Sleep and performance--recent trends.
Sleep and sleep deprivation are intimately related to performance. Sleep management of people working in different sectors of the society like multi shift workers, nurses, doctors, students in professional schools and the armed forces has a great bearing on performance, health and safety of the subject population. The detrimental effects of sleep deprivation on psychological performance are indicated as increased lapsing, cognitive slowing, memory impairment, decrease in vigilance and sustained attention and shift in optimum response capability. Its effects on physical performance are manifested as decline in ability to perform maximal exercise, self-selected walking pace and increase in perceived exertion. Sleep deprivation appears to have no effect in respect of muscle contractile properties and maximum anaerobic power. At high altitude (HA), there is a reduction in NREM sleep with frequent awakening due to hypoxia as a physiological adaptive measure to prevent accentuation of hypoxemia due to sleep-hypoventilation. Total sleep deprivation for 48 hours at high altitude can affect the acclimatization status, thermoregulation efficiency and cognitive functions. The concept of 'sleepiness' has also been studied, as it is an emerging concept for better understanding of the effects of sleep deprivation and its effects on performance. A special mention of sustained operations in the armed forces has been made keeping in mind its uniqueness in challenging the normal sleep-work schedule and its deployment in extreme environment and operational condition. This article reviews in detail the functions of sleep, its requirement and the effects of sleep deprivation on human performance.


Risk factors for treatment failure in smokers: relationship to alcohol use and to lifetime history of an alcohol use disorder.
Little is known about the impact of alcohol involvement on smoking cessation relapse or possible mechanisms for these associations. We addressed these issues using data from a randomized clinical trial of two types of framed messages (gain vs. loss) in conjunction with open label sustained-release (SR) bupropion (Toll et al., 2007) (N = 249). Participants were categorized according to whether or not they were diagnosed with a lifetime alcohol use disorder (AUD; i.e., current or past alcohol abuse or past alcohol dependence) and according to three levels of alcohol use: abstinence, moderate, or hazardous use. Alcohol use categories were established for drinking at baseline, during the 6-week treatment period and through 12 weeks post-quit. There were few significant differences by baseline alcohol use level or AUD history for a series of predictors of smoking cessation failure (e.g., depressive symptoms). During treatment and follow-up, the probability of any smoking on heavy drinking days was significantly higher than the probability of smoking on moderate drinking or abstinent days. AUD history did not predict smoking cessation relapse in any analysis, nor were any alcohol usexAUD history interactions significant. Moderate alcohol users and, to a lesser extent, abstainers from alcohol at baseline were less likely than hazardous drinkers to have relapsed at 12 weeks post-quit. Based on these findings, it appears that risk of any smoking and of relapse was associated primarily with heavy drinking days and a hazardous pattern of use respectively, rather than with moderate drinking.


The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking.
Leukocyte migration and trafficking is dynamically regulated by various chemokine and adhesion molecules and is vital to the proper function of the immune system. We describe a role for the Cas and Hef-1-associated signal transducer in hematopoietic cells (Chat-H) as a critical regulator of T lymphocyte migration, by using lentivirus-mediated RNA interference (RNAi). Impaired migration of Chat-H-depleted cells coincided with defective inside-out signaling shown by diminished chemokine-induced activation of the Rap-1 GTPase and integrin-mediated adhesion. Localization of Chat-H to the plasma membrane, association with its binding partner Crk-associated substrate in lymphocytes (CasL), and Chat-H-mediated CasL serine-threonine phosphorylation were required for T cell migration. These results identify Chat-H as a critical signaling intermediate acting upstream of Rap1 to regulate chemokine-induced adhesion and migration.


Immunoreactive growth hormone levels in pigs fed protein or energy restricted diets during the postweaning period.
Developmental changes in growth hormone levels during protein or energy malnutrition was studied in weaned pigs. Three or 4 weeks old pigs from control dams were fed a control diet (18% protein), an energy-restricted diet (18% protein) or a low protein diet (6% protein) for 8 weeks. Energy restriction was achieved by feeding the control diet in amounts that allowed very little growth. After the restriction period, all pigs were fed the control diet ad libitum for another 8 weeks. Blood samples were collected at intervals throughout the experiment and the plasma was analyzed for growth hormone by radioimmunoassay. Post weaning protein deprivation resulted in higher growth hormone levels during the restriction period as compared to control pigs or pigs with a restricted energy intake.


Primary and post-irradiation inactivation of the sulfhydryl enzyme malate synthase: correlation of protective effects of additives.
The presence of additives during X-irradiation of malate synthase led to radioprotective effects against primary and post-irradiation inactivation. Pronounced effects were provided by typical scavengers, sulfhydryl reagents and specific ligands (substrates, products, analogues). The results show that scavenging and specific protection are responsible for the protective efficiency of additives. Scavengers delete noxious species formed during irradiation or post-radiationem. Sulfhydryl reagents may act as repair substances. Specific ligands protect the active site of the enzyme and the essential sulfhydryls; specific protection is more pronounced post-radiationem. Ligands and sulfhydryl reagents may additionally act as scavengers. A cumulative index for the protective power of additives against both sorts of inactivation was established.


Experts and Peripheries: Ongoing Research and Future Challenges.
Based on existing research on Spain and Greece, the essay is focused upon the activity of experts in criminal courts and advisory committees. Following the experts in these settings, we offer examples of their roles in governing techno-sciences in societies of the European periphery. We highlight the tensions between the creative powers of localities and the movement of expert knowledge in a world marked by striking inequalities concerning economic, political and academic power. We claim that a comparative study of these movements will be refine the historical understanding of experts and expertise.


Reproductive outcomes of HIV seropositive women treated by assisted reproduction.
Over one million Americans are infected with HIV, and approximately 300,000 are women. Overall health in HIV infected persons has improved, and many seropositive women desire children. This study describes the reproductive outcomes of HIV seropositive women treated by assisted reproduction at our center and compares their clinical results with age-matched HIV seronegative controls. From January 1, 1998 to December 31, 2011, 36 HIV seropositive women received treatment with in vitro fertilization (IVF) at a single center. The mean age at start of fertility treatment was 37.7±4.8 years. At presentation, 92% of seropositive women were using antiretrovirals and all had undetectable viral loads at time of cycle initiation. Clinical outcomes of seropositive women were compared in a one-to-one ratio to those of randomly selected age-matched seronegative controls undergoing treatment for male factor infertility during the same time period. Comparisons were stratified by age--women less than 35 and greater than 35 years of age. Fifteen treatment cycles resulted in live births (21 infants born without HIV infection). HIV seropositive and seronegative women < 35 years of age had nearly identical IVF clinical outcome parameters, including clinical pregnancy rates and live birth rates. For women 35 years of age or older, baseline serum estradiol levels and live birth rates were significantly lower in HIV seropositive women. This study demonstrates that the presence of well-controlled HIV infection does not impair fertility treatment in women undergoing IVF. Virally infected women should be encouraged to seek treatment in appropriate cases.


Effect of the seaweed Ascophyllum nodosum on lambs during forced walking and transport.
The objective of this study was to determine the effect of feeding Ascophyllum nodosum (ANOD) to lambs at 0 (control), 0.5, 1, or 2% of DMI/d for 2 wk on lamb physiology in response to forced walking and transport during hot weather. Forty-four lambs (26 kg +/- 4.3) were used, and each lamb swallowed 3 gelatin capsules filled with ANOD or their normal 16% CP, pelleted grain ration twice daily, with the amount of ANOD dependent on the treatment. The amount of ANOD did not affect ear canal temperature or cortisol concentrations during 60 min of forced walking. The range between the minimum and maximum ear canal temperature for each lamb during 12 h of transport was narrower in lambs receiving the 2% ANOD than the control group (P = 0.05), and the 2% ANOD group also had lower (P = 0.05) ear canal temperatures than the control group during hot periods of transport. After 4 (P = 0.09) and 8 h (P = 0.05) of transport, the control group tended to have greater cortisol concentrations than the 2% ANOD group. Many differences among treatments were found in plasma protein, albumin, calcium, phosphorus, glucose, blood urea nitrogen, aspartate aminotransferase, magnesium, sodium, potassium, and chloride concentrations posttransport; mainly, the control and 0.5% ANOD groups had greater (P < 0.05) concentrations than the other 2 treatments. Aldosterone concentrations were greater in the control and 0.5% ANOD group than in the 1 and 2% ANOD groups before transport, whereas the concentrations were not different after transport, suggesting pretransport concentrations were lowered by supplementation. The 1 and 2% ANOD groups lost more BW than the control group as a result of transport (P = 0.04). After transport, no differences were observed in the latency for lambs to drink, eat, or lay. There was a suppression of the IgG and IgM antibody responses at 4 and 7 d after administration of ovalbumin, with greater ANOD supplementation rates suppressing antibody response the greatest. Although ANOD decreased ear canal temperature in hot periods of transport, stabilized electrolyte concentrations, and decreased cortisol throughout transport, it also suppressed the antibody response indicating that the effect of ANOD on immune function merits further investigation.


Beyond Body Mass Index: Using Anthropometric Measures and Body Composition Indicators to Assess Odds of an Endometriosis Diagnosis.
Body mass index (BMI) and endometriosis have been inversely associated. To address gaps in this research, we examined associations among body composition, endometriosis, and physical activity. Women from 14 clinical sites in the Salt Lake City, Utah and San Francisco, California areas and scheduled for laparoscopy/laparotomy were recruited during 2007-2009. Participants (N = 473) underwent standardized anthropometric assessments to estimate body composition before surgery. Using a cross-sectional design, odds of an endometriosis diagnosis (adjusted odds ratio [aOR]; 95% confidence interval [CI]) were calculated for anthropometric and body composition measures (weight in kg; height in cm; mid upper arm, waist, hip, and chest circumferences in cm; subscapular, suprailiac, and triceps skinfold thicknesses in mm; arm muscle and fat areas in cm2; centripetal fat, chest-to-waist, chest-to-hip, waist-to-hip, and waist-to-height ratios; arm fat index; and BMI in kg/m2). Physical activity (metabolic equivalent of task-minutes/week) and sedentariness (average minutes sitting on a weekday) were assessed using the International Physical Activity Questionnaire-Short Form. Measures were modeled continuously and in quartiles based on sample estimates. Adjusted models were controlled for age (years, continuous), site (Utah/California), smoking history (never, former, or current smoker), and income (below, within 180%, and above of the poverty line). Findings were standardized by dividing variables by their respective standard deviations. We used adjusted models to examine whether odds of an endometriosis diagnosis were moderated by physical activity or sedentariness. Inverse relationships were observed between endometriosis and standardized: weight (aOR = 0.71, 95% CI 0.57-0.88); subscapular skinfold thickness (aOR = 0.79, 95% CI 0.65-0.98); waist and hip circumferences (aOR = 0.79, 95% CI 0.64-0.98 and aOR = 0.76, 95% CI 0.61-0.94, respectively); total upper arm and upper arm muscle areas (aOR = 0.76, 95% CI 0.61-0.94 and aOR = 0.74, 95% CI 0.59-0.93, respectively); and BMI (aOR = 0.75, 95% CI 0.60-0.93), despite similar heights. Women in the highest versus lowest quartile had lower adjusted odds of an endometriosis diagnosis for: weight; mid-upper arm, hip, and waist circumferences; total upper arm and upper arm muscle areas; BMI; and centripetal fat ratio. There was no evidence of a main effect or moderation of physical activity or sedentariness. In a surgical cohort, endometriosis was inversely associated with anthropometric measures and body composition indicators.


Hyperplasia of antral G cells in uraemic patients.
In this study we have performed a quantitative analysis of antral gastrin cells in 9 uraemic patients under dialytic treatment compared to a group of 10 chronic gastritis patients with a similar histological degree of gastritis. Immunocytochemistry was carried out on endoscopic biopsies of both groups. Using a computerised image analysing system we showed a significant increase of G-cell density (number of cells/mm2) in uraemic patients compared to non-uraemics (p less than 0.001). These findings provide a further morphological basis for the elevation of gastrin levels in chronic uraemic patients, suggesting the existence of a specific factor inducing G-cell proliferation in these patients.


Molecular mechanisms of decreased interleukin-2 production after thermal injury.
Among the fundamental immunologic abnormalities induced by serious traumatic or thermal injury are alterations in T cell activation, reduced lymphocyte interleukin-2 (IL-2) production, and associated depression of T lymphocyte proliferation. This study attempts to localize the cellular mechanisms underlying abnormal IL-2 production in thermal injury. Following National Institutes of Health guidelines, 150 A/J mice were anesthetized, subjected to a 20% full-thickness scald burn injury or sham burn, and killed at intervals from 4 to 21 days later; splenocytes were harvested for in vitro studies. For measurement of IL-2 production, cells were cultured with either concanavalin A or a combination of the phorbol ester PMA, which directly activates protein kinase C, and the calcium ionophore A23187, which increases intracellular calcium. Cytokine mRNA expression was measured by Northern blot analysis and IL-2 production by bioassay. Both IL-2 production and IL-2 mRNA expression were consistently suppressed in concanavalin A-stimulated cells from burned mice compared with sham burns. This suppression of IL-2 and IL-2 mRNA also occurred when T cells were activated with PMA and A23187, bypassing the earlier stages of the signal transduction mechanism. IL-1 beta and tumor necrosis factor-alpha mRNA expression were consistently increased in burned animals, indicating that decreased IL-2 mRNA expression was specific to IL-2 and not representative of a global decrease in cytokine mRNA expression. These results suggest that the principal cellular abnormalities that result in altered T cell activation and IL-2 production after thermal injury lie downstream of the initiating signal transduction events and before IL-2 gene transcription.


MATING PATTERN AND FITNESS-COMPONENT ANALYSIS ASSOCIATED WITH INVERSION POLYMORPHISM IN A NATURAL POPULATION OF DROSOPHILA BUZZATII.
Direct studies of mating success or mating pattern associated with Mendelian factors rarely have been carried out in nature. From the samples taken for the standard analyses of selection components, it is not usually possible to obtain the mating table, and only directional selection for male mating success can be detected. Both processes, mating pattern and differential mating probability, together with other fitness components, have been investigated for the inversion polymorphism of a natural population of the cactophilic species Drosophila buzzatii. Two independent samples of adult flies were collected: nonmating or single individuals (base population) and mating pairs (mating population). All individuals were karyotyped for the second and fourth chromosomes. A sequence of models with increasing simplicity was fitted to the data to test null hypotheses of no selection and random union of gametes and karyotypes. The main results were (1) no deviations from random mating were found; (2) differential mating probability was nonsignificant in both sexes; (3) inversion and karyotypic frequencies did not differ between sexes; and (4) karyotypic frequencies did not depart from Hardy-Weinberg expectations. These results are discussed in light of complementary evidence showing the need for interpreting with caution no-effect hypotheses such as the ones tested here. The use of complementary selective tests in these studies is suggested.


Negative ion photoelectron spectroscopy confirms the prediction that (CO)5 and (CO)6 each has a singlet ground state.
Cyclobutane-1,2,3,4-tetraone has been both predicted and found to have a triplet ground state, in which a b2g σ molecular orbital (MO) and an a2u π MO are each singly occupied. In contrast, (CO)5 and (CO)6 have each been predicted to have a singlet ground state. These predictions have been tested by generating the (CO)5(•-) and (CO)6(•-) radical anions in the gas phase, using electrospray vaporization of solutions of, respectively, the croconate (CO)5(2-) and rhodizonate (CO)6(2-) dianions. The negative ion photoelectron (NIPE) spectrum of the (CO)5(•-) radical anion gives an electron affinity of EA = 3.830 eV for formation of the singlet ground state of (CO)5. The triplet is found to be higher in energy by 0.850 eV (19.6 kcal/mol). The NIPE spectrum of the (CO)6(•-) radical anion gives EA = 3.785 eV for forming the singlet ground state of (CO)6, with the triplet state higher in energy by 0.915 eV (21.1 kcal/mol). (RO)CCSD(T)/aug-cc-pVTZ//(U)B3LYP/6-311+G(2df) calculations give EA values that are only approximately 1 kcal/mol lower than those measured and ΔE(ST) values that are 2-3 kcal/mol higher than those obtained from the NIPE spectra. Calculations of the Franck-Condon factors for transitions from the ground state of each radical anion, (CO)n(•-) to the lowest singlet and triplet states of the n = 4-6 neutrals, nicely reproduce all of the observed vibrational features in the low-binding energy regions of all three NIPE spectra. Thus, the calculations of both the energies and vibrational structures of the two lowest energy bands in each of the NIPE spectra support the interpretation of the spectra in terms of a singlet ground state for (CO)5 and (CO)6 but a triplet ground state for (CO)4.


[Food hygiene aspects in the production of food fish in fishing].
The development of the aerob-mesophilic bacteria on epidermis and peritoneum of 68 barbels was determined at 0, 4 and 8 hours after slaughtering. Therefore, one group of 34 animals was stored at 15.3 degrees C, an other equal one at 21.6 degrees C. A change in germ counts per cm2 could be seen in none of the groups during the first 4 hours. However, unrefrigerated carcasses showed an increase of bacteria up to 5-fold between the 4th and 8th hour, whereas in the refrigerated group no change occurred during that time, too. Rinsing the fish after slaughtering resulted in a decrease of the initial bacterial counts by up to 65.4% and so in significantly lower germ loads at the end of the storage time. These results were confirmed by contaminating 24 rainbow trout with Salmonella Infantis artificially. The frequency of detection did not change in refrigerated fish over 8 hours, while nearly doubling in unrefrigerated ones. Moreover, it could be shown that a Salmonella-concentration of only 30 CFU per 100 ml water was sufficient for contaminating fish in detectable grades. The study leads to the conclusion that the storage of instantly slaughtered fish in a common thermobox with freezing elements is suited for preserving its microbiological status for at least 8 hours. The caging of living fish after capture, which must be regarded critically under the aspect of treating animals in a humane way, seems therefore unnecessary.


Paeoniflorin and Plycyrrhetinic Acid Synergistically Alleviate MPP+/MPTP-Induced Oxidative Stress through Nrf2-Dependent Glutathione Biosynthesis Mechanisms.
Recently, combination therapy has proven to be an effective strategy for treating polygenic/multifactorial/complex disorder such as Parkinson's disease (PD). Here, we hypothesized that dual up-regulation of glutamate cysteine ligase (GCL) catalytic subunit (GCLc) and GCL modifier subunit (GCLm) via nuclear factor E2-related factor (Nrf2) contribute to the antioxidant effect of paeoniflorin (PF) synergistically with glycyrrhetinic acid (GA) (henceforth called PF/GA) in the context of MPP+/MPTP neurotoxicity. Expectedly, CompuSyn synergism/antagonism analysis showed that PF/GA exerts synergistic neuroprotection. Moreover, the antioxidant effect of PF was significantly enhanced by the combined administration of GA, although GA alone did not confer the effect. Mechanistically, PF triggered extracellular signal-regulated kinase (ERK1/2) phosphorylation, resulting in Nrf2 nuclear translocation from cytoplasmic pool via de novo synthesis in MPP+-challenged SH-SY5Y cells. Concomitantly, GA activates Akt which in turn induces nuclear accumulation of Nrf2. Especially, PF/GA up-regulated glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) are formed via two separate pathways. Furthermore, these results were confirmed through pathway blockade assays using PD98059 (ERK1/2 inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), and shRNA-induced Nrf2 knockdown. Additionally, using a mouse MPTP-induced model of PD, we demonstrated that PF/GA synergistically ameliorates both motor deficits and oxidative stress in the ventral midbrain. In parallel, PF/GA also up-regulated both GCLc and GCLm expression at levels of transcription and translation. Conversely, antiparkinsonism and antioxidant effects of PF/GA were not observed in Nrf2-knockout MPTP-mice. Collectively, these results show that ERK1/2 and Akt activation contribute to the synergistic antioxidant effect of PF/GA. Hence, PF/GA regimen warrants further preclinical and possible clinical study for PD.


Expression of human alpha-galactosidase leads to reduction of major xenoepitope Galalpha(1,3) Gal in NIH 3T3 cell.
To examine the effects of the expression of alpha-galactosidase on the expression of the major xenoepitope Galalpha(1,3) Gal (G antigen) in NIH 3T3 cell. The expression levels of G antigen and H antigen and binding of human natural antibodies (IgG and IgM) and complement (C3c) to NIH 3T3 cells were analyzed by flow cytometry. Western blot was employed to further determine the expression of glycoproteins of G antigen. Cytolysis assay with normal human serum was performed by MTT assay. In transfectants, Western blot showed that the binding of human IgG to glycosylated proteins located on the cell membrane was decreased, even abrogated totally. Together with the reduced binding of Gs-IB4 (Griffonia simplicifolia) to transfectants, the stable expression of human alpha-galactosidase effectively inhibited Galalpha(1,3) Gal, Gal epitope synthesis in NIH 3T3 cell. As a result, the xenoreactivities of human IgG, IgM, and C3c were reduced by 73.4 %, 22.3 % and 47.9 %, respectively, while the cell lysis mediated by human XNA and complements was decreased by 42.4 %. The stable expression of human alpha-galactosidase in NIH 3T3 cell strongly inhibits the expression of Gal epitopes, resulting in abrupt reduction in xenorejection induced by human serum.


Methods to address poultry robustness and welfare issues through breeding and associated ethical considerations.
As consumers and society in general become more aware of ethical and moral dilemmas associated with intensive rearing systems, pressure is put on the animal and poultry industries to adopt alternative forms of housing. This presents challenges especially regarding managing competitive social interactions between animals. However, selective breeding programs are rapidly advancing, enhanced by both genomics and new quantitative genetic theory that offer potential solutions by improving adaptation of the bird to existing and proposed production environments. The outcomes of adaptation could lead to improvement of animal welfare by increasing fitness of the animal for the given environments, which might lead to increased contentment and decreased distress of birds in those systems. Genomic selection, based on dense genetic markers, will allow for more rapid improvement of traits that are expensive or difficult to measure, or have a low heritability, such as pecking, cannibalism, robustness, mortality, leg score, bone strength, disease resistance, and thus has the potential to address many poultry welfare concerns. Recently selection programs to include social effects, known as associative or indirect genetic effects (IGEs), have received much attention. Group, kin, multi-level, and multi-trait selection including IGEs have all been shown to be highly effective in reducing mortality while increasing productivity of poultry layers and reduce or eliminate the need for beak trimming. Multi-level selection was shown to increases robustness as indicated by the greater ability of birds to cope with stressors. Kin selection has been shown to be easy to implement and improve both productivity and animal well-being. Management practices and rearing conditions employed for domestic animal production will continue to change based on ethical and scientific results. However, the animal breeding tools necessary to provide an animal that is best adapted to these changing conditions are readily available and should be used, which will ultimately lead to the best possible outcomes for all impacted.


Simvastatin induces growth inhibition and apoptosis in HepG2 and Huh7 hepatocellular carcinoma cells via upregulation of Notch1 expression.
Statins, cholesterol‑lowering drugs, are one of the most commonly prescribed types of medications. Previous studies have suggested that simvastatin may inhibit the cell function and tumor growth of hepatocellular carcinoma (HCC) cells; however, the molecular mechanisms underlying simvastatin‑induced apoptosis in HCC cells remains to be elucidated. The aim of the present study was to investigate the role of simvastatin in the regulation of cell viability, proliferation and apoptosis in HepG2 and Huh7 HCC cells, and to elucidate the specific regulatory mechanisms by which simvastatin proceeds. MTT, trypan blue and flow cytometric analyses were performed in order to detect viability, proliferation and apoptosis in HepG2 and Huh7 cells. The results of the present study demonstrated that simvastatin significantly decreased cell viability and proliferation as well as increased apoptosis in HepG2 and Huh7 cells compared to that in untreated cells. In addition, reverse transcription quantitative polymerase chain reaction and western blot analysis revealed that simvastatin‑treated cells exhibited increased expression levles of Notch1, p53, and Bax, as well as decreased expression levels of B cell lymphoma 2; furthermore, Notch1 upregulation resulted in the inhibition of Akt phosphorylation. In conclusion, the results of the present study indicated that simvastatin significantly promoted apoptosis in HCC cells, the mechanism of which may have proceeded via the upregualtion of the Notch1 gene in the Akt‑dependent signaling pathway.


[Indications for shoulder prosthetics in degenerative and inflammatory diseases].
Shoulder arthroplasty has since it's more widespread introduction in the early seventies found a general acceptance as an excellent tool for treating late stage arthritis of the shoulder joint. The indications will vary from primary osteoarthritic disease to inflammatory diseases such as rheumatoid arthritis, or psoriatric arthritis. It is also used as a primary tool in multifragmented shoulder fractures, which can not be restored anatomically, or are felt at risk for avascular necrosis. The surgeon setting out for this procedure has to decide whether a total arthroplasty is required in cases with glenoid destruction, or at risk of developing secondary degenerative changes in the glenoid early on. A hemiarthroplasty will only replace the humeral side of the joint, but while well accepted in the fracture patient, the arthritic patients tend to fare better with a total joint replacement for pain relief.


Ultra-low supply voltage crystal quartz oscillator.
In this paper, an ultra-low-voltage crystal quartz oscillator is proposed. The design of the proposed oscillator is essentially based on using a HEMT operating in an unsaturated dc regime and a quartz resonator as a resonant impedance transformer. The 25 MHz prototype shows steady oscillations at the supply voltage of less than 17 mV and the power consumption as low as 300 nW, i.e., 1-2 orders of magnitude lower than the other to-date oscillators. This approach is good for building ultra-low consumption radio devices including those working at low temperatures.


Adaptive testing for association between two random vectors in moderate to high dimensions.
Testing for association between two random vectors is a common and important task in many fields, however, existing tests, such as Escoufier's RV test, are suitable only for low-dimensional data, not for high-dimensional data. In moderate to high dimensions, it is necessary to consider sparse signals, which are often expected with only a few, but not many, variables associated with each other. We generalize the RV test to moderate-to-high dimensions. The key idea is to data adaptively weight each variable pair based on its empirical association. As the consequence, the proposed test is adaptive, alleviating the effects of noise accumulation in high-dimensional data, and thus maintaining the power for both dense and sparse alternative hypotheses. We show the connections between the proposed test with several existing tests, such as a generalized estimating equations-based adaptive test, multivariate kernel machine regression (KMR), and kernel distance methods. Furthermore, we modify the proposed adaptive test so that it can be powerful for nonlinear or nonmonotonic associations. We use both real data and simulated data to demonstrate the advantages and usefulness of the proposed new test. The new test is freely available in R package aSPC on CRAN at https://cran.r-project.org/web/packages/aSPC/index.html and https://github.com/jasonzyx/aSPC.


Trapped-molecule charge-transfer complexes with huge dipoles: M-C(2)F(6)-X (M = Na to Cs, X = Cl to I).
Novel intermolecular complexes, with a small molecule sterically trapped between a pair of ions, are designed and characterized. The molecule is found to undergo minor shape distortions and to remain almost neutral, and the complexes to have very large dipole moments (up to approximately 40 D). The systems' stability, ion-molecule interaction and stored energy are investigated, and the vertical excitation, ionization and electron-attachment are described. Variations of geometry and of the above properties with the alkali-metal and halogen components are analysed as well.


Alternative splicing coupled nonsense-mediated decay generates neuronal cell type-specific expression of SLM proteins.
The unique physiological and morphological properties of neuronal populations are crucial for the appropriate functioning of neuronal circuits. Alternative splicing represents an attractive mechanism for generating cell type-specific molecular repertoires that steer neuronal development and function. However, the mechanisms that link neuronal identity to alternative splicing programs are poorly understood. We report that cell type-specific, mutually exclusive expression of two alternative splicing regulators, SLM1 and SLM2, in the mouse hippocampus is achieved by a cross-repression mechanism. Deletion of SLM2 in vivo modifies alternative splicing of its paralog Slm1 and stabilizes its mRNA, resulting in expression of SLM1 in previously SLM2-expressing cells. Despite this ectopic upregulation of SLM1, loss of SLM2 severely disrupts the alternative splicing regulation of Nrxn1, Nrxn2, and Nrxn3, highlighting that the two SLM paralogs have partially divergent functions. Our study uncovers a hierarchical, SLM2-dependent mechanism for establishing cell type-specific expression of neuronal splicing regulators in vivo.


[Forming mycelium pellet and decolorization of dye wastewater under opening conditions].
Removal of three water-soluble dyes through biosorption of four fungal strains was investigated. Some key factors affecting the formation of pellets and removal of dye under opening conditions was examined and the possibility of repeated inoculation of pellets was evaluated. The results show that removal of acid brilliant red B by 4 strains was almost 100%; the removal of all three tested dyes by Trichoderma sp. was more than 99%. Trichoderma sp. formed pellets well under opening conditions when its fragmentized mycelium obtained by 3 min grinding pellets at high concentration was inoculated, as 100% removal of acid brilliant red B was achieved by biosorption of newly growing pellets. Repeated inoculation of pellets accelerated dye removal, time for 100% decolorization reduced from first inoculation 72h to third inoculation 12h.


Changes in Glycemic Control and Body Weight After Initiation of Dapagliflozin or Basal Insulin Supported Oral Therapy in Type 2 Diabetes: A Primary Care Database Study.
The aim was to compare changes in HbA1c and body weight after initiation of dapagliflozin or basal insulin supported oral therapy (BOT) in type 2 diabetes patients in primary care practices. Patients from 983 primary care practices who started dapagliflozin or BOT between December 2012 and July 2015 (index date, ID) were retrospectively analyzed (Disease Analyzer; Germany). Changes in HbA1c (%) and body weight (kg) were evaluated 90-270 days after ID. Propensity score (PS) matching (1:1) was used to adjust for differences in baseline clinical characteristics (180-0 days before ID: age, sex, health insurance, diabetologist care, glucose lowering therapy, HbA1c, body mass index) and duration (days) between start of therapies and last HbA1c or weight documentation after ID. After PS matching, 766 dapagliflozin (mean ± SD; age: 63 ± 10 years; HbA1c: 8.9 ± 1.2%) and 766 BOT (age: 63 ± 10 years; HbA1c: 8.7 ± 1.1%) patients were included. HbA1c decreased by mean (SD) of 1.0% (1.3) in dapagliflozin and by 1.0% (1.4) in BOT patients after 90-270 days (HbA1c reduction; dapagliflozin vs BOT: -0.01%; P = .79). In 440 dapagliflozin users with available data, body weight (97.4 ± 19.9 kg) decreased by 3.1 (5.8) kg after 90-270 days, whereas no significant weight change was observed in 440 matched BOT patients (97.5 ± 19.9 kg) (weight reduction; dapagliflozin vs BOT: -3.0 kg; P < .05). Initiation of dapagliflozin therapy reduced HbA1c similar to basal insulin with the additional benefit of weight reduction in type 2 diabetes patients treated in general practices.


Emotional hypochondriasis, hyperbole, and the borderline patient.
The authors define a new defense mechanism, emotional hypochondriasis, that is hypothesized to be central to borderline psychopathology. The behavioral manifestation of this defense-the hyperbolic stance of the borderline patient-is also defined and related to the complex phenomenology of borderline personality disorder. Borderline patients are seen as making an active attempt to maintain a tolerable, if tenuous, adaptation in the face of tremendous subjective emotional pain that has been shaped in large measure by traumatic childhood events that have never been validated. Twelve treatment implications and three expectable, if overlapping, stages of treatment stemming from the use of this defense and its behavioral sequelae are detailed.


The Impact of Enterprise Management Elements on College Students' Entrepreneurial Behavior by Complex Adaptive System Theory.
At present, with the continuous rise in public consumption level, the pressure on college students' entrepreneurship or employment is increasingly severe. Under the concept of positive psychological intervention, the present work aims to alleviate the entrepreneurial pressure of college students and improve college students' entrepreneurial education through the analysis of enterprise management elements. A 3-month intervention experiment, including the pre-test, preventive curriculum intervention, post-test, and delayed test, is conducted on a control group and an experimental group, to investigate entrepreneurial intention, emotional management ability, and ability to deal with entrepreneurial pressure of college students. In addition, based on a complex adaptive system (CAS), the enterprise management elements are analyzed, and a three-layer network model is constructed. Meanwhile, new diversified elements of enterprise management are defined to discuss the effectiveness and psychological impact of diversified management, proving that psychological security plays an intermediary role in the cross-layer relationship chain in the three-layer CAS network. The experimental results indicate that on the whole, the positive psychological intervention reduces the pressure of students in the experimental group, significantly ameliorates depression and anxiety, and promotes the positive personality in all directions. Besides, in the delayed test after 3 months, the experimental group can maintain a relatively better state than the control group. By exploring the role effectiveness and characteristics of diversified management, this experiment confirms that the improvement of psychological security under positive psychological intervention has a positive impact on the effectiveness of diversified management. The present work discusses the hierarchical construction in enterprise management and puts forward reasonable suggestions and theoretical development for the influence of the entrepreneurial practice of college students.


Field-improvised war surgery in Kosovo: use of kitchen utensils as surgical instruments.
After years of conflict between Serbia and neighboring Kosovo, a full-blown war started in March 1999 when the Serbian and Yugoslav armies began a statewide military crackdown against ethnic Albanians and the Kosovo Liberation Army. Most ethnic Albanians were displaced to Macedonia or Albania. Some, however, found refuge in the Molopolce mountain region of Kosovo among military personnel, thus necessitating the creation of a field medical facility. Patient treatment at the field-improvised Nerodime Military Hospital, and the management of work took place under very difficult conditions including a chronic lack of appropriate medical equipment. Improvised lifesaving surgeries were performed with kitchen utensils serving as retractors at the field hospital. This article compares the treatment of patients between the two hospitals, and is the first article to date describing the war experience in general at the field hospitals in Kosovo.


Pharmacological manipulation of CB1 receptor function alters development of tolerance to alcohol.
The current study investigated the efficacy of CB1 receptor-targeted drugs on the development and expression of tolerance to alcohol (EtOH). An EtOH-inhalation model was used to induce tolerance, as measured by EtOH-induced sedation and hypothermia after a 24 h withdrawal period. Two drug treatment procedures, (i) co-treatment with EtOH and (ii) acute drug administration following chronic EtOH treatment, were used to test the efficacy of CB1 receptor manipulations on EtOH tolerance. The effects of the CB1 receptor agonist CP-55,940 varied depending on paradigm and behavioural measure. Chronic CP-55,940 co-treatment blocked tolerance to EtOH-induced hypothermia but not to the sedative effect (sleep time) in EtOH-exposed mice. However, chronic CP-55,940 administration alone resulted in tolerance to the sedative effect of a challenge dose of EtOH in control mice. Acute CP-55,940 administration after chronic alcoholization blocked the development of tolerance to EtOH-induced sedation compared to the EtOH alone exposed group, but induced tolerance to the hypothermic effects of EtOH in control mice. Chronic blockade of CB1 receptor function by SR141716A resulted in tolerance to both the sedative and hypothermic effects of EtOH in control mice, but had no effect on EtOH-exposed mice. The data support a role for the endocannabinoid (EC) system in EtOH tolerance/dependence and suggest that drugs targeted against EC system could be therapeutically useful in treating alcohol-related disorders.


Assembly mechanism of the pleomorphic immature poxvirus scaffold.
In Vaccinia virus (VACV), the prototype poxvirus, scaffold protein D13 forms a honeycomb-like lattice on the viral membrane that results in formation of the pleomorphic immature virion (IV). The structure of D13 is similar to those of major capsid proteins that readily form icosahedral capsids in nucleocytoplasmic large DNA viruses (NCLDVs). However, the detailed assembly mechanism of the nonicosahedral poxvirus scaffold has never been understood. Here we show the cryo-EM structures of the D13 trimer and scaffold intermediates produced in vitro. The structures reveal that the displacement of the short N-terminal α-helix is critical for initiation of D13 self-assembly. The continuous curvature of the IV is mediated by electrostatic interactions that induce torsion between trimers. The assembly mechanism explains the semiordered capsid-like arrangement of D13 that is distinct from icosahedral NCLDVs. Our structures explain how a single protein can self-assemble into different capsid morphologies and represent a local exception to the universal Caspar-Klug theory of quasi-equivalence.


Vascular endothelial growth factor (VEGF) in physiological and pathological conditions.
Vascular endothelial growth factor (VEGF) is the major endothelial-cell specific stimulatory factor regarded as the most important positive regulator of angiogenesis and vascular permeability. Due to its powerful angiogenic and mitogenic properties, VEGF takes part in a variety of crucial biological processes, including wound repair and tumorigenesis. The elevated expression of VEGF and its receptors has been found in malignancies of various origin as being associated with metastasis formation and poor prognosis. Recently, some possibilities appeared to block the VEGF action when it is undesirable or promote its activity when it can be useful. These new therapeutic strategies based upon the knowledge of VEGF biological role, are being tried and up till now they proved to be successful, especially in anticancer therapy and the coronary heart disease treatment.


Photosynthesis in hydrogen-dominated atmospheres.
The diversity of extrasolar planets discovered in the last decade shows that we should not be constrained to look for life in environments similar to early or present-day Earth. Super-Earth exoplanets are being discovered with increasing frequency, and some will be able to retain a stable, hydrogen-dominated atmosphere. We explore the possibilities for photosynthesis on a rocky planet with a thin H2-dominated atmosphere. If a rocky, H2-dominated planet harbors life, then that life is likely to convert atmospheric carbon into methane. Outgassing may also build an atmosphere in which methane is the principal carbon species. We describe the possible chemical routes for photosynthesis starting from methane and show that less energy and lower energy photons could drive CH4-based photosynthesis as compared with CO2-based photosynthesis. We find that a by-product biosignature gas is likely to be H2, which is not distinct from the hydrogen already present in the environment. Ammonia is a potential biosignature gas of hydrogenic photosynthesis that is unlikely to be generated abiologically. We suggest that the evolution of methane-based photosynthesis is at least as likely as the evolution of anoxygenic photosynthesis on Earth and may support the evolution of complex life.


Porous hydroxylapatite granules and blocks as alveolar ridge augmentation materials: a preliminary report.
Porous hydroxylapatite (PHA) blocks and granules were used in the augmentation of 30 maxillary and mandibular ridges in 28 patients. The postoperative evaluation period was 2 years in all cases. The patients were evaluated clinically and radiographically, and by patient questionnaires. An increased incidence of dehiscence was noted with the blocks as compared with the granules. Overall prosthodontic assessment showed 95% improvement among the granule cases when compared with the preoperative ridge, and 88% improvement noted among the block cases. Patient rating of their general satisfaction with their dentures showed 82% improvement in the granule patients, and 55% in the block cases. Radiographically, the granules showed an average decrease of 8%. The results of this study show that PHA granules can be used as satisfactory alveolar ridge augmentation material, while the blocks show an increased number of complications and should be used only in very selected cases.


Peyer's patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice.
We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (sigma1) and nonstructural (sigmaNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both sigma1 and sigmaNS, indicating productive viral replication. In contrast, sigma1, but not sigmaNS, was detected in the subepithelial dome (SED) in association with CD11c(+)/CD8alpha(-)/CD11b(lo) DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained sigma1, but not sigmaNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, sigma1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4(+) T cells in vitro. These studies show that CD8alpha(-)/CD11b(lo) DCs in the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4(+) T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection.


[NMDA receptor antagonists in focal cerebral ischemia. An experimental model].
Ischemic cerebrovascular disease is an important cause of morbidity and mortality. One common final pathway in neuronal ischemic damage is the uncontrolled influx of calcium into the cell, mediated by voltage dependent channels or activation of the NMDA (N-methyl D-aspartate) receptor. The therapeutic utility of a non-competitive NMDA blocker (MK-801, 2 mg/kg i.p.), to prevent the neuronal ischemic damage in an experimental middle cerebral artery occlusion model has been tested. The drug was administered 10 minutes before (group 3) and one hour after the arterial occlusion (group 4), and the results were compared with a group in which no medicament was utilized (group 2) and a control group (sham operation, group 1). MK-801 reduced significantly the area of infarction in relation to the control group (p < 0.05), mainly if the MK-801 was administered before the occlusion (group 3). These results suggest that MK-801 may be useful for the prevention of the neuronal ischemic damage caused by focal ischemia. However, before recommending its use in humans, all the possible collateral effects must be defined.


Ergonomics application in the N250 aircraft design process, approach, analysis, and assessment model.
In the decade of the 1990's the human aspect has once again taken center stage in the design and operation of commercial aircraft. As occupation health and safety has gained importance in society in general, it has gained even more importance in the design an operation of commercial aircraft. In aircraft design today, the man-machine interface is considered in every task of the human workload. The discipline of ergonomics truly impacts each phase of product or tool design. At IPTN, the ergonomics effort is principally being applied to the design of the cockpit, cabin and cargo compartment of the N250. The ergonomists at IPTN are keenly aware that there would be a conflict between the user and his working environment without proper attention to the human considerations in the design is left for ergonomists and innovative programs like IPTN's participatory approach, to ensure that the human aspect is optimized in the man-machine interface.


[Leg pain : differential diagnosis and treatment].
Acute or chronic leg pain is a common reason for consultation. It is not a specific symptom and several potential causes have to be considered. Both functional and vital prognosis can be engaged. The diagnosis is often based on patient history and clinical examination, whereas the overuse of complementary investigations can lead to confusion. A good knowledge of anatomy, as well as the different etiologic entities, is essential to evaluate acute or chronic leg pain and to guide the diagnostic and therapeutic strategies.


Do extracellular-matrix-regulating enzymes play a role in cervical artery dissection?
An underlying extracellular matrix defect is suspected in patients with spontaneous cervical artery dissection (SCAD). We test the hypothesis that levels of matrix metalloproteinase (MMP) 2 and 9, and elastase, extracellular-matrix-regulating enzymes involved in the vascular wall remodeling process, are modified in SCAD. The authors prospectively and consecutively recruited 47 patients with SCAD and 52 patients with an ischemic stroke from another cause in 2 centers, and measured their plasmatic level of MMP-2, MMP-9 and elastase 3 months after the vascular event. Patients with SCAD had a higher mean MMP-2 level compared with controls [379.2 (SD = 76.6) vs. 355.9 (75.1) ng/ml; p = 0.11] and had more frequently a high level of MMP-2 (>326 ng/ml) than controls (77.8 vs. 54.5%, p = 0.019). This association was stronger in patients with multiple dissection than single artery dissection or controls (84.6, 75.0 and 54.5%, respectively, p = 0.018). The levels of MMP-9 and elastase were similar in cases and controls, but more patients had a high level of these enzymes in the group with multiple dissections than in the group with single artery dissection or controls. Patients with SCAD have higher plasma levels of proteases, particularly MMP-2. The association is stronger in patients with multiple dissections.


Antiproliferative effect of extracts and pyranonaphthoquinones obtained from Cipura paludosa bulbs.
Cipura paludosa Aubl. (Iridaceae) is widely used in folk medicine to treat several ailments. Experimental studies have confirmed its anti-inflammatory, antinociceptive, and neuroprotective effects. This study evaluates the possible antiproliferative potential of the crude methanol extract and three isolated compounds from the bulbs of C. paludosa. Phytochemical analysis was carried out by conventional chromatographic techniques, and the resulting compounds were identified by NMR (1)H and (13)C. The antiproliferative activity was analysed using the sulforhodamine B assay. Crude methanol extract of C. paludosa bulbs showed GI50 values of between 1.6 and 30.8 μg/mL. The naphthoquinone derivatives (eleutherine, isoeleutherine, and eleutherol) isolated from the bulbs of C. paludosa exhibited promising cytotoxicity against several human tumour cell lines, especially the two main compounds, eleutherine and isoeleutherine, against glioma and breast cancer cell lines, with TGI values of between 2.6 and 13.8 μg/mL. Cipura paludosa bulbs produce active principles with relevant antiproliferative potential, such as naphthoquinone derivatives, identified as eleutherine, isoeleutherine, and eleutherol. This is the first report indicating C. paludosa with antiproliferative potential.


The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance.
Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C-->T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.


Sodium Selenite as an Anticancer Agent.
Selenium (Se) is a ubiquitous, albeit not uniformly distributed metalloid present in earth crust. Consequently, its human intake with food products, particularly grains and vegetables, is also very uneven, and in certain cases can result in a severe Se deficiency. It was also documented that Se deficiency observed in some countries and/or geographic regions (e.g. Keshan region in China), is associated with an increased morbidity and mortality of neoplastic diseases. To correct this problem a number of organic and inorganic selenium compounds were developed and tested. However, it is now firmly established that only an inorganic sodium selenite with four-valent Se, and not that with six-valent (selenate) cation shows anticancer activity. This difference in their biological activities is due to their physicochemical properties. Thus selenite (Se+4) can undergo redox reaction, for example with protein's sulfhydryl groups expressed on the surface of tumor cells. In this way selenite prevents non-enzymatic formation of parafibrin that coats tumors cells and hence presents them as 'self' to the innate cellular immune system. Consequently, macrophages of the lymphatic system do not recognize neoplastic cells as 'foreign' bodies and spare them from the immune destruction. This mechanism can explain the failure of various immunotherapies to completely eliminate tumors from human bodies. Another contributing factor to carcinogenesis is the excessive consumption of red meat containing redox-active iron (Fe+3) that initiates parafibrin formation from blood fibrinogen. In conclusion, sodium selenite is a readily available and inexpensive drug of choice in the cancer treatment and prevention.


Immunologic reactivity to soluble autochthonous tumor extracts in dogs with spontaneous malignancies.
The presence of tumor-associated antigens (TAA) in dogs with spontaneous lymphoma (L) or solid tumors (ST) was investigated by testing soluble tumor cell extracts for their ability to stimulate autochthonous in vitro lymphocyte blastogenesis and in vivo intradermal delayed hypersensitivity responses. Tumor extracts were prepared from tumor biopsies and control extracts were prepared from buffycoat cells of tumor dogs by hypertonic KCl solubilization. Blastogenic responses to intact, cryopreserved, autochthonous tumor cells were also determined. Fifteen of 26 (58%) L dogs and 23 of 32 (72%) ST dogs had positive blastogenic responses to at least one concentration of autochthonous tumor extracts. Blastogenic responses to tumor extract and to cryopreserved whole tumor cells correlated well when the tests were performed simultaneously. No consistent effect of autochthonous serum on the lymphocyte response to autochthonous tumor extract was observed. Two of 11 L dogs showed a positive skin test to autochthonous tumor extract and none reacted to control extract. Three of 21 ST dogs showed a positive skin test and two had a borderline response, while two ST dogs had a positive response to control extract. However, five of seven L and nine of 18 ST dogs were anergic as defined by failure to respond to intradermal PPD challenge after sensitization with Bacille Calmette-Guerin. In conclusion, lymphocytes from most dogs with spontaneous tumors underwent blastogenesis in vitro in response to autochthonous soluble tumor extracts, and these responses when tested simultaneously correlated well with responses to cryopreserved intact tumor cells. These results are compatible with the presence of TAA in extracts from cells of spontaneous canine tumors. Delayed skin test reactivity, however, was an uncommon and unpredictable finding, and does not appear to be useful in detecting TAA in the dog.


A versatile molecular layer-by-layer thin film fabrication technique utilizing copper(I)-catalyzed azide-alkyne cycloaddition.
We have developed a rapid and versatile layer-by-layer (LbL) thin film fabrication method using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) or "click" chemistry in the construction of molecular multilayer assemblies. Multilayers containing synthetic porphyrins, perylene diimides, and mixtures of the two have been constructed in order to highlight the versatility of this method. Characterization of thin films using UV-vis absorption, water contact angle, and electrochemical techniques indicate that multilayer growth is consistent over tens of layers. Preliminary X-ray reflectivity measurements yield an average bilayer thickness of 2.47 nm for multilayers of 1 and 3 grown on glass. Polarized absorption measurements suggest that the dense thin films exhibit moderate ordering in their molecular structure with partial alignment with respect to the surface normal.


Increased metabolism in the R6/2 mouse model of Huntington's disease.
Huntington's disease (HD) is a hereditary disorder characterized by personality changes, chorea, dementia and weight loss. The cause of this weight loss is unknown. The aim of this study was to examine body weight changes and weight-regulating factors in HD using the R6/2 mouse model as a tool. We found that R6/2 mice started losing weight at 9 weeks of age. Total locomotor activity was unaltered and caloric intake was not decreased until 11 weeks of age, which led us to hypothesize that increased metabolism might underlie the weight loss. Indeed, oxygen consumption in R6/2 mice was elevated from 6 weeks of age, indicative of an increased metabolism. Several organ systems that regulate weight and metabolism, including the hypothalamus, the stomach and adipose tissue displayed abnormalities in R6/2 mice. Together, these data demonstrate that weight loss in R6/2 mice is associated with increased metabolism and changes in several weight-regulating factors.


Atom-Precise Chiral Lanthanide-Silver(I) Heterometallic Clusters Ln3Ag5.
Three pairs of chiral Ln-Ag(I) clusters d/l-Ln3Ag5 with C3 symmetry were prepared by d/l-penicillamine as multidentate ligand bridged Ln3+ and Ag(I) ions. The chiral ligand induced the molecular cluster to be chiral, and the CD spectra of the chiral compounds d/l-Ln3Ag5 were slightly blue-shifted due to the lanthanide contraction. The studies of optical properties indicated that tunable photoluminescence from {AgS}-to-Ln3+ was achieved by introducing Ln3+ ions with different emission bands or regulating various excitation light.


A MYB-Related Transcription Factor from Lilium lancifolium L. (LlMYB3) Is Involved in Anthocyanin Biosynthesis Pathway and Enhances Multiple Abiotic Stress Tolerance in Arabidopsis thaliana.
Most commercial cultivars of lily are sensitive to abiotic stresses. However, tiger lily (Lilium lancifolium L.), one of the most widely distributed wild lilies in Asia, has strong abiotic stresses resistance. Thus, it is indispensable to identify stress-responsive candidate genes in tiger lily for the stress resistance improvement of plants. In this study, a MYB related homolog (LlMYB3) from tiger lily was functionally characterized as a positive regulator in plant stress tolerance. LlMYB3 is a nuclear protein with transcriptional activation activity at C-terminus. The expression of LlMYB3 gene was induced by multiple stress treatments. Several stress-related cis-acting regulatory elements (MYBRS, MYCRS, LTRE and DRE/CRT) were located within the promoter of LlMYB3; however, the promoter activity was not induced sufficiently by various stresses treatments. Overexpressing LlMYB3 in Arabidopsis thaliana L. transgenic plants showed ABA hypersensitivity and enhanced tolerance to cold, drought, and salt stresses. Furthermore, we found LlMYB3 highly co-expressed with LlCHS2 gene under cold treatment; yeast one-hybrid (Y1H) assays demonstrated LlMYB3 was able to bind to the promoter of LlCHS2. These findings suggest that the stress-responsive LlMYB3 may be involved in anthocyanin biosynthesis pathway to regulate stress tolerance of tiger lily.


Barriers to care for women with low-grade endometrial cancer and morbid obesity: a qualitative study.
Obesity is a major risk factor for low-grade endometrial cancer. The surgical management of patients with obesity is challenging, and they may face unique barriers to accessing care. We completed a qualitative study to understand the experiences of low-grade endometrial cancer patients with morbid obesity, from symptom onset to diagnosis to surgery. Semi-structured interviews were performed with endometrial cancer patients with morbid obesity (body mass index (BMI) >40 kg/m2) referred for primary surgery. Transcribed interviews were coded line-by-line and analysed using an interpretive descriptive approach that drew on labelling theory to understand patients' experiences. Thematic sufficiency was confirmed after 15 interviews. Two tertiary care centres in Toronto, Ontario, Canada. Fifteen endometrial cancer patients with a median age of 61 years (range: 50-74) and a median BMI of 50 kg/m2 (range: 44-70) were interviewed. Thematic analysis identified that (1) both patients and providers lack knowledge on endometrial cancer and its presenting symptoms and risk factors; (2) patients with morbid obesity are subject to stigma and poor communication in the healthcare system and (3, 4) although clinical, administrative, financial, geographic and facility-related barriers exist, quality care for patients with morbid obesity is an achievable goal. Improved education on the prevention and identification of endometrial cancer is needed for both patients and providers. Delivery of cancer care to patients with morbid obesity may be improved through provider awareness of the impact of weight stigma and establishing streamlined care pathways at centres equipped to manage surgical complexity.


Effects of thyroidectomy or thiouracil treatment on copulatory behavior in adult male rats.
Male copulatory behavior and the function of the hypothalamo-hypophysial-gonadal axis in hypothyroid male rats were investigated in the present study. Hypothyroidism was induced by thyroidectomy or thiouracil. In male copulatory behavior test, intromission latencies in hypothyroid rats were significantly longer than those in euthyroid rats and ejaculation frequencies were reduced in hypothyroid male rats compared to control rats without reduction of plasma concentrations of testosterone. These changes in copulatory behavior in hypothyroid male rats were restored to control levels by administration of T4 (5 micrograms/rat). Hypothyroidism decreased adrenal weights, and basal and peak concentrations of corticosterone during diurnal variation, whereas it increased peak concentrations of ACTH in adult male rats. These results indicate that hypothyroidism causes adrenal dysfunction directly and results in hypersecretion of ACTH. The adrenal disturbance observed in hypothyroid rats may affect male copulatory behavior.


Burden of Hand Maladies in US Emergency Departments.
Hand conditions commonly present to the emergency department (ED), yet data are lacking regarding the magnitude of hand-related conditions in the emergency setting. The purpose of this study is to describe the burden and quantify the health care resource utilization of hand conditions seen in EDs across the United States. Using the National Emergency Department Sample, we identified all ED encounters by patients at least 18 years of age that were associated with a hand condition in 2009 to 2012. The primary outcomes were prevalence, etiology, and associated health care charges for specific categories of hand conditions. The final sample included 34.4 million ED encounters associated with a common hand condition generating $180.4 billion in health care charges. The volume of hand-related presentations varied in a predictable and cyclical manner, peaking in July and waning in December of each year. Trauma was the most common etiology (77.5%) predominantly due to falls (26.2%) and lacerations (19.7%). Over 4 years, the volume of ED encounters rose (5% increase, P < .001) and as did the resulting health care charges (24.6% increase, P < .001). Our study confirms that hand-related conditions contribute significantly to ED volume and consume a growing quantity of health care resources in the United States. The volume of patients presenting to EDs with hand-related conditions fluctuates cyclically throughout the year. Open wounds are the most common cause of presentation and mostly occur in young adults, followed by joint pain, contusions, and fractures.


Ibd1p, a possible spindle pole body associated protein, regulates nuclear division and bud separation in Saccharomyces cerevisiae.
The proper spatial and temporal coordination of mitosis and cytokinesis is essential for maintaining genomic integrity. We describe the identification and characterization of the Saccharomyces cerevisiae IBD1 gene, which encodes a novel protein that regulates the proper nuclear division and bud separation. IBD1 was identified by the limited homology to byr4, a dosage-dependent regulator of cytokinesis in Schizosaccharomyces pombe. IBD1 is not an essential gene, and the knock-out cells show no growth defects except for the reduced mating efficiency [1]. However, upon ectopic expression from an inducible promoter, IBD1 is lethal to the cell and leads to abnormal nuclear division and bud separation. In detail, approximately 90% of the IBD1 overexpressing cells arrest at large bud stages with dividing or divided nuclei. In some IBD1 overexpressing cells, spindle elongation and chromosome separation occur within the mother cell, leading to anucleated and binucleate daughter cells. The anucleated cell can not bud, but the binucleate cell proceeds through another cell cycle(s) to produce a cell with multiple nuclei and multiple buds. Observations of the F-actin and chitin rings in the IBD1 overexpressing cells reveal that these cells lose the polarity for bud site selection and growth or attain the hyper-polarity for growth. Consistent with the phenotypes, the IBD1 overexpressing cells contain a broad range of DNA content, from 2 to 4 N or more. A functional Ibd1p-GFP fusion protein localizes to a single dot at the nuclear DNA boundary in the divided nuclei or to double dots in dividing nuclei, suggesting its localization on the spindle pole body (SPB). The cross-species expressions of IBD1 in S. pombe and byr4 in S. cerevisiae cause defects in shape, implicating the presence of a conserved mechanism for the control of cytokinesis in eukaryotes. We propose that Ibd1p is an SPB associated protein that links proper nuclear division to cytokinesis and bud separation.


Chiral interaction in double-wall carbon nanotubes: simple rules deduced from a large sampling of tubes.
We study a large sampling of chiral double-wall carbon nanotubes to propose simple formula describing the dependence of the interwall energy, the chiral discrimination energy, and the radial breathing mode frequencies as a function of the main characteristics of the tubes, i.e., their radius, length and chiral angle. It is shown that tube pairs with the same handedness are more stable than enantiomeric pairs, and this discrimination, though small, mainly occurs in the first step of the growth of an inner tube inside an outer one. Chiral splittings of the breathing mode frequencies for the two DWCNT diastereoisomers (n(i),m(i))@(n(o),m(o)) and (m(i),n(i))@(n(o),m(o)) can reach a few wave numbers.


[Quantitative evaluation of carotid elasticity in normal adults by ET technique].
This investigation was aimed to detect the carotid elasticity in normal adults by use of echo-tracking (ET) technique. The stiffness parameter (beta), pressure-strain elasticity modulus (Ep), arterial compliance (AC), argumentation index (AI) and one-point pulse wave velocity (PWV beta) of carotid in 145 normal adults with the average age of 47.0 were calculated. The population were divided into five groups according to age: 20-29 y, 30-39 y,40-49 y, 50-59 y and > or = 60 y. The elasticity parameters between left and right side, between male female and between different age groups were compared using SAS 6.12 statistic software. There was no difference in carotid elasticity regarding the side and gender. The carotid beta, Ep, AI and PWV beta were noted to increase with age while AC was noted to decrease with age. The carotid elasticity was found to correlate with age significantly, but not with side and gender. This change can be detected by ET technique.


Appraising qualitative research articles in medicine and medical education.
Although qualitative research is gaining recognition in medicine and in medical education, most clinical teachers do not know how to perform a critical appraisal of articles in these fields. This article describes a grid for the critical appraisal of qualitative research articles so that clinical teachers are in a better position to evaluate this type of research and to teach the critical appraisal of it. The grid is comprised of 12 items with an explanation and suggestions for additional reading for each item.


Evaluation of combined dynamic compression and single channel noise reduction for hearing aid applications.
Single-channel noise reduction (SCNR) and dynamic range compression (DRC) are important elements in hearing aids. Only relatively few studies have addressed interaction effects and typically used real hearing aids with limited knowledge about the integrated algorithms. Here the potential benefit of different combinations and integration of SCNR and DRC was systematically assessed. Ten different systems combining SCNR and DRC were implemented, including five serial arrangements, a parallel and two multiplicative approaches. In an instrumental evaluation, signal-to-noise ratio (SNR) improvement and spectral contrast enhancement (SCE) were assessed. Quality ratings at 0 and +6 dB SNR, and speech reception thresholds (SRTs) in noise were measured using stationary and babble noise. Thirteen young normal-hearing (NH) listeners and 12 hearing-impaired (HI) listeners participated. In line with an increased segmental SNR and spectral contrast compared to a serial concatenation, the parallel approach significantly reduced the perceived noise annoyance for both subject groups. The proposed multiplicative approaches could partly counteract increased speech distortions introduced by DRC and achieved the best overall quality for the HI listeners. For high SNRs well above the individual SRT, the specific combination of SCNR and DRC is perceptually relevant and the integrative approaches were preferred.


CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway.
Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells. Moreover, cystine starvation induced mitochondrial fragmentation, dysfunction, and ROS production. A mitochondrial ROS scavenger, Necrox-5, can prevent cystine-starvation-induced cell death. In addition, cystine starvation was found to activate GCN2, but not PERK, to increase the phosphorylation of eIF2α at serine 51, the protein expression of ATF4, and the expression of ATF4 target genes such as CHAC1, which might be downstream of the RIP1/RIP3-MLKL pathway and contribute to cystine-starvation-induced cell death. Knockdown of CHAC1 rescued the cystine-starvation-induced reduction in glutathione (GSH) levels and cell death. Furthermore, N-acetyl-cysteine (NAC), Trolox, and Nec-1 significantly prevented the cystine-starvation-induced increase in intracellular ROS levels, mitochondrial fragmentation and cell death. In summary, these results suggest that CHAC1 degradation of GSH enhances cystine-starvation-induced necroptosis and ferroptosis through the activated GCN2-eIF2α-ATF4 pathway in TNBC cells. Our findings improve our understanding of the mechanism underlying cystine-starvation-induced TNBC cell death.


Screening for carriage of methicillin-resistant Staphylococcus aureus shortly after exposure may lead to false-negative results.
We evaluated a double screening strategy for carriage of methicillin-resistant Staphylococcus aureus (MRSA) in patients exposed to a newly detected MRSA carrier. If the first screening of the exposed patient yielded negative results, screening was repeated 4 days later. This strategy detected 12 (28%) of the 43 new MRSA carriers identified during the study period. The results suggest that there is an incubation period before MRSA carriage is detectable.


Metabolic effects of a low-pressure tourniquet system compared with a high-pressure tourniquet system in arthroscopic anterior crucial ligament reconstruction.
Bloodless field is an integral part of orthopedic surgery. Use of tourniquet is associated with a risk of skeletal muscle ischemia and reperfusion injury. The purpose of this prospective, open-randomized study was to determine if the use of a tourniquet system using low pressure, with a wide, curved cuff connected to a microprocessor pump is safer than a standard tourniquet system with a narrow, straight cuff using higher inflation pressures. Test parameters used as markers of muscular injury and anaerobic metabolism were femoral vein blood lactate, pH, pCO2, pO2, potassium, aspartate aminotransferase activity, myoglobin, creatine kinase and creatine kinase-MM activity levels after release of tourniquet. Twenty-six ASA I-II patients were studied. Tourniquet times varied between 30 and 144 min. Deflation of the tourniquet caused a significant release of lactate, myoglobin and potassium detected in the femoral vein blood. pCO2 increased, but pH and pO2 decreased after tourniquet deflation. There were no differences between the study groups. The tourniquet time showed a significant correlation with femoral vein lactate. The main finding of this study was that the metabolic changes were more pronounced with the longer tourniquet time. The results of the study did not show any difference on metabolic markers of muscular injury during the first hour after release of tourniquet between the two tourniquet systems.


A two-phase model for flow of blood in narrow tubes with increased effective viscosity near the wall.
A two-phase model for the flow of blood in narrow tubes is described. The model consists of a central core of suspended erythrocytes and a cell-free layer surrounding the core. It is assumed that the viscosity in the cell-free layer differs from that of plasma as a result of additional dissipation of energy near the wall caused by the red blood cell motion near the cell-free layer. A consistent system of nonlinear equations is solved numerically to estimate: (i) the effective dimensionless viscosity in the cell-free layer (beta), (ii) thickness of the cell-free layer (1-lambda) and (iii) core hematocrit (H(c)). We have taken the variation of apparent viscosity (mu(app)) and tube hematocrit with the tube diameter (D) and the discharge hematocrit (H(D)) from in vitro experimental studies [16]. The thickness of the cell-free layer computed from the model is found to be in agreement with the observations [3,21]. Sensitivity analysis has been carried out to study the behavior of the parameters 1-lambda, beta, H(c), B (bluntness of the velocity profile) and mu(app) with the variation of D and H(D).


The Effects of Trauma History and Prenatal Affective Symptoms on Obstetric Outcomes.
Prenatal maternal mood may inform the adverse obstetric outcomes seen in disadvantaged populations. The contribution of having a trauma history is not well studied. We examined the impact of trauma exposure and mood symptoms on obstetric outcomes in 358 women. Women with antecedent trauma were more likely to have a history of depression, odds ratio = 2.83, 95% confidence interval [1.81, 4.42], were younger at their first pregnancy, 18.86 years versus 20.10 years, and had a higher number of previous pregnancies, 2.01 versus 1.54, compared to those with no trauma exposure. Women with prenatal anxiety had significantly smaller babies than nonanxious women, 3,313.17 g, (SD = 441.58) versus 3,429.27 g, (SD = 437.82) Trauma history magnified the effects of maternal prenatal mood on birthweight; the moderating effect was limited to those who first experienced a trauma under 18 years of age. Childhood trauma exposure increased vulnerability for low birthweight delivery associated with prenatal mood disturbance. Screening pregnant women for trauma history and current mood symptoms is indicated.


A case of a patient with both chorea and restless legs syndrome.
The patient was a 44-yr-old man with end-stage renal disease who had developed chorea as a result of hypoglycemic injury to the basal ganglia and thalamus and who was subsequently diagnosed with depression and restless legs syndrome (RLS). For proper management, the presence of a complex medical condition including two contrasting diseases, chorea and RLS, had to be considered. Tramadol improved the pain and dysesthetic restlessness in his feet and legs, and this was gradually followed by improvements in his depressed mood, insomnia, lethargy, and feelings of hopelessness. This case suggests that the dopaminergic system participates intricately with the opioid, serotoninergic, and noradrenergic systems in the pathophysiology of RLS and pain and indirectly of depression and insomnia.


Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction.
The fibroblast growth factor receptors (FGFR) play a major role in angiogenesis and are desirable targets for the development of therapeutics. Groups of Wistar Han rats were dosed orally once daily for 4 days with a small molecule pan-FGFR inhibitor (5mg/kg) or once daily for 6 days with a small molecule MEK inhibitor (3mg/kg). Serum phosphorous and FGF23 levels increased in all rats during the course of the study. Histologically, rats dosed with either drug exhibited multifocal, multiorgan soft tissue mineralization. Expression levels of the sodium phosphate transporter Npt2a and the vitamin D-metabolizing enzymes Cyp24a1 and Cyp27b1 were modulated in kidneys of animals dosed with the pan-FGFR inhibitor. Both inhibitors decreased ERK phosphorylation in the kidneys and inhibited FGF23-induced ERK phosphorylation in vitro in a dose-dependent manner. A separate cardiovascular outcome study was performed to monitor hemodynamics and cardiac structure and function of telemetered rats dosed with either the pan-FGFR inhibitor or MEK inhibitor for 3 days. Both compounds increased blood pressure (~+ 17 mmHg), decreased heart rate (~-75 bpm), and modulated echocardiography parameters. Our data suggest that inhibition of FGFR signaling following administration of either pan-FGFR inhibitor or MEK inhibitor interferes with the FGF23 pathway, predisposing animals to hyperphosphatemia and a tumoral calcinosis-like syndrome in rodents.


Metabolic health is more closely associated with decrease in lung function than obesity.
Previous studies have evaluated the link between metabolic syndrome and obesity with impaired lung function, however findings have been controversial. We aimed to compare lung function among subjects with different metabolic health and obesity status. Total 10,071 participants were evaluated at the Health Promotion Center in Seoul St. Mary's Hospital between January 2012 and December 2014. Being metabolically healthy was defined as having fewer than three of the following risk factors: high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol and abdominal obesity. Obesity status was defined as body mass index (BMI) higher than 25 kg/m2. Analyses of pulmonary function were performed in four groups divided according to metabolic health and obesity: metabolically healthy non-obese (MHNO), metabolically health obese (MHO), metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO). Metabolically unhealthy subjects were more prone to decreased lung function compared with their metabolically healthy counterparts, regardless of obesity status. When multinomial logistic regression analysis was performed according to quartiles of forced vital capacity (FVC) or forced expiratory volume in 1 second (FEV1) (% pred), after adjusting for age, sex, and smoking status, odds ratio (OR) for the lowest FVC and FEV1 (% pred) quartiles were significantly higher in MUHO subjects (1.788 [95% CI, 1.531-2.089] and 1.603 [95% CI, 1.367-1.881]) and lower in MHO subjects (0.768 [95% CI, 0.654-0.902] and 0.826 [95% CI, 0.700-0.976]) with MHNO group as the reference, when OR for highest FVC and FEV1 quartiles were considered as 1.0. Metabolic health is more closely associated with impaired lung function than obesity.


Patient-related factors influencing satisfaction in the patient-doctor encounters at the general outpatient clinic of the university of calabar teaching hospital, calabar, Nigeria.
Medical consultation is at the centre of clinical practice. Satisfaction of a patient with this process is a major determinant of the clinical outcome. This study sought to determine the proportion of patients who were satisfied with their doctor-patient encounter and the patient-related factors that affected patients' satisfaction with the consultation process. A clinic-based, cross-sectional study using a modified version of the General Practice Assessment Questionnaire (GPAQ), which employed a systematic sampling technique, was used. The questionnaires were administered on 430 patients within the ages of 18 years and 65 years. Among the 430 subjects within the ages of 18 years and 65 years studied, 200 (46.5%) were males and 230 (53.5%) were females. Only 59.3% were satisfied with their patient-doctor encounter. The patient's perception of time spent in the consultation, illness understanding after the visit, ability to cope with the illness after the visit, and ability to maintain health after visit were the only factors that affected patient's satisfaction with the consultation. In our environment, nonsatisfaction with the patient-doctor encounter is high. Only few factors considered to encourage a patients satisfaction at primary care consultation contributed to end-of-consultation satisfaction. This calls for refocusing so as to improve the overall patient care in our cultural context and meet the patient needs in our environment.


Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay.
We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.


Identification of imidazo[4,5-c]pyridin-2-one derivatives as novel Src family kinase inhibitors against glioblastoma.
Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.


Two-dimensional phases of confined 5-cyano-biphenyl: Computer simulation study.
The properties of composites of mesogens and two-dimensional (2D) materials are of great interest due to their practical applications in flexible displays, optoelectronics, microelectronics, and novel nanodevices. The properties of such composites are very complex and strongly depend on the interactions between the host material and the mesogen filling. We have performed molecular dynamics simulations for 4-cyano-4^{'}-pentylbiphenyl embedded between graphene and hexagonal 2D boron nitride layers. The structural and dynamical properties of such systems were investigated in terms of the order parameters, density profiles, mean square displacement, and autocorrelation function of the single-molecule dipole moment. Our simulations have shown that the mesogenic molecules form highly stable ordered layered structures and that their dynamics are strongly related to the structural properties. We have investigated not only the effects of the polarization of the host material, but also the effects of the spatial repetition of such composites by using two models of mesogens embedded in 2D layers: the direct sheet and the structure formed by multiplying a single unit of the composite in the direction perpendicular to the substrate surface.


Flow-Driven Assembly of Microcapsules into Three-Dimensional Towers.
By harnessing biochemical signaling and chemotaxis, unicellular slime molds can aggregate on a surface to form a long, vertical stalk. Few synthetic systems can self-organize into analogous structures that emerge out of the plane. Through computational modeling, we devise a mechanism for assembling tower-like structures using microcapsules in solution as building blocks. In the simulations, chemicals diffusing from a central patch on a surface produce a concentration gradient, which generates a radially directed diffusioosmotic flow along the surface toward the center. This toroidal roll of a fluid pulls the microcapsules along the surface and lifts them above the patch. As more capsules are drawn toward the patch, some units are pushed off the surface but remain attached to the central microcapsule cluster. The upward-directed flow then draws out the cluster into a tower-like shape. The final three-dimensional (3D) structure depends on the flow field, the attractive capsule-capsule and capsule-surface interaction strengths, and the sedimentation force on the capsules. By tuning these factors, we can change the height of the structures that are produced. Moreover, by patterning the areas of the wall that are attractive to the capsules, we can form multiple vertical strands instead of a single tower. Our approach for flow-directed assembly can permit the growth of reconfigurable, 3D structures from simple subunits.


Cutaneous lupus erythematosus: clinico-pathologic correlation.
Cutaneous lupus erythematosus (CLE) is a chronic-relapsing disease. It is defined as a LE localized to the skin without any significant systemic symptoms. Its annual incidence is of 4 cases per 100,000 persons with a prevalence of 73 cases per 100,000 persons. The etiology is unknown but it is considered as a prototype of autoimmune disease in which genetic factors (HLA), environmental factors (photo exposure and cigarette smoking) and pharmacological agents play an important role. The most accepted classification includes three clinical variants: acute (ACLE), subacute (SCLE) and chronic (CCLE). A fourth variety is the intermittent form (ICLE) also called "lupus tumidus" (LET) which is considered by some authors a distinct form from CCLE. The skin lesions are subdivided into LE specific and LE non-specific. The latter have a considerable importance as a symptom of evolution of the disease towards a systemic form of lupus (SLE). The histopathology of CLE is characterized by an interface dermatitis with vacuolization of the basal layer, a predominantly lymphocytic, perivascular and periadnexal infiltrate, epidermal and follicular hyperkeratosis, deposit of positive PAS material at the dermo-epidermal junction leading to atrophic-cicatricial evolution. Depending on the clinical variants, these microscopic features are more or less evident and are associated with peculiarities such as deposits of mucin (SCLE and LET), involvement of the panniculus in LE panniculitis, disappearance of the adnexa (cicatricial alopecia). The relationship between SLE/CLE is still under study: the progression of CLE in SLE is reported in a variable percentage of cases ranging from 12 to 18%. CLE therapy is aimed at preventing recurrences and scarring outcomes. Photoprotection with clothing, chemical and physical sunscreens active on UVA and UVB radiations is very important. Topical therapy is based on the use of steroids and calcineurin inhibitors, while the systemic therapy includes hydroxychloroquine as the first drug of choice.


[Research Progress of Application of Microfluidics Techniques in Cryopreservation].
Microfluidics technology may be an effective method to solve some problems in cryopreservation. This review presents the research progress of microfluidics technology in the field of cell membrane transport properties, cryoprotectant addition and washout and the vitrification for cryopreservation of biological materials. Existing problems of microfluidics technology in the application of cryopreservation are summarized and future research directions are indicated as well.


Neospora caninum in beef herds in New South Wales, Australia. 2: analysis of risk factors.
To determine the influence of farm-level and animal-level factors on the seroprevalence of antibodies to Neospora caninum and associations between seropositivity and reproductive outcomes. A questionnaire for a cross-sectional survey was posted to the 63 properties with a herd size ≥50 beef breeding cows that had participated in a previous seroprevalence study. Correspondence analysis, which does not appear to have been used previously in any Australian studies of livestock diseases, was used in conjunction with logistic regression to analyse the data. Geographic factors that increased the risk of seropositivity included higher rainfall North Coast location. Herd management factors that increased the risk of seropositivity included the use of Bos indicus genetics, cross-breeding and running several breeds in the one herd. Using fox control measures was found to be protective against infection with N. caninum. The risk of abortion was 12-fold greater in individual animals that were seropositive for N. caninum. Within a herd, the calving rate was 10.4% lower in herds with one or more N. caninum-positive animals (P = 0.03), but the difference in abortion rate was not significant between seropositive and seronegative herds (0.3% higher, P > 0.3). This study confirmed previous observations of increased risks for N. caninum seropositivity with being located in the coastal subtropics, some styles of herd management and canid exposure. In addition, it suggested that cross-breeding and proximity to an urban area may increase the risk, and that having pet dogs may reduce the risk of seropositivity.


Intracranial vessel wall imaging framework - Data acquisition, processing, and visualization.
Assessment of vessel walls is an integral part in diagnosis and disease monitoring of vascular diseases such as vasculitis. Vessel wall imaging (VWI), in particular of intracranial arteries, is the domain of Magnetic Resonance Imaging (MRI) - but still remains a challenge. The tortuous anatomy of intracranial arteries and the need for high resolution within clinically acceptable scan times require special technical conditions regarding the hardware and software environments. In this work a dedicated framework for intracranial VWI is presented offering an optimized, black-blood 3D T1-weighted post-contrast Compressed Sensing (CS)-accelerated MRI sequence prototype combined with dedicated 3D-GUI supported post-processing tool for the CPR visualization of tortuous arbitrary vessel structures. Using CS accelerated MRI sequence, the scanning time for high-resolution 3D black-blood CS-space data could be reduced to under 10 min. These data are adequate for a further processing to extract straightened visualizations (curved planar reformats - CPR). First patient data sets could be acquired in clinical environment. A highly versatile framework for VWI visualization was demonstrated utilizing a post-processing tool to extract CPR reformats from high-resolution 3D black-blood CS-SPACE data, enabling simplified and optimized assessment of intracranial arteries in intracranial vascular disorders, especially in suspected intracranial vasculitis, by stretching their tortuous course. The processing time from about 15-20 min per patient (data acquisition and further processing) allows the integration into clinical routine.