized mice. In addition, CTL specific for at least one of these epitopes also recognized the naturally processed epitope presented on transfected EL4 target cells. These mycobacteria-derived CTL epitopes could be important for future analysis of the involvement of CD8+ T cells in M. tuberculosis infection, pathogenesis and vaccine development.


Is the Protein-Mediated Uptake of Drugs by Organic Anion Transporting Polypeptides a Real Phenomenon or an Artifact?
Plasma proteins or human serum albumin (HSA) have been reported to increase the in vitro intrinsic uptake clearance (CLint,uptake) of drugs by hepatocytes or organic anion transporting polypeptide (OATP)-transfected cell lines. This so-called protein-mediated uptake effect (PMUE) is thought to be due to an interaction between the drug-protein complex and the cell membrane causing an increase in the unbound drug concentration at the cell surface, resulting in an increase in the apparent CLint,uptake of the drug. To determine if the PMUE on OATP-mediated drug uptake is an artifact or a real phenomenon, we determined the effect of 1%, 2%, and 5% HSA on OATP1B1-mediated [human embryonic kidney (HEK)293 transfected cells] and passive CLint,uptake (mock HEK293 cells) on a cocktail of five statins. In addition, we determined the non-specific binding (NSB) of the statin-HSA complex to the cells/labware. The increase in uptake of atorvastatin, fluvastatin, and rosuvastatin in the presence of HSA was completely explained by the extent of NSB of the statin-HSA complex, indicating that the PMUE for these statins is an artifact. In contrast, this was not the case for OATP1B1-mediated uptake of pitavastatin and passive uptake of cerivastatin, suggesting that the PMUE is a real phenomenon for these drugs. Additionally, the PMUE on OATP1B1-mediated uptake of pitavastatin was confirmed by a decrease in its unbound IC50 in the presence of 5% HSA versus Hank's balanced salt solution buffer (HBSS). These data question the utility of routinely including plasma proteins or HSA in uptake experiments and the previous findings on PMUE on OATP-mediated drug uptake. SIGNIFICANCE STATEMENT: Here we report, for the first time, that the protein-mediated uptake effect (PMUE) on organic anion transporting polypeptide (OATP)-transported drugs could be an artifact of the non-specific binding (NSB) of the drug-albumin complex to cells/labware. Future experiments on PMUE must take into consideration such NSB. In addition, mechanisms other than PMUE need to be explored to explain the underprediction of in vivo OATP-mediated hepatic drug clearance from in vitro uptake studies.


Miz1 is required for early embryonic development during gastrulation.
Miz1 is a member of the POZ domain/zinc finger transcription factor family. In vivo, Miz1 forms a complex with the Myc oncoprotein and recruits Myc to core promoter elements. Myc represses transcription through Miz1 binding sites. We now show that the Miz1 gene is ubiquitously expressed during mouse embryogenesis. In order to elucidate the physiological function of Miz1, we have deleted the mouse Miz1 gene by homologous recombination. Miz1(+/-) mice are indistinguishable from wild-type animals; in contrast, Miz1(-/-) embryos are not viable. They are severely retarded in early embryonic development and do not undergo normal gastrulation. Expression of Goosecoid and Brachyury is detectable in Miz1(-/-) embryos, suggesting that Miz1 is not required for signal transduction by Nodal. Expression of p21Cip1, a target gene of Miz1 is unaltered; in contrast, expression of p57Kip2, another target gene of Miz1 is absent in Miz1(-/-) embryos. Miz1(-/-) embryos succumb to massive apoptosis of ectodermal cells around day 7.5 of embryonic development. Our results show that Miz1 is required for early embryonic development during gastrulation.


Magnetic-field dependence of tunnel couplings in carbon nanotube quantum dots.
By means of sequential and cotunneling spectroscopy, we study the tunnel couplings between metallic leads and individual levels in a carbon nanotube quantum dot. The levels are ordered in shells consisting of two doublets with strong- and weak-tunnel couplings, leading to gate-dependent level renormalization. By comparison to a one- and two-shell model, this is shown to be a consequence of disorder-induced valley mixing in the nanotube. Moreover, a parallel magnetic field is shown to reduce this mixing and thus suppress the effects of tunnel renormalization.


Human processes of control: tracing the goals and strategies of control room teams.
This study utilized a process tracing methodology to analyse the goals and strategies of control room teams in dealing with an unpredicted plant disturbance. The human processes of control used by operators and their supervisors, and interactions between them, were analysed during phases of detection, diagnosis, and control of a small plant leak. Five control room teams were videotaped tackling this simulated scenario on a full-scale simulator. The results found substantial differences both within and between teams in how the goals of monitoring and implementing procedures during the detection phase, and problem-solving and plant control during the diagnosis phase were achieved. The temporal patterning of the activities associated with these goals revealed that the teams used different strategies. The training implications of these findings are discussed, in particular with respect to the control room supervisor who had a pivotal role.


Cooperating attackers in neural cryptography.
A successful attack strategy in neural cryptography is presented. The neural cryptosystem, based on synchronization of neural networks by mutual learning, has been recently shown to be secure under different attack strategies. The success of the advanced attacker presented here, called the "majority-flipping attacker," does not decay with the parameters of the model. This attacker's outstanding success is due to its using a group of attackers which cooperate throughout the synchronization process, unlike any other attack strategy known. An analytical description of this attack is also presented, and fits the results of simulations.


Substitution of critical isoleucines in the KH domains of Drosophila fragile X protein results in partial loss-of-function phenotypes.
Fragile X mental retardation proteins (FMRP) are RNA-binding proteins that interact with a subset of cellular RNAs. Several RNA-binding domains have been identified in FMRP, but the contribution of these individual domains to FMRP function in an animal model is not well understood. In this study, we have generated flies with point mutations in the KH domains of the Drosophila melanogaster fragile X gene (dfmr1) in the context of a genomic rescue fragment. The substitutions of conserved isoleucine residues within the KH domains with asparagine are thought to impair binding of RNA substrates and perhaps the ability of FMRP to assemble into mRNP complexes. The mutants were analyzed for defects in development and behavior that are associated with deletion null alleles of dfmr1. We find that these KH domain mutations result in partial loss of function or no significant loss of function for the phenotypes assayed. The phenotypes resulting from these KH domain mutants imply that the capacities of the mutant proteins to bind RNA and form functional mRNP complexes are not wholly disrupted and are consistent with biochemical models suggesting that RNA-binding domains of FMRP can function independently.


Synergistic interaction between total glucosides and total flavonoids on chronic constriction injury induced neuropathic pain in rats.
Shaoyao Gancao Decoction (SGD), a famous herbal medicine, consists of two herbs (Paeoniae Radix and Glycyrrhizae Radix) and is traditionally used for the treatment of pain. To investigate the synergistic potential of total glucosides of Paeoniae Radix (TGP) and total flavonoids of Glycyrrhizae Radix (TFL). Oral administration of TGP and TFL alone at the doses of 60,120 and 240 mg/kg or in combination were given only one time to the neuropathic pain rat induced by chronic constriction injury. Paw pressure and heat immersion tests were performed to assess degrees of mechanical allodynia and thermal hyperalgesia, respectively. Synergistic interactions between TGP and TFL were characterized using isobolographic analysis. Expressions of Sirt1 protein were detected by immunohistochemistry. On day 14 after surgery, single oral administration of TGP and TFL both produced significant anti-allodynic and anti-hyperalgesic effects in dose-dependent and time-dependent manners. The ED(50) value of TGP was 249.4 ± 10.8 mg/kg while TFL was 871.4 ± 30.5 mg/kg. Isobolographic analysis revealed that the combination of TGP with TFL at the fixed ratios of 3:1 exerted the highest sub-additive (synergistic) interaction, of which the experimental ED(50) value was 95.1 ± 9.0 mg/kg. SGD could also downregulate Sirt1 protein expression, which was 4.2-fold higher than that of model rats in dorsal root ganglion. Analgesic effects of SGD may contribute to simultaneous inhibition of Sirt1 overexpression and could warrant further evaluation as a possible agent for the treatment of neuropathic pain.


Ontogeny and localization of an oncostatin M-like protein in the rat testis: its possible role at the start of spermatogenesis.
Oncostatin M (OSM), a member of the interleukin 6 family of cytokines, was found to be highly expressed in the late fetal and early neonatal rat testis, as well as in the maturing and adult testis. Two different forms of OSM were observed, one of M(r) 22,000 and the other of M(r) 36,000. In the prepubertal rat testis [19 days post coitum, 8 days post partum (dpp), and 15 dpp], the form with the higher molecular weight prevailed, whereas in the maturing testis (30 dpp, 45 dpp, and 12 weeks post partum), a shift toward the lower molecular weight form was observed, as well as a decrease in its relative amount. By immunohistochemistry on testicular sections, OSM-specific immunostaining was observed in the interstitial tissue at every age studied. In contrast, OSM immunoreaction was localized in the Sertoli cells exclusively around the start of spermatogenesis, being strongest at 3 dpp. In vitro studies revealed that neonatal Sertoli cells produce OSM. The possible role of OSM at the start of spermatogenesis was investigated by using a coculture of Sertoli cells and gonocytes isolated from newborn rats. OSM significantly increased the survival of both Sertoli cells and gonocytes in a dose-dependent manner. The proliferative activity of the Sertoli cells was not affected by OSM, whereas that of gonocytes was increased by almost 60% after 6 days of culture. Comparison of the effect of OSM on these cocultures with other members of the interleukin 6 family of cytokines demonstrated that this factor is more potent than leukemia inhibitory factor or ciliary neurotrophic factor. On the basis of these findings, it can be concluded that OSM is present in the rat testis, and it is likely to play an important role at the start of spermatogenesis.


Functional maturation of the neuroendocrine system in the perinatal period: studies of the somatotropic axis in the ovine fetus.
Studies of the maturation of hypothalamic control of adenohypophyseal hormone secretion are reviewed with particular reference to the somato-tropic axis in the ovine fetus. In the ovine fetus, circulating growth hormone concentrations are 20-fold higher than postnatal concentrations falling in the 72 h prior to delivery. These high fetal growth hormone concentrations are postulated to reflect an immaturity of hypothalamic control mechanisms. Synthetic human growth hormone releasing factor (10 micrograms/kg) markedly stimulates fetal circulating growth hormone release between 77 and 135 days of gestation. The response decreases with advancing maturation. Thus fetal growth hormone release is not under maximal stimulation. Fetal growth hormone, thyrotropin and gonadotropin release is pulsatile in nature and the growth hormone and thyrotropin pulses have exaggerated amplitudes compared to the postnatal pattern. It is suggested that in each case, this enhanced pulsatility is a consequence of immature feedback loops. Stereotaxic lesioning of the fetal median eminence at 110 days of gestation abolishes the pulsatility of fetal growth hormone release. However the basal secretion of growth release remains elevated in some fetuses compared to postnatal growth hormone concentrations. The basis for this high basal rate of secretion is speculative but it is postulated to reflect immaturity of inhibitory control mechanisms, in particular of the negative feedback loop. Neuropharmacological studies of circulating growth hormone release in the perinatal period are reviewed. These demonstrate that the potential for many neurotransmitters to influence fetal circulating growth hormone release has differentiated by midgestation. However antagonist studies have not demonstrated a tonic role for any stimulatory neurotransmitters, only for the inhibitory neurotransmitter, GABA. Growth hormone does not exert a major influence upon fetal growth. Studies of the ontogeny of growth hormone receptors in the ovine liver show that somatotropic receptors are first detected in the newborn lamb suggesting receptor immaturity as the basis for this lack of an effect of growth hormone in utero. The two insulin-like growth factors, IGF-I and IGF-II show different patterns of secretion in the perinatal period. IGF-I levels are low in utero, rise gradually through gestation with a marked postnatal rise perhaps related to the development of hepatic growth hormone receptors. IGF-II levels are high in the fetus and fall over the 3 days prior to delivery but are not affected by fetal decapitation. The role of placental lactogen as a stimulus of fetal IGF-II secretion is suggested.(ABSTRACT TRUNCATED AT 400 WORDS)


Is there a difference in timing and cause of death after fractures in the elderly?
Patients who sustain osteoporotic fractures have excessive mortality compared to age-matched controls, which is most pronounced within the first 6 months postfracture. However, the timing and cause of death in the first 3 months after sustaining a fracture are unclear. We therefore evaluated and compared the timing and cause of death in patients who sustained a pelvic, proximal femoral, spinal, or proximal humeral fracture 30 and 90 days after fracture. From medical records, we recorded age at time of fracture, sex, fracture site, comorbidities, date of death, and cause of death of 1630 patients with 1630 fractures admitted to our department between 2001 and 2007. The median age at the time of fracture was 83 years and 89% of the patients were women. Fifty-eight patients died within 30 days after fracture (3.6%), and 122 patients (7.5%) died within 90 days after fracture. Cardiovascular causes of death were most frequent in all fracture groups. Patients who suffered from spinal fractures died earlier within 30 days after fracture than patients who suffered from other types of fractures. This shows the severity and impact of a spinal injury compared to other typical fragility fractures.


Surgical management of a ruptured pseudoaneurysm late after total arch replacement with omentoplasty.
Aortic pseudoaneurysm is a rare, life-threatening complication after cardiac or aortic surgery. In this article, we report reoperation on an 86-year-old man undergoing total arch replacement and omentoplasty for an infectious aortic aneurysm, 5 years previously. He was transferred to our hospital and fell into shock. Prompt drainage of the right-side pleural cavity manifested 2000 ml of blood. Computed tomography revealed contrast extravasation into a pseudoaneurysm, which arose from the proximal anastomotic site of the ascending aorta. The patient underwent emergent surgery that included an extremely careful dissection of the omentum and pericardial adherences, through the re-sternotomy. The patient recovered without neurological sequelae.


Reactivity of shrimp allergy-related IgE antibodies to krill tropomyosin.
Krill, which morphologically resembles small shrimp, represents small ocean crustaceans and has been used for human consumption in Japan and some other countries. The major allergen in crustaceans has been reported to be tropomyosin, but the allergenicity of krill tropomyosin remains uncertain. Amino acid sequences of tropomyosin in two species of krill (Euphausia superba and E. pacifica) were deduced. Recombinant krill tropomyosins were produced in Escherichia coli using a pCold IV vector system, and the cross-reactivity of shrimp allergy-related IgE to the recombinant tropomyosins and several animal protein extracts was assessed by immunoblotting. The deduced amino acid sequences of the E. superba and E. pacifica tropomyosins (designated as Eup s 1 and Eup p 1, respectively) were 284 residues and showed significant homology to those of shrimp, lobster and crab tropomyosins. Shrimp allergy-related IgE reacted to approximately 38-kDa protein bands in krill (E. superba), shrimp, lobster and crab protein extracts but did not react to protein extracts from either mollusks or vertebrates. Furthermore, the IgE recognized rEup s 1 and rEup p 1 as 38-kDa protein bands, and absorption of the IgE with rEup s 1 removed IgE reactivity to recombinant tropomyosins and protein extracts from krill and shrimp. Krill tropomyosins included highly homologous sequences to previously reported IgE-binding epitopes in Pen a 1 (tropomyosin of Penaeus aztecus). The cross-reactivity in shrimp allergy-related IgE binding among krill, shrimp, lobster and crab tropomyosins was revealed. These observations suggest the potential allergenicity of krill tropomyosin.


Comparison of the multi-layer multi-configuration time-dependent Hartree (ML-MCTDH) method and the density matrix renormalization group (DMRG) for ground state properties of linear rotor chains.
We demonstrate the applicability of the Multi-Layer Multi-Configuration Time-Dependent Hartree (ML-MCTDH) method to the problem of computing ground states of one-dimensional chains of linear rotors with dipolar interactions. Specifically, we successfully obtain energies, entanglement entropies, and orientational correlations that are in agreement with the Density Matrix Renormalization Group (DMRG), which has been previously used for this system. We find that the entropies calculated by ML-MCTDH for larger system sizes contain nonmonotonicity, as expected in the vicinity of a second-order quantum phase transition between ordered and disordered rotor states. We observe that this effect remains when all couplings besides nearest-neighbor are omitted from the Hamiltonian, which suggests that it is not sensitive to the rate of decay of the interactions. In contrast to DMRG, which is tailored to the one-dimensional case, ML-MCTDH (as implemented in the Heidelberg MCTDH package) requires more computational time and memory, although the requirements are still within reach of commodity hardware. The numerical convergence and computational demand of two practical implementations of ML-MCTDH and DMRG are presented in detail for various combinations of system parameters.


Dapagliflozin and xanthine oxidase inhibitors improve insulin resistance and modulate renal glucose and urate transport in metabolic syndrome.
Disturbance in glucose and uric acid metabolism is the major disorder of metabolic syndrome (MetS). The kidneys play an important role in the management of glucose and uric acid. The aim of our study was to investigate alterations in renal glucose and uric acid transporters in animals with MetS after treatment with dapagliflozin and xanthine oxidase inhibitors (allopurinol and febuxostat). Sprague-Dawley rats were fed normal chow or a high fructose diet for the first 3 months. The fructose-fed animals were then treated with dapagliflozin, allopurinol, febuxostat, or no treatment for the next 3 months. Fasting glucose, insulin resistance, and hyperuricaemia were improved in all treatment groups except that in the fructose group (all p < 0.05). Both allopurinol and febuxostat reversed the increase in levels of sodium glucose cotransporter (SGLT) 1, SGLT2, and glucose transporter (GLUT) 2 (all p < 0.05). Dapagliflozin alleviated hyperuricaemia and induced uricosuria without affecting serum xanthine oxidase activity. Dapagliflozin suppressed the expression of GLUT9, urate transporter, and urate anion exchanger 1 (all p < 0.05), which was similar to the effects of allopurinol and febuxostat. The results suggest that treatment with dapagliflozin and xanthine oxidase inhibitors improved insulin resistance and reversed the increased expression of glucose and urate transporters in the kidney.


Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor.
The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists ('beta-blockers') thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor-ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r(2) approximately 0.8) with experimental data.


Cytosolic calcium oscillators: critical discussion and stochastic modelling.
In the last few years, an immense amount of experimental data on agonist-induced cytosolic Ca2+ oscillations has emphasized the necessity of theoretical models accounting for these phenomena. In the first part of the paper, a critical analysis of different minimal Ca2+ oscillator models is presented, which reveals that not all of the so far proposed mechanisms are capable to reproduce experimental data adequately. The second part of the paper is devoted to a computational method using a stochastic simulation algorithm which describes the time evolution of Ca2+ oscillations at the molecular level. In contrast to the deterministic formulation of the models presented so far, the stochastic treatment takes account of the inherent fluctuations of cytosolic Ca2+ in cellular subcompartments. In the macroscopic limit, the stochastic models display dynamics analogous to the deterministic ones.


Explicit determination of mean first-passage time for random walks on deterministic uniform recursive trees.
The determination of mean first-passage time (MFPT) for random walks in networks is a theoretical challenge, and is a topic of considerable recent interest within the physics community. In this paper, according to the known connections between MFPT, effective resistance, and the eigenvalues of graph Laplacian, we first study analytically the MFPT between all node pairs of a class of growing treelike networks, which we term deterministic uniform recursive trees (DURTs), since one of its particular cases is a deterministic version of the famous uniform recursive tree. The interesting quantity is determined exactly through the recursive relation of the Laplacian spectra obtained from the special construction of DURTs. The analytical result shows that the MFPT between all couples of nodes in DURTs varies as N ln N for large networks with node number N. Second, we study trapping on a particular network of DURTs, focusing on a special case with the immobile trap positioned at a node having largest degree. We determine exactly the average trapping time (ATT) that is defined as the average of FPT from all nodes to the trap. In contrast to the scaling of the MFPT, the leading behavior of ATT is a linear function of N. Interestingly, we show that the behavior for ATT of the trapping problem is related to the trapping location, which is in comparison with the phenomenon of trapping on fractal T-graph although both networks exhibit tree structure. Finally, we believe that the methods could open the way to exactly calculate the MFPT and ATT in a wide range of deterministic media.


Functionalisation of Polysaccharides for the Purposes of Electrospinning: A Case Study Using HPMC and Si-HPMC.
Hydrogels are a suitable scaffold material for a variety of tissue engineering applications. However, these materials have a weak structure and require reinforcement. Integrating electrospun fibers could strengthen material properties. This study created fibers and evaluated the influence of the presence of polar head groups within a polysaccharide backbone following functionalization: silated-hydroxypropyl methylcellulose (Si-HPMC). Electrospinning is a multi-parameter, step by step process that requires optimization of solution and process parameters to understand and control the process. Fibers were created for 2%⁻3% wt/v solutions in water and ethanol. Viscosities of solutions were correlated with spinnability. Variations on process parameters did not reveal major variation on fiber morphology. Once controlled, the process was used for HPMC/Si-HPMC mixture solutions. Solubilization and dilution of Si-HPMC were made with common solvents for electrospinning. Two forms of polymer conformation were electrospun: silanol ending and silanolate ending. Microstructures and resulting nanofibers were analyzed by scanning electron microscopy (SEM) and Energy Dispersive Analysis (EDX). The results show the feasibility of our strategy for creating nanofibers and the influence of polar head groups on electrospinnability.


NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis.
NF-kappaB is known to exert a cytoprotective action against TNF-alpha-induced apoptosis. To study the role of NF-kappaB in various TNF-alpha-treated epithelial cell lines, we generated stable transfectants overexpressing a mutated unresponsive form of the IkappaBalpha inhibitor (MT cells). As NF-kappaB prevented TNF-alpha-induced apoptosis in various epithelial cancer cell lines, we searched for NF-kappaB target gene products responsible for this difference of sensitivity. We observed an increased Bcl-X(L) expression level in OVCAR-3 cells compared with OVCAR-3 cells expressing a mutated IkappaBalpha inhibitor (MT cells). Induction of the antioxidant enzyme MnSOD was detected only in TNF-alpha-treated OVCAR, MCF7A/Z and HCT116 cells but not in MT cells. Moreover, reactive oxygen species were involved in TNF-alpha-induced apoptosis, as various antioxidants partially protected these cells from apoptosis. At last, transfection of the MnSOD cDNA in MT cells, which do not express this protein after TNF-alpha stimulation, partially restored resistance to TNF-alpha-induced cell death, as observed by clonogenic assays. However, transfection of the Bcl-X(L) cDNA did not induce any protective effect. Therefore, MnSOD expression is induced by NF-kappaB in epithelial cancer cells in response to TNF-alpha, and is at least partially responsible for their resistance to TNF-alpha-induced apoptosis, presumably through the clearance of death-inducing ROS.


Procalcitonin as a Predictor of Septic Knee Arthritis: A Retrospective Cohort Study.
Differentiating septic arthritis from aseptic arthritis (AA) of the knee is difficult without arthrocentesis. Although procalcitonin (PCT) has shown diagnostic value in identifying bacterial infections, it has not been established as a reliable marker for identifying septic arthritis (SA). Recent studies have shown promise in the use of PCT as a useful systemic marker for identifying septic arthritis versus AA. This observational retrospective review compares PCT with routine inflammatory markers as a tool for differentiating septic arthritis versus AA in patients with acute, atraumatic knee pain. Fifty-three consecutive patients (24 SA, 29 AA) were retrospectively reviewed at one institution with concern for SA. SA was diagnosed based on a physical examination, laboratory markers, and arthrocentesis. Laboratory indices were compared between the septic arthritis and AA groups. Data analysis was conducted to define sensitivity and specificity. Receiver operator characteristic curve analysis and regression were conducted to determine the best marker for acute SA of the knee. Using multiple logistic regression, bacteremia (OR 6.75 ± 5.75) was determined to be the greatest predictor of SA. On linear regression, concomitant bacteremia (coef 3.07 ± 0.87), SA (coef 2.18 ± 0.70), and the presence of pseudogout crystals (coef 1.80 ± 0.83) on microscopy predicted an increase in PCT. Using a PCT cutoff of 0.25 ng/mL yields a sensitivity of 91.7% and specificity of 55.2% for predicting SA; however, the ideal cutoff in our series was 0.32 ng/mL with a sensitivity of 79.2% and specificity of 72.4%. PCT was superior to the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein in the area under the receiver-operating characteristic curve analysis. Procalcitonin seems to be the most sensitive and specific systemic marker in differentiating septic from AA.


Phosphorus flows and balances of the European Union Member States.
Global society faces serious "phosphorus challenges" given the scarcity, essentiality, unequal global distribution and, at the same time, regional excess of phosphorus (P). Phosphorus flow studies can be used to analyze these challenges, providing insight into how society (re)uses and loses phosphorus, identifying potential solutions. Phosphorus flows were analyzed in detail for EU-27 and its Member States. To quantify food system and non-food flows, country specific data and historical context were considered. The sectors covered were crop production (CP), animal production (AP), food processing (FP), non-food production (NF) and consumption (HC). The results show that the EU-27 imported 2392 Gg P in 2005, half of which accumulated in agricultural soils (924 Gg) and half was lost as waste (1217 Gg). Net accumulation was 4.9 kg P/ha/year ranging between +23.2 (Belgium) and -2.8 (Slovakia). From the system losses, 54% was lost from HC in diverse waste flows and 28% from FP, mainly through incinerated slaughter residues. The largest HC losses (655 Gg) were wastewater (55%), food waste (27%), and pet excreta (11%). Phosphorus recycling rates were 73% in AP, 29% in FP, 21% in HC and ~0% in NF. The phosphorus use efficiencies showed that, relative to sector input, about 70% was taken up by crops (CP), 24% was retained in animals (AP), 52% was contained in food products (FP), 76% was stored in non-food materials (NF), and 21% was recycled (HC). Although wide-ranging variation between countries, generally phosphorus use in EU-27 was characterized by relatively (1) large dependency on (primary) imports, (2) long-term accumulation in agricultural soils, especially in west European countries, (3) leaky losses throughout entire society, especially emissions to the environment and sequestered waste, (4) little recycling with the exception of manure, and (5) low use efficiencies, because of aforementioned issues, providing ample opportunities for improvement.


Involvement of inositol 1,4,5-trisphosphate in Ca2+ influx in thrombin stimulated human platelets.
By incubating platelets at low temperature (10 degrees C), the relationship between Ca2+ mobilization and formation of inositol 1,4,5-trisphosphate (IP3) in thrombin stimulated platelets could be precisely investigated. In the presence of 1 mM EGTA, time dependent changes in the intracellular free calcium concentration [( Ca2+]i) were closely related to those in IP3 formation. Time course of the influx of external Ca2+, estimated by delta [Ca2+]i obtained by subtracting [Ca2+]i in the presence of 1 mM EGTA from that in the presence of 1 mM CaCl2 was also very similar to that of IP3 formed. Furthermore, the increase in delta [Ca2+]i was extremely well correlated with the amount of IP3 formed (Y = 49X - 34, r = 0.99). Thus, these data indicate that IP3 might be involved not only in intracellular Ca2+ mobilization but in Ca2+ influx of human platelets stimulated by thrombin.


[Factors Affecting Duration of Stay in IntensiveCare Unit After Coronary Artery Bypass Surgery].
We studied predictors of prolonged stay in intensive care unit (ICU) after coronary surgery without cardiopulmonary bypass. Factors significantly associated with duration of ICU stay were elevated levels of glucose and lactate in venous blood, types of conduits used, and type of bypass surgery. Results of this study can be used for elaboration of a quantitative scale for prediction of duration of postoperative treatment in ICU.


BALANCING SELECTION IN A DESERT STREAM-DWELLING FISH, POECILIOPSIS MONACHA.
The desert stream-dwelling fish Poeciliopsis monacha is exposed to extreme seasonal and spatial variation in physical stresses. We examined four diallelic gene loci (Ldh-1, Idh-2, Pgd, and Ck-A) in P. monacha and tested whether genotypes were associated with differential survival of individuals exposed to acute stress. For each locus, the common allele was associated with higher survival during heat and hypoxic stress, whereas the alternate allele was associated with higher survival during cold stress. In most cases, survival of heterozygotes was intermediate and they exhibited less variance in survival than corresponding homozygotes. Identification of substantial linkage disequilibrium in these fish confounds our ability to discern whether the allozymes are the direct targets of selection, or if they just mark chromosomal regions that contain the true modifiers of survival. Nevertheless, the present results clearly identified balancing processes that can serve to stabilize genetic polymorphism in this species.


Genotypic characterization and multivariate survival analysis of chronic lymphocytic leukemia in Taiwan.
In Taiwan, as in other areas of Asia, the incidence of chronic lymphocytic leukemia (CLL) is low. A retrospective analysis was conducted to elucidate the clinicopathologic features of CLL patients in Taiwan. Of the 47 cases of CLL enrolled in this study, 45 were immunophenotyped as B-CLL; the other 2 were T-CLL. It was found that the lower the Binet and Rai stages of the B-CLL, the longer patients survive (p = 0.0131 and 0.0142, respectively). Univariate analysis showed that fatigue, splenomegaly, hepatomegaly and anemia are associated with poor survival with p values of 0.0203, 0.0184, 0.0001 and 0.171, respectively. By multivariate analysis with Cox's proportional hazard model, hepatomegaly and decrease in body weight were the two most significant predictors of survival. However, molecular parameters of kappa or lambda immunoglobulin (Ig) gene rearrangement or double allele rearrangement of Ig gene did not significantly increase the predictability of the prognosis.


[Intranuclear inclusions in the cells of different tissues of the aging rat].
Ultrastructure of neuronal and glial nuclei has been studied in various parts of the CNS, in parenchymatous cells of internal organs, in endotheliocytes and pericytes of their blood capillaries in intact rats--mature (6-8-month-old) and old (26-28-month-old), as well as at certain experimental influences. In all the cellular populations studied (most often in neurons), various in their structure, intranuclear inclusions (INI) have been revealed, that are considered as five main types. The number of INI increases sharply at ageing, that is especially noticeable under experimental conditions. Some INI are situated in morphologically preserved, actively working cells, being normal components of the nucleus, others--reflect profound rearrangements of nuclear proteins, disturbances in lipid metabolism up to irreversible destructive processes in the nucleus.


[Grafts in esthetic and functional corrective rhinoplasty].
Results of the use of grafts in primary and secondary rhinoplasty are reported, the grafts being either of cartilage (concha auriculae, nasal septum, alar cartilage), bone (mastoid, ilium) or connective tissue (temporal aponeurosis). The distinction is made between modelling grafts of softened cartilage, supporting grafts of non-softened cartilage and mastoid bone, of bone reconstruction and of cartilaginous filling grafts.


Takagi-Sugeno fuzzy modeling and chaos control of partial differential systems.
In this paper a unified approach is presented for controlling chaos in nonlinear partial differential systems by a fuzzy control design. First almost all known chaotic partial differential equation systems are represented by Takagi-Sugeno fuzzy model. For investigating design procedure, Kuramoto-Sivashinsky (K-S) equation is selected. Then, all linear subsystems of K-S equation are transformed to ordinary differential equation (ODE) systems by truncated Fourier series of sine-cosine functions. By solving Riccati equation for each ODE systems, parallel stabilizing feedback controllers are determined. Finally, a distributed fuzzy feedback for K-S equation is designed. Numerical simulations are given to show that the distributed fuzzy controller is very easy to design, efficient, and capable to extend.


Severe Spinal Injury in Hirayama Disease.
Hirayama disease is a rare neurological disorder characterized by an insidious progressive subacute unilateral or bilateral weakness of the hands and forearm muscles leading to a painless amyotrophy. The disease primarily affects young men in the second to third decades of life. It has always been described as a second motor neuron disease, thus sparing the pyramidal and sensitive pathways. It usually has a slow progression course of 3 to 5 years followed by stabilization. Since its initial description by Keyzo Hirayama in 1959, most cases have been reported in Asia, particularly Japan and India, although the disease reportedly has worldwide distribution.


Frailty and safety: the example of diabetes.
Frailty is considered a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia and disability. In addition, there is a close relationship between age-related metabolic changes and the occurrence of comorbidities that may in turn lead to frailty.Even though the downward spiral of frailty is activated more quickly in older persons with type 2 diabetes, it is reversible with appropriate interventions before reaching a high level of severity. The hazard for geriatric patients with type 2 diabetes is that frailty encompasses diverse complications already associated with or caused by diabetes. Frailty is also associated with cognitive impairment, reduced ability to perform activities of daily living and increased expression of inflammatory and coagulation markers that may contribute to the adverse microvascular effects of diabetes. Although glycaemic control remains the main targeting achievement in type 2 diabetes, especially in well-functioning older persons, this is not appropriate for those with frailty. Frail elderly people with type 2 diabetes are a specific group in need of treatment parameters for both initial and maintenance therapy with oral antidiabetic agents. Therefore, the prescription of an antidiabetic agent in such individuals must take into consideration not only the standard goal of lowering hyperglycaemic levels, but also improving the quality of life and life expectancy. The clinical management of this population is currently particularly demanding, requiring special considerations with good medical decision making. Clinical aspects complicating diabetes care in older people include cognitive decline, physical functional decline and frailty. Available oral antidiabetic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), α-glucosidase inhibitors, thiazolidinediones and inhibitors of glucagon-like peptide 1 (GLP-1) degrading enzyme dipeptidyl peptidase 4. In addition, we will discuss injection treatment with GLP-1 analogues. This review will underline the association between diabetes and some frailty components in old patients and how specific antidiabetic agents may play a specific role in improving outcomes.