Effects of moderate energy restriction on physical performance and substrate utilization in non-obese men.
Energy restriction (ER) has shown to be an effective 'anti-aging' factor in rodents, resulting in an increased life span and preventing or delaying the occurrence of many age-related diseases in rodents. As a part of a feasibility study on the potential application of ER in humans, we studied the effects of moderate ER on physical performance in 24 apparently healthy, non-obese middle-aged men. After two weeks of weight maintenance the ER group (n = 16) received 80% of their habitual energy intake, while a control group (n = 8) still received their weight-maintaining diet for ten weeks. Physical performance (bicycle ergometer) was estimated by a maximal (until exhaustion) and a submaximal (30 min at 60% of VO2max) exercise test. After the experimental period the subjects in ER group had a significantly shorter cycling time (delta = 1.31 +/- 1.14 vs -0.45 +/- 1.56 min, p = 0.01), and thus had a lower maximal power output (delta = 4.3 +/- 5.9 vs -6.3 +/- 13.6 watt, p < 0.05) and maximal oxygen uptake (delta = 0.03 +/- 0.18 vs -0.18 +/- 0.321/min, p = 0.05) during the maximal exercise test, than the subjects in the control group. None of these changes correlated with weight loss. As in every exercise test, motivation could have played an important role. During the submaximal exercise test no significant changes between the two groups in HR, VO2, RER and FFA, glucose, lactate and catecholamine levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced high-energy phosphate levels in rat hearts. II. Effects of sodium cyanate.
The effects of increased blood-oxygen affinity, due to carbamylation of hemoglobin in vivo, on aerobic metabolism in the heart were studied in rats. Adult male rats were injected intraperitoneally 3 times weekly for 10 wk with sodium cyanate (60 mg/kg). Significant derangement of blood-oxygen interaction was observed. Oxygen-dissociation curves were left shifted by 13 mmHg (35.1-21.8), and the overall deoxygenation rate (k) was reduced 41% (6.142-3.624; s(-1)); P is less than 0.001 for each parameter. Heart ATP and PCr levels were reduced (ATP: 19.4-16.7; PCr: 15.0-11.0, mum/g dry wt; P is less than 0.001 for each). In addition, glycogen levels fell (161.4-112.9, mum C6/g dry wt; P is less than 0.001). Myocardial lactate levels increased 54% (2.6-4.0, mum/g dry wt; P is less than 0.01) in the cyanate-treated group. These findings strongly suggest a hypoxia-induced activation of glycolysis as a consequence of altered oxidative metabolism in rats treated with sodium cyanate.


Carbon-Based Adsorbents for Postcombustion CO2 Capture: A Critical Review.
The persistent increase in atmospheric CO2 from anthropogenic sources makes research directed toward carbon capture and storage imperative. Current liquid amine absorption technology has several drawbacks including hazardous byproducts and a high-energy requirement for regeneration; therefore, research is ongoing to develop more practical methods for capturing CO2 in postcombustion scenarios. The unique properties of carbon-based materials make them specifically promising for CO2 adsorption at low temperature and moderate to high partial pressure. This critical review aims to highlight the development of carbon-based solid sorbents for postcombustion CO2 capture. Specifically, it provides an overview of postcombustion CO2 capture processes with solid adsorbents and discusses a variety of carbon-based materials that could be used. This review focuses on low-cost pyrogenic carbon, activated carbon (AC), and metal-carbon composites for CO2 capture. Further, it touches upon the recent progress made to develop metal organic frameworks (MOFs) and carbon nanomaterials and their general CO2 sorption potential.


Developing age-friendly cities and communities in Australia.
The aim of the study is to present case studies and assess the impact of political, policy, consultative, and research processes used to implement Age Friendly Cities (AFC) initiatives in Australia. A review and interpretation was conducted based on public documents, community consultations, survey analyses, and participant observation. Governments in Australia have drawn on World Health Organization (WHO) concepts to establish AFC initiatives. In Melbourne, state political leadership established Positive Ageing plans that have reinforced local government actions. In Canberra, a baseline survey and an Older Persons Assembly were followed by modest positive ageing plans. In Sydney, a State Ageing Strategy developed a whole-of-government plan that has yet to be incorporated into budget processes. AFC initiatives in Australia have had promising and varied starts with some aims to benefit disadvantaged older people. Notwithstanding the potential benefits, AFC influence on mainstream actions of government has been limited by uncertain political commitment and growing fiscal austerity.


Laser curettage: where do we stand?
The literature suggests that curettage has no benefit beyond traditional scaling and root planing. However, claims abound as to the benefits of curettage with the laser, including less postoperative pain, less bleeding, and reduction in microbial count. This paper explores whether any of these claims are true and whether laser curettage has any benefit in periodontal treatment.


West Nile virus infection in horses in Jordan: clinical cases, seroprevalence and risk factors.
The objectives of this study are to report clinical WNV infection in horses and to determine the seroprevalence of and risk factors for WNV infection in horses in Jordan. In late summer and early fall of 2012, two mares were presented for evaluation of neurological signs. The first mare had hind-limb ataxia. The second mare was slightly depressed and lethargic. She had ataxia in her four limbs and cranial nerves deficits. Both horses were found positive for WNV IgM antibodies using commercial IgM-capture ELISA test. Both horses were treated symptomatically and recovered uneventfully. The occurrence of clinical cases initiated the need for a seroprevalence and risk factors study. Two hundred and fifty-three normal horses were randomly enrolled in the study. Enrolled horses were grouped into five major regions according to the geographical proximity and climatic similarities. From each region, around 50 horses were sampled. The serum collected from each horse was screened by a competitive ELISA, and those that reacted positive using the previous ELISA test were further tested using commercial IgM-capture ELISA test. Sixty-three horses (24.9%) of the 253 surveyed were seropositive to WNV. Of the 63 horses, none had IgM antibodies for WNV. The region with the highest prevalence was Jordan Valley and Balqa. Horses used for polo (OR = 9.77; 95%CI = 1.32-25.44) and horses located in Jordan Valley and Balqa region (OR = 13.31; 95% CI = 2.33-32.54) were identified as risk factors for seropositivity to WNV in Jordan. These risk factors were attributed to the hot and humid weather, which enhance vector availability. West Nile virus appears to be endemic in Jordan. Future studies are warranted to evaluate the virus situation in the country during the next few years in an attempt to control it.


Adeno-Associated Virus Vector-Mediated Expression of Antirespiratory Syncytial Virus Antibody Prevents Infection in Mouse Airways.
Infants and older adults are especially vulnerable to infection by respiratory syncytial virus (RSV), which can cause significant illness and irreparable damage to the lower respiratory tract and for which an effective vaccine is not readily available. Palivizumab, a recombinant monoclonal antibody (mAb), is an approved therapeutic for RSV infection for use in high-risk infants only. Due to several logistical issues, including cost of goods and scale-up limitations, palivizumab is not approved for other populations that are vulnerable to severe RSV infections, such as older adults. In this study, we demonstrate that intranasal delivery of adeno-associated virus serotype 9 (AAV9) vector expressing palivizumab or motavizumab, a second-generation version of palivizumab, significantly reduced the viral load in the lungs of the BALB/c mouse model of RSV infection. Notably, we demonstrate that AAV9 vector-mediated prophylaxis against RSV was effective despite the presence of serum-circulating neutralizing AAV9 antibodies. These findings substantiate the feasibility of repeatedly administering AAV9 vector to the airway for seasonal prophylaxis against RSV, thereby expanding the application of vectored delivery of mAbs as an effective prophylaxis strategy against various airborne viruses.


Oscillatory states in thermal convection of a paramagnetic fluid in a cubical enclosure subjected to a magnetic field gradient.
We report experimental and numerical studies of combined natural and magnetic convection of a paramagnetic fluid inside a cubical enclosure heated from below and cooled from above and subjected to a magnetic field gradient. Values of the magnetic field gradient are in the range 9≤|grad|b(0)|(2)|≤900 T(2)/m for imposed magnetic field strengths in the center of the superconducting magnet bore of 1≤|b(0)|(max)≤10 T. Very good agreement between experiments and simulation is obtained in predicting the integral heat transfer over the entire range of working parameters (i.e., thermal Rayleigh number 1.15×10(5)≤Ra(T)≤8×10(6), Prandtl number 5≤Pr≤700, and magnetization number 0≤γ≤58.5). We present a stability diagram containing three characteristic states: steady, oscillatory (periodic), and turbulent regimes. The oscillatory states are identified for intermediate values of Pr (40≤Pr≤70) and low magnetic field (|b(0)|(max)≤2 T). Turbulent states are generated from initially stable flow and heat transfer regimes in the range of 70≤Pr≤500 for sufficiently strong magnetic field (|b(0)|(max)≥4 T).


Spectral broadening of the Soret band in myoglobin: an interpretation by the full spectrum of low-frequency modes from a normal modes analysis.
In this work the temperature dependence of the Soret band line shape in carbon-monoxy myoglobin is re-analyzed by using both the full correlator approach in the time domain and the frequency domain approach. The new analyses exploit the full density of vibrational states of carbon-monoxy myoglobin available from normal modes analysis, and avoid the artificial division of the entire set of vibrational modes coupled to the Soret transition into "high-frequency" and "low-frequency" subsets; the frequency domain analysis, however, makes use of the so-called short-times approximation, while the time domain one avoids it. Time domain and frequency domain analyses give very similar results, thus supporting the applicability of the short-times approximation to the analysis of hemeprotein spectra; in particular, they clearly indicate the presence of spectral heterogeneity in the Soret band of carbon-monoxy myoglobin. The analyses also show that a temperature dependence of the Gaussian width parameter steeper than the hyperbolic cotangent law predicted by the Einstein harmonic oscillator and/or a temperature dependence of inhomogeneous broadening are not sufficient to obtain quantitative information on the magnitude of an-harmonic contributions to the iron-heme plane motion. However, the dependence of the previous two quantities may be used to obtain semiquantitative information on the overall coupling of the Soret transition to the low-frequency modes and therefore on the dynamic properties of the heme pocket in different states of the protein.


Effect of body composition on metabolic responses to carbohydrate feeding in males during exposure to 8, 12, and 27 degrees C.
The effect of body composition on thermoregulation in response to a feeding regime was evaluated in eight male volunteers (21-27 years of age) during 120 min of exposure at 8, 12, and 27degrees C. Subjects were divided with respect to body fat [high fat (HF) = 19-28%, N = 4: low fat (LF) = 10-15%, N= 4] and randomly assigned the three air temperature conditions twice to examine the thermogenic effect of a sequential timed feeding regime of either a carbohydrate (CHO) or placebo (PL) beverage during exposure. Tissue insulation (I), rectal temperature (T(re)), mean skin temperature (T(sk)), metabolism (M), and respiratory exchange ratio (R) were examined. T(re), T(sk), M, and I revealed no significant differences between treatment (PL vs. CHO) at any temperature (8, 12, or 27 degrees C). However, pooled T)(sk) at 27 degrees C, and pooled I at 12 degrees C revealed significant (p < .05) differences between the LF and HF groups. In addition, at 8, 12, and 27 degrees C, pooled T(re), T(sk), and I decreased (p < .05) during the length of exposure, whereas pooled M increased (p < .05) at 8 and 12 degrees C. Pooled R increased during the length of exposure (p < .05) at 8 and 12 degrees C and differed (p < .05) between the LF and HF groups at 8 degrees C only. From these data, it appears that whereas substrate utilization differed between dietary treatment (8 degrees C) and across time (8 and 12 degrees C), there was a differential effect between LF and HF groups (T(sk) at 27 degrees C and I at 12 degrees C) that was not influenced by feeding regime.


The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride.
Ketamine hydrochloride was administered intravenously to unpremedicated and xylazine-treated calves. The plasma concentrations of ketamine and norketamine were measured at several time intervals after drug administration and the data were fitted to a two-compartment open model. In unpremedicated female calves the distribution and elimination half-lives averaged 6.9 and 60.5 min, respectively. The volume of the central compartment was 1.21 l/kg and the peripheral compartment was 4.04 l/kg. Total body clearance of ketamine averaged 40.4 ml/min/kg. Premedication with xylazine, whilst not affecting the half-lives significantly, reduced volumes of distribution and the clearance rate of the drug by approximately 50%. The results for the male calves which were premedicated were intermediate between the two groups of female calves.


Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits.
Epsin consists of an epsin NH(2)-terminal homology domain that promotes interaction with phospholipids, several AP-2-binding sites, two clathrin-binding sequences and several Eps15 homology domain-binding motifs. Epsin additionally possesses ubiquitin-interacting motifs (UIMs) and has been demonstrated to bind ubiquitinated cargo. We therefore investigated whether epsin promoted clathrin-mediated endocytosis of the ubiquitinated EGF receptor (EGFR). By immunoprecipitation, we found that epsin 1 interacted with ubiquitinated EGFR and that functional UIMs were essential for complex formation. Furthermore, RNA interference-mediated knockdown of epsin 1 was found to inhibit internalization of the EGFR, while having no effect on endocytosis of the transferrin receptor. Additionally, upon knockdown of epsin 1, translocation of the EGFR to central parts of clathrin-coated pits was inhibited. This supports the contention that epsin 1 promotes endocytosis of the ubiquitinated EGFR.


Multimodal Treatment of Vasoactive Intestinal Polypeptide-producing Pancreatic Neuroendocrine Tumors with Liver Metastases.
A 53-year-old man presented with diarrhoea and hypokalaemia and was diagnosed with a neuroendocrine tumour of unknown origin with multiple liver metastases. Somatostatin analogues led to a reduction in the size of the tumours and improvement of his symptoms. However, after several years, the tumours grew in size, and the patient's clinical symptoms recurred. The patient underwent transcatheter arterial embolization (TAE) of the hepatic artery to treat the liver metastases. Immediately after embolization, the symptoms disappeared. Although the patient had an unresectable vasoactive intestinal polypeptide-producing neuroendocrine tumour, the endocrine symptoms were able to be controlled with chemotherapy and TAE, resulting in a long-term survival.


Rho GDP dissociation inhibitor alpha interacts with estrogen receptor alpha and influences estrogen responsiveness.
Estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor that regulates expression of estrogen-responsive genes. Upon binding of the ligand-occupied ER alpha to estrogen response elements (EREs) in DNA, the receptor interacts with a variety of coregulatory proteins to modulate transcription of target genes. We have isolated and identified a number of proteins associated with the DNA-bound ER alpha. One of these proteins, Rho guanosine diphosphate (GDP) dissociation inhibitor alpha (RhoGDI alpha), is a negative regulator of the Rho family of GTP-binding proteins. In this study, we demonstrate that endogenously expressed RhoGDI alpha is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, and that RhoGDI alpha binds directly to ER alpha, alters the ER alpha-ERE interaction, and influences the ability of ER alpha to regulate transcription of a heterologous estrogen-responsive reporter plasmid in transient transfection assays as well as endogenous, estrogen-responsive genes in MCF-7 cells. Our studies suggest that, in addition to the activity of RhoGDI alpha in the cytoplasm, it also influences ER alpha signaling in the nucleus.


Revisiting Bloom's taxonomy for ethics and other educational domains.
In the process of developing competency-based health services administration education, the Ethics Faculty Forum Co-Chairs from the Association of University Programs in Health Administration (AUPHA) were asked not only to identify their domains and competencies, but also to review six other faculty fora research outcomes. This article was written by the Ethics Faculty Forum Co-Chairs in response to the AUPHA request. Reviewing the work of the original six faculty fora using Bloom's taxonomy, we found that the fora focused mainly on the cognitive objectives and generally did not consider the affective objectives. The intent of this paper is to help those who teach healthcare ethics refine their current courses to include both cognitive and affective objectives. The paper pursues five objectives: 1. review of Bloom's taxonomy as a framework for creating course objectives in both the cognitive and affective domains; 2. present fora research and their domain outcomes; 3. present an overview of healthcare ethics literature; 4. provide a demonstration of healthcare ethics competencies in both the cognitive and affective domains; and 5. present possible directions for healthcare ethics and other educational domain research.


Food iron absorption in human subjects. III. Comparison of the effect of animal proteins on nonheme iron absorption.
The ability of various animal proteins to enhance the absorption of dietary nonheme iron was evaluated by performing multiple radioiron absorption measurements in 70 volunteer subjects. Protein equivalent substitutions of nine animal foods were made in two basic test meals. The first was a standard meal of high iron availability (mean absorption, 8.3%) containing beef muscle as the animal protein. The second was a semisynthetic meal of low iron availability (mean absorption, 1.4%) containing ovalbumin as the protein source. Two categories of animal protein were defined. Substitution of beef, lamb, pork, liver, fish, and chicken for the egg ovalbumin in the sannisynthetic meal resulted in a significant, 2-fold to 4-fold increase in iron absorption whereas no increase was observed with milk, cheese, or egg. Reciprocal findings were obtained when these foods were substituted for the beef contained in the standard meal. All sources of animal proteins are not equivalent in their effect on nonheme iron absorption.


BCNU solubility and toxicity in the treatment of malignant astrocytomas.
Administration of BCNU into the carotid artery as treatment for malignant astrocytomas has produced retinal and brain toxicity. It is unclear whether the BCNU diluent, ethanol, is the cause of the toxicity, but the elimination of the ethanol is an attractive possibility. Clinically, decreasing the ethanol from 2.0 ml/100 mg BCNU to 0.75 ml/100 mg BCNU resulted in a marked decrease in eye toxicity. To simulate this clinical situation, three 500-mg solutions of BCNU, ethanol, and saline were prepared, decreasing the ethanol concentration from 3.0 ml to 2.0 ml to 0.75 ml/100 mg BCNU. The amount of BCNU recovered in vitro after simulated clinical administration of the three solutions decreased from 84.9% to 38.3% as the diluent decreased. Therefore, drug delivery at a fixed BCNU dose will decrease with the amount of ethanol diluent used. The clinical decrease in eye toxicity must be partly attributed to a decrease in the amount of BCNU delivered to the retina. Simulated administration of a solution of 500 mg BCNU/150 ml of 5% dextrose in water (D5W) gave 83.7% BCNU recovery. The D5W gives solubility comparable to that provided by 3.0 ml ethanol to each 100 mg BCNU, and its use eliminates ethanol as a potential retinal and brain toxin.


[Characteristics of the cytodifferentiation of omega-particle symbiotic bacteria from the micronucleus of Paramecium caudata clone M1-48].
The structure of the omega-particle-bacteria, growing in the micronucleus of Paramecium caudatum (Ciliata, Protozoa), was studied by electrom microscopy in the course of their life cycle. The cytoplasm of the spindle-shaped vegetative cells contains a large number of dense particles and transparent regions comprising the fibrillar material. Such cells, via several intermediate stages, are transformed into elongated twisted cells that are regarded as spores. The spore consists of two parts: homogeneous, and that containing the membrane system and rounded light bodies. The membranes are often double and connected with the fibrils. The cell wall is constructed, during all stages, of the outer membrane layer and the inner electron-dense layer.


Reversible Changes in Resistance of Perovskite Nickelate NdNiO3 Thin Films Induced by Fluorine Substitution.
Perovskite nickel oxides are of fundamental as well as technological interest because they show large resistance modulation associated with phase transition as a function of the temperature and chemical composition. Here, the effects of fluorine doping in perovskite nickelate NdNiO3 epitaxial thin films are investigated through a low-temperature reaction with polyvinylidene fluoride as the fluorine source. The fluorine content in the fluorinated NdNiO3-xFx films is controlled with precision by varying the reaction time. The fully fluorinated film (x ≈ 1) is highly insulating and has a bandgap of 2.1 eV, in contrast to NdNiO3, which exhibits metallic transport properties. Hard X-ray photoelectron and soft X-ray absorption spectroscopies reveal the suppression of the density of states at the Fermi level as well as the reduction of nickel ions (valence state changes from +3 to +2) after fluorination, suggesting that the strong Coulombic repulsion in the Ni 3d orbitals associated with the fluorine substitution drives the metal-to-insulator transition. In addition, the resistivity of the fluorinated films recovers to the original value for NdNiO3 after annealing in an oxygen atmosphere. By application of the reversible fluorination process to transition-metal oxides, the search for resistance-switching materials could be accelerated.


Time trends of persistent organic pollutants and heavy metals in umbilical cord blood of Inuit infants born in Nunavik (Québec, Canada) between 1994 and 2001.
Inuit inhabitants of Nunavik (northern Québec, Canada) consume great quantities of marine food and are therefore exposed to high doses of food chain contaminants. In this study, we report the time trends of persistent organic pollutants, mercury, and lead in umbilical cord blood of infants from three communities of the east coast of Hudson Bay in Nunavik. We analyzed 251 cord blood samples collected from 1994 through 2001 for polychlorinated biphenyls (PCBs), dichlorodiphenyl trichloroethane (DDT), dichlorodiphenyl dichloroethylene (DDE), hexachlorobenzene (HCB), chlordanes, lead, and mercury. Using an exponential model, we found strongly significant decreasing trends for PCBs (7.9% per year, p < 0.001), DDE (9.1% per year, p < 0.001), DDT (8.2% per year, p < 0.001), and HCB (6.6% per year, p < 0.01). No significant trends were detected for chlordanes. A significant reduction of lead and mercury concentrations was found, but there was no clear linear or exponential trend. The decreases observed could be explained by a decrease in food contamination, by changes in dietary habits, or, most likely, by a combination of both.


Polar growth in the infectious hyphae of the phytopathogen ustilago maydis depends on a virulence-specific cyclin.
The maize smut fungus Ustilago maydis switches from yeast to hyphal growth to infect maize (Zea mays) plants. This switching is promoted by mating of compatible cells and seems to be required for plant penetration. Although many genes distinctively expressed during this dimorphic switch have been identified and shown to be essential for the infection process, none seems to be explicitly required for polar growth control. Here, we report the characterization of pcl12, encoding a cyclin that interacts specifically with Cdk5, an essential cyclin-dependent kinase with regulatory roles in morphogenesis in U. maydis. Pcl12 fulfills the requirements to be a virulence-specific regulator of polar growth in U. maydis. First, pcl12 expression is induced during the pathogenic development. Secondly, Pcl12 is sufficient to induce hyperpolarized growth in U. maydis cells, as haploid cells overexpressing pcl12 in axenic conditions produce filaments that were morphologically indistinguishable from those produced during the infection process. Finally, cells defective in pcl12 showed impaired polar growth during the formation of the b-dependent filament, the induction of the conjugation tubes, or the formation of a promycelium in spore germination. However, in spite of this pivotal role during morphogenesis, pcl12 mutants were virulent. We discuss the implications of these results for the role of polar growth during the infection process.


Scaling Up Global Mental Health Services During the COVID-19 Pandemic and Beyond.
Every health care system requires an adequate health care workforce, service delivery, financial support, and information technology. During the COVID-19 pandemic, global health systems were ill prepared to address the rising prevalence of mental health problems, especially in low- and middle-income countries (LMICs), thereby increasing treatment gaps. To close these gaps globally, task shifting and telepsychiatry should be made available and maximized, particularly in LMICs. Task shifting to nonspecialist health workers to improve essential mental health coverage and encourage efficient use of the available resources and technology has become the most viable strategy.


Haploid selection within a single ejaculate increases offspring fitness.
An inescapable consequence of sex in eukaryotes is the evolution of a biphasic life cycle with alternating diploid and haploid phases. The occurrence of selection during the haploid phase can have far-reaching consequences for fundamental evolutionary processes including the rate of adaptation, the extent of inbreeding depression, and the load of deleterious mutations, as well as for applied research into fertilization technology. Although haploid selection is well established in plants, current dogma assumes that in animals, intact fertile sperm within a single ejaculate are equivalent at siring viable offspring. Using the zebrafish Danio rerio, we show that selection on phenotypic variation among intact fertile sperm within an ejaculate affects offspring fitness. Longer-lived sperm sired embryos with increased survival and a reduced number of apoptotic cells, and adult male offspring exhibited higher fitness. The effect on embryo viability was carried over into the second generation without further selection and was equally strong in both sexes. Sperm pools selected by motile phenotypes differed genetically at numerous sites throughout the genome. Our findings clearly link within-ejaculate variation in sperm phenotype to offspring fitness and sperm genotype in a vertebrate and have major implications for adaptive evolution.


Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex.
The enzymes that regulate the brain arachidonic acid (AA) cascade have been implicated in bipolar disorder and neuroinflammation. Fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats decreases the concentration of docosahexaenoic acid (DHA) and increases its half-life within the brain. Based on this, we hypothesized that such dietary deprivation would decrease expression of enzymes responsible for the metabolic loss of DHA while increasing expression of those responsible for the metabolism of AA. Fifteen weeks of n-3 PUFA deprivation significantly decreased the activity, protein and mRNA expression of the DHA regulatory phospholipase A2 (PLA2), calcium-independent iPLA2, in rat frontal cortex. In contrast the activities, protein and mRNA levels of the AA selective calcium-dependent cytosolic phospholipase (cPLA2) and secretory sPLA2 were increased. Cyclooxygenase (COX)-1 protein but not mRNA was decreased in the n-3 PUFA-deprived rats whereas COX-2 protein and mRNA were increased. This study suggests that n-3 PUFA deprivation increases the half-live of brain DHA by downregulating iPLA2. The finding that n-3 PUFA deprivation increases cPLA2, sPLA2 and COX-2 is opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests that n-3 PUFA deprivation may increase susceptibility to bipolar disorder.


[Pharmacological studies on expectorants (author's transl)].
Perry and Boyd's method described in 1941 appears to be the most suitable for evaluating the efficacy of expectorants. In this method, changes in volume of respiratory tract fluid (RTF) collected by postural drainage from animals breathing air kept at a constant temperature and humidity are used as criteria. We attempted to improve on the method and to establish the optimum experimental conditions for rabbits. Accordingly, an air conditioning apparatus and tracheal cannula were re-designed and basic experimental conditions essential for quantitative collection of RTF were studied. Using this method, the effects of drugs on the volume of respiratory tract fluid (VRTF) were determined. Bromhexine and emetine as expectorants increased VRTF, and the former showed far more remarkable effects. Codeine and dextromethorphan as antitussives, isoproterenol, clorprenaline and C-78 as bronchodilators decreased VTRF. On the other hand, fominoben and eprazinone as antitussives increased VRTF. Our findings with application of this new approach indicate that this method is applicable for evaluating not only the efficacy of expectorants which increase VRTF but also that of other drugs which decrease VRTF.


Ntr1 activates the Prp43 helicase to trigger release of lariat-intron from the spliceosome.
DEAD/H-box NTPases remodel the spliceosome at multiple steps during the pre-mRNA splicing cycle. The RNA-dependent NTPase Prp43 catalyzes dissociation of excised lariat-intron from the spliceosome, but it is unclear how Prp43 couples the energy of ATP hydrolysis to intron release. Here, we report that activation of Prp43's inherently feeble helicase activity by the splicing factor Ntr1 is required for lariat-intron release. Lethal Prp43 mutants T384A and T384V, which are active for ATP hydrolysis and fail to dissociate lariat-intron from spliceosomes, are refractory to stimulation of RNA unwinding by Ntr1. An N-terminal 120-amino-acid segment of Ntr1 suffices for binding to Prp43 and for stimulating its helicase activity. We identify missense mutations in Prp43 and Ntr1 that disrupt protein-protein interaction and impair Ntr1 enhancement of Prp43 RNA unwinding. Our results demonstrate for the first time that regulating the motor activity of a DEAH-box protein by an accessory factor is critical for mRNA splicing.


Cost-effectiveness analysis of implants versus autologous perforator flaps using the BREAST-Q.
Reimbursement has been recognized as a physician barrier to autologous reconstruction. Autologous reconstructions are more expensive than prosthetic reconstructions, but provide greater health-related quality of life. The authors' hypothesis is that autologous tissue reconstructions are cost-effective compared with prosthetic techniques when considering health-related quality of life and patient satisfaction. A cost-effectiveness analysis from the payer perspective, including patient input, was performed for unilateral and bilateral reconstructions with deep inferior epigastric perforator (DIEP) flaps and implants. The effectiveness measure was derived using the BREAST-Q and interpreted as the cost for obtaining 1 year of perfect breast health-related quality-adjusted life-year. Costs were obtained from the 2010 Nationwide Inpatient Sample. The incremental cost-effectiveness ratio was generated. A sensitivity analysis for age and stage at diagnosis was performed. BREAST-Q scores from 309 patients with implants and 217 DIEP flap reconstructions were included. The additional cost for obtaining 1 year of perfect breast-related health for a unilateral DIEP flap compared with implant reconstruction was $11,941. For bilateral DIEP flaps compared with implant reconstructions, the cost for an additional breast health-related quality-adjusted life-year was $28,017. The sensitivity analysis demonstrated that the cost for an additional breast health-related quality-adjusted life-year for DIEP flaps compared with implants was less for younger patients and earlier stage breast cancer. DIEP flaps are cost-effective compared with implants, especially for unilateral reconstructions. Cost-effectiveness of autologous techniques is maximized in women with longer life expectancy. Patient-reported outcomes findings can be incorporated into cost-effectiveness analyses to demonstrate the relative value of reconstructive procedures.


F-18 stilbenes as PET imaging agents for detecting beta-amyloid plaques in the brain.
Imaging agents targeting beta-amyloid (Abeta) may be useful for diagnosis and treatment of patients with Alzheimer's disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Abeta plaques in AD brain homogenates (Ki = 15 +/- 6 and 5.0 +/- 1.2 nM, respectively). In vivo biodistributions of [18F]3e and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75% dose/g at 2 min), and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Abeta plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Abeta plaque imaging agents for studying patients with AD.


Testicular germ cell tumours: should current classification be revised?
The potential inadequacies of current classifications of germ cell tumours are examined in the light of recent evidence high-lighting their high incidence of HCG and AFP production together with the responsible cell types.


Fast and Accurate Prediction of Numerical Relativity Waveforms from Binary Black Hole Coalescences Using Surrogate Models.
Simulating a binary black hole coalescence by solving Einstein's equations is computationally expensive, requiring days to months of supercomputing time. Using reduced order modeling techniques, we construct an accurate surrogate model, which is evaluated in a millisecond to a second, for numerical relativity (NR) waveforms from nonspinning binary black hole coalescences with mass ratios in [1, 10] and durations corresponding to about 15 orbits before merger. We assess the model's uncertainty and show that our modeling strategy predicts NR waveforms not used for the surrogate's training with errors nearly as small as the numerical error of the NR code. Our model includes all spherical-harmonic _{-2}Y_{ℓm} waveform modes resolved by the NR code up to ℓ=8. We compare our surrogate model to effective one body waveforms from 50M_{⊙} to 300M_{⊙} for advanced LIGO detectors and find that the surrogate is always more faithful (by at least an order of magnitude in most cases).


A predictive model of shell morphology in CdSe/CdS core/shell quantum dots.
Lattice mismatch in core/shell nanoparticles occurs when the core and shell materials have different lattice parameters. When there is a significant lattice mismatch, a coherent core-shell interface results in substantial lattice strain energy, which can affect the shell morphology. The shell can be of uniform thickness or can be rough, having thin and thick regions. A smooth shell minimizes the surface energy at the expense of increased lattice strain energy and a rough shell does the opposite. A quantitative treatment of the lattice strain energy in determining the shell morphology of CdSe/CdS core/shell nanoparticles is presented here. We use the inhomogeneity in hole tunneling rates through the shell to adsorbed hole acceptors to quantify the extent of shell thickness inhomogeneity. The results can be understood in terms of a model based on elastic continuum calculations, which indicate that the lattice strain energy depends on both core size and shell thickness. The model assumes thermodynamic equilibrium, i.e., that the shell morphology corresponds to a minimum total (lattice strain plus surface) energy. Comparison with the experimental results indicates that CdSe/CdS nanoparticles undergo an abrupt transition from smooth to rough shells when the total lattice strain energy exceeds about 27 eV or the strain energy density exceeds 0.59 eV/nm(2). We also find that the predictions of this model are not followed for CdSe/CdS nanoparticles when the shell is deposited at very low temperature and therefore equilibrium is not established.


Chemical vapor generation of Cu: optimization of generation media.
Acetic acid was used to enhance the efficiency of chemical vapor generation (CVG) of copper. The volatile product was formed at room temperature following merging of the sample solution with a flowing stream of 0.1% NaBH4; ICP-OES was used for detection. A precision of 1.6% RSD (n=11, 0.2 mg/L) was realized at sampling frequencies of about 90/h. A detection limit of 0.4 ng/mL (3sigma) was obtained. Sensitivity was enhanced approximately 8-fold over conventional pneumatic nebulization sample introduction. Compared with CVG in an optimized HCl or HNO3 medium, sensitivity was increased by an order of magnitude using acetic acid and the reductant concentration was reduced to only 10% of that required with HCl or HNO3. The generation efficiency was estimated to be 18% or 70%, depending on the method used to evaluate it. The methodology was successfully used to the determine copper in human hair and low alloy steel certified reference materials.


The Evolving Role of Omega 3 Fatty Acids in Cardiovascular Disease: Is Icosapent Ethyl the Answer?
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality globally. Despite significant advances in pharmacotherapies and the beneficial effects of statin therapy on ASCVD outcomes and progression of atherosclerosis, residual cardiovascular (CV) risk remains. Extensive evidence has identified the contribution of atherogenic dyslipidaemia, which is particularly characterised by elevated triglycerides (TGL) as a key driver of CV risk, even if low-density lipoprotein cholesterol levels are well controlled. Epidemiologic and genetic/Mendelian randomisation studies have demonstrated that elevated TGL levels serve as an independent marker for an increased risk of ischaemic events, highlighting TGLs as a suitable therapeutic target. Clinical studies have shown that omega 3 fatty acids (OM3FA) are effective in lowering TGLs; however, to date, trials and meta-analyses of combined OM3FA products have not demonstrated any clinical CV outcome benefit in patients receiving statins. However, icosapent ethyl (IPE) - a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) - has been rigorously demonstrated in multiple studies to be a useful adjunctive therapy to address residual CV risk. EPA is an omega-3 polyunsaturated fatty acid that is incorporated into membrane phospholipid bilayers and is reported to exert multiple beneficial effects along the pathway of coronary atherosclerosis. In this brief review, we will provide an overview of the mode of action of IPE in coronary atherosclerosis, the robust clinical evidence and trial data supporting its use, and expert consensus/recommendations on its use in specific populations, as an adjunct to existing anti-atherosclerotic therapies.


Linac-based stereotactic radiation therapy for canine non-lymphomatous nasal tumours: 29 cases (2013-2016).
Twenty-nine dogs were treated with linac-based stereotactic radiation therapy (SRT) for non-lymphomatous nasal tumours. Only dogs with a follow-up time >365 days were included in this retrospective analysis. No dogs had evidence of distant metastasis at diagnosis. Treatment was planned and a total of 30 Gy in 3 daily 10 Gy fractions was delivered using intensity-modulation, cone-beam CT-based image guidance and a robotic treatment couch. Clinical signs improved in all cases. Nineteen dogs had CT scans 3-4 months post-SRT and all had partial or complete tumour response. Minimal acute toxicities were detected. Clinically significant late toxicities included oronasal or nasocutaneous fistulas (N = 3) and biopsy-confirmed fungal rhinitis with no evidence of tumour progression (N = 2). The median progression-free survival (PFS) was 354 days, with 49% and 39% progression-free at 1 and 2 years post-SRT, respectively. The median survival time (ST) was 586 days, with 69% and 22% alive 1 and 2 years post-SRT, respectively. Neither the clinical parameters evaluated (modified Adams' stage, histopathology, presence of intracranial extension of the tumour) nor dosimetric data were predictive for PFS or ST. This SRT protocol appears to be well tolerated, and PFI and ST are comparable or superior to those reported in other definitive-intent radiotherapy protocols.


Interfaces and ventilator settings for long-term noninvasive ventilation in COPD patients.
The establishment of high-intensity (HI) noninvasive ventilation (NIV) that targets elevated PaCO2 has led to an increase in the use of long-term NIV to treat patients with chronic hypercapnic COPD. However, the role of the ventilation interface, especially in more aggressive ventilation strategies, has not been systematically assessed. Ventilator settings and NIV compliance were assessed in this prospective cross-sectional monocentric cohort study of COPD patients with pre-existing NIV. Daytime arterialized blood gas analyses and lung function testing were also performed. The primary end point was the distribution among study patients of interfaces (full-face masks [FFMs] vs nasal masks [NMs]) in a real-life setting. The majority of the 123 patients studied used an FFM (77%), while 23% used an NM. Ventilation settings were as follows: mean ± standard deviation (SD) inspiratory positive airway pressure (IPAP) was 23.2±4.6 mbar and mean ± SD breathing rate was 16.7±2.4/minute. Pressure support ventilation (PSV) mode was used in 52.8% of patients, while assisted pressure-controlled ventilation (aPCV) was used in 47.2% of patients. Higher IPAP levels were associated with an increased use of FFMs (IPAP <21 mbar: 73% vs IPAP >25 mbar: 84%). Mean compliance was 6.5 hours/day, with no differences between FFM (6.4 hours/day) and NM (6.7 hours/day) users. PaCO2 assessment of ventilation quality revealed comparable results among patients with FFMs or NMs. This real-life trial identified the FFM as the predominantly used interface in COPD patients undergoing long-term NIV. The increased application of FFMs is, therefore, likely to be influenced by higher IPAP levels, which form part of the basis for successful application of HI-NIV in clinical practice.


Young age does not protect against the adverse effects of reduced ovarian reserve--an eight year study.
Ovarian reserve significantly influences IVF outcome. Low response to ovarian stimulation due to reduction of ovarian reserve is occasionally encountered in young women. The aim of this study was to evaluate the outcome of IVF treatment in young patients with reduced ovarian reserve. Between January 1993-2001, 762 consecutive patients satisfied the definition of reduced ovarian reserve (raised early follicular phase FSH or gonadotrophin stimulation cycles where three or fewer oocytes were retrieved after routine FSH stimulation) and were included in the study. They were classified into three age groups: young (< or = 30 years), intermediate (31-38 years) and older (>38 years). The three age groups were similar with respect to basal (day 3) serum FSH and estradiol concentrations, cause of infertility and number of previous treatment cycles. Implantation (13, 9.6 and 9.8%), clinical pregnancy (11.8, 10.2 and 10%) and live birth (7.4, 7.3 and 6.8%) rates were not significantly different in the three age groups respectively (P > 0.05). This study shows that younger patients with reduced ovarian reserve have a poor outcome of IVF treatment similar to their older counterparts. Such information may be helpful in counselling these patients who otherwise might anticipate an outcome related to their chronological age.


The Association of Blood Urea Nitrogen to Creatinine Ratio and the Prognosis of Critically Ill Patients with Cerebral Infarction: A Cohort Study.
To evaluate the association between blood urea nitrogen (BUN) to creatinine (Cr) (BUN/Cr) ratio and the in-hospital mortality of critically ill patients with cerebral infarction in intensive care unit (ICU). In this cohort study, the data of 3059 participants with cerebral infarction were collected from the Medical Information Mart for Intensive Care (MIMIC)-III and the MIMIC-IV database. After propensity score matching (PSM) on age and gender, 2085 people were involved in and divided into the alive group (n = 1390) and the dead group (n = 695) based on the results of follow-up. Multivariate logistic analyses were applied to identify the confounders and the association between BUN/Cr and mortality of cerebral infarction. The median follow-up time was 10.5 days. Among 2778 participants, 695 were dead at the end of follow-up. Univariate analysis revealed that BUN/Cr [risk ratio (RR) = 1.01, 95% confidence interval (CI): 1.01-1.02] might be associated with the in-hospital mortality of cerebral infarction patients. After adjusting for respiratory failure, malignant cancer, anticoagulation, liver disease, white blood cell (WBC), red cell distribution width (RDW), glucose, bicarbonate, and temperature, BUN/Cr had week correlation with the increased risk of in-hospital mortality of cerebral infarction patients (RR = 1.01, 95% CI: 1.01-1.02). This study evaluated the association between BUN/Cr and the in-hospital mortality of cerebral infarction patients in ICU and found that BUN/Cr had weak correlation with the increased risk of in-hospital mortality of patients with cerebral infarction in ICU especially in males and those with respiratory failure, malignant cancer, and without liver disease, as well as those receiving anticoagulation.


Evaluation of musical emotion perception and language development in children with cochlear implants.
While the primary purpose of cochlear implant (CI) fitting is to improve individuals' receptive and expressive skills, musical emotion perception (MEP) is generally ignored. This study assesses the MEP and language skills (LS) of children using CI. 26 CI users and 26 matched healthy controls between the ages of 6 and 9 were included in the study. The Test of Language Development (TOLD) was applied to evaluate the LS of the participants, and the Montreal Emotion Identification Test (MEI) was applied to evaluate the MEP. MEI test scores and all subtests of TOLD were statistically significantly lower in the CI group. Also, there was a statistically significant and moderate correlation between the listening subtest of TOLD and the MEI test. MEP and language skills are poor in children with CI. Although language skills are primarily targeted in CI performance, improving MEP should also be included in rehabilitation programs. The relationship between music and the TOLD's listening subtest may provide evidence that listening skills can be improved by paying attention to the MEP, which is frequently ignored in rehabilitation programs.


Subspecific Differentiation Events of Montane Stag Beetles (Coleoptera, Lucanidae) Endemic to Formosa Island.
Taxonomic debates have been carrying on for decades over Formosan stag beetles, which consist of a high proportion of endemic species and subspecies featuring morphological variations associated with local adaptation. With the influence of periodical Pleistocene glaciations and the presence of several mountain ranges, the genetic differentiation and taxonomic recognition, within this medium-size island, of two endemic subspecies for each of four montane stag beetles, i.e. Lucanus ogakii, L. kanoi, Prismognathus davidis, and Neolucanus doro, has been an appealing issue. Based on monophyletic lineages and population structure, possible divergent scenarios have been proposed to clarify the subspecific status for each of the above mentioned stag beetles. Phylogenetic inferences based on COI+16S rDNA+28S rDNA of 240 Formosan lucanids have confirmed most species are monophyletic groups; and the intraspecific (<2%) and interspecific (>2%) genetic distances of the two mitochondrial genes could be applied concordantly for taxonomic identification. On account of Bayesian-based species delimitation, geographic distribution, population structure, and sequence divergences, the subspecific status for L. ogakii, L. kanoi, and Pri. davidis are congruent with their geographic distribution in this island; and the calibration time based on the mitochondrial genes shows the subspecific split events occurred 0.7-1 million years ago. In addition, a more complicated scenario, i.e. genetic differentiation including introgression/hybridization events, might have occurred among L. ogakii, L. kanoi, and L. maculifemoratus. The geological effects of mountain hindrance accompanied by periodical glaciations could have been vital in leading to the geographical subspecific differentiation of these montane stag beetles.


Theoretical Studies on Two-Photon Fluorescent Hg2+ Probes Based on the Coumarin-Rhodamine System.
The development of fluorescent sensors for Hg2+ has attracted much attention due to the well-known adverse effects of mercury on biological health. In the present work, the optical properties of two newly-synthesized Hg2+ chemosensors based on the coumarin-rhodamine system (named Pro1 and Pro2) were systematically investigated using time-dependent density functional theory. It is shown that Pro1 and Pro2 are effective ratiometric fluorescent Hg2+ probes, which recognize Hg2+ by Förster resonance energy transfer and through bond energy transfer mechanisms, respectively. To further understand the mechanisms of the two probes, we have developed an approach to predict the energy transfer rate between the donor and acceptor. Using this approach, it can be inferred that Pro1 has a six times higher energy transfer rate than Pro2. Thus the influence of spacer group between the donor and acceptor on the sensing performance of the probe is demonstrated. Specifically, two-photon absorption properties of these two probes are calculated. We have found that both probes show significant two-photon responses in the near-infrared light region. However, only the maximum two-photon absorption cross section of Pro1 is greatly enhanced with the presence of Hg2+, indicating that Pro1 can act as a potential two-photon excited fluorescent probe for Hg2+. The theoretical investigations would be helpful to build a relationship between the structure and the optical properties of the probes, providing information on the design of efficient two-photon fluorescent sensors that can be used for biological imaging of Hg2+ in vivo.


Depression of norepinephrine and 5-hydroxytryptamine in the brain by benzoquinolizine derivatives.
The effects of two benzoquinolizine derivatives on the 5-hydroxytryptamine and norepinephrine content of the brain of mice, and some pharmacological actions, are described. Certain central effects (such as sedation and narcosis potentiation) of benzoquinolizine derivatives and possibly of Rauwolfia alkaloids may be due to changes of norepinephrine metabolism rather than to changes of 5-hydroxytryptamine metabolism in the brain.


[Jaundice caused by methimazole].
Three female patients with cholestatic jaundice related to methimazole therapy are presented. The jaundice appeared after more or less 30 days of therapy. Markers for hepatitis A and B were negative in all. None of them had previous history of alcoholism or ingestion of potentially hepatotoxic drugs. Characteristically there was a marked elevation of alkaline phosphatase and gamma-glutamyltranspeptidase with only moderate increase of the aminotransferases. Liver biopsy performed in all showed intensive cholestasis with low degree of inflammatory reaction confined to the portal tracts. The three patients presented a prolonged duration of the liver injury in spite of the interruption of the drug lasting in one of them up to one year, but all ultimately resolved.


Molecular regulation of blood clotting in tumor biology.
TF expression is a hallmark of cancer progression. The procoagulant functions of TF that lead to thrombin generation are critically important to support metastasis, in part through the generation of fibrin that assures prolonged arrest of tumor cells in target organs. In addition, the coagulation initiation complex, i.e. TF-VIIa-Xa, generates autocrine cell signaling though protease activated receptors. A cooperation of the TF cytoplasmic domain with protease signaling may explain the diverse contributions of TF to metastasis and angiogenesis.


PDGF-BB Carried by Endothelial Cell-Derived Extracellular Vesicles Reduces Vascular Smooth Muscle Cell Apoptosis in Diabetes.
Endothelial cell-derived extracellular vesicles (CD31EVs) constitute a new entity for therapeutic/prognostic purposes. The roles of CD31EVs as mediators of vascular smooth muscle cell (VSMC) dysfunction in type 2 diabetes (T2D) are investigated herein. We demonstrated that, unlike serum-derived extracellular vesicles in individuals without diabetes, those in individuals with diabetes (D CD31EVs) boosted apoptosis resistance of VSMCs cultured in hyperglycemic condition. Biochemical analysis revealed that this effect relies on changes in the balance between antiapoptotic and proapoptotic signals: increase of bcl-2 and decrease of bak/bax. D CD31EV cargo analysis demonstrated that D CD31EVs are enriched in membrane-bound platelet-derived growth factor-BB (mbPDGF-BB). Thus, we postulated that mbPDGF-BB transfer by D CD31EVs could account for VSMC resistance to apoptosis. By depleting CD31EVs of platelet-derived growth factor-BB (PDGF-BB) or blocking the PDGF receptor β on VSMCs, we demonstrated that mbPDGF-BB contributes to D CD31EV-mediated bak/bax and bcl-2 levels. Moreover, we found that bak expression is under the control of PDGF-BB-mediated microRNA (miR)-296-5p expression. In fact, while PDGF-BB treatment recapitulated D CD31EV-mediated antiapoptotic program and VSMC resistance to apoptosis, PDGF-BB-depleted CD31EVs failed. D CD31EVs also increased VSMC migration and recruitment to neovessels by means of PDGF-BB. Finally, we found that VSMCs, from human atherosclerotic arteries of individuals with T2D, express low bak/bax and high bcl-2 and miR-296-5p levels. This study identifies the mbPDGF-BB in D CD31EVs as a relevant mediator of diabetes-associated VSMC resistance to apoptosis.


Cardiac involvement in systemic sclerosis: differences between clinical subsets and influence on survival.
Cardiac involvement (CI) is a known complication of SSc associated with increased mortality. Our objective was to describe a cohort of patients with SSc and CI and to assess the differences between cutaneous subsets regarding their presentation and survival. Three hundred and ninety-three Spanish patients from a single center, diagnosed with SSc, were retrospectively studied for evidence of CI using noninvasive and invasive tests from 1976 to 2011. Clinical, epidemiological, immunological and therapeutic features of patients with CI were compared to those without it and within the different cutaneous subsets of SSc. CI was present in 173 (44 %) patients. Mitral regurgitation (67 %), conduction alterations (45 %) and left ventricle diastolic dysfunction (40 %) were the most common findings. Pericardial involvement and heart failure were more frequent in diffuse SSc (dcSSc) than in limited or sine scleroderma SSc. CI accounted for 20 % of deaths, and it was an independent mortality risk factor (HR 2.1, P = 0.02), but once CI was established, classical dcSSc mortality risk factors determined mortality. Patients with dcSSc developed CI faster than limited (HR 1.9, P = 0.003) or sine SSc patients (HR 2.5, P = 0.002), specially during the first year after SSc onset. We found statistically significant differences between the 3 SSc subsets in the presentation of pericardial involvement and heart failure. CI increased the mortality and appeared at a higher rate, especially during the first year after SSc onset. Screening for heart involvement should be performed at diagnosis and during follow-up.


Strategies to avoid blacklisting: The case of statistics on money laundering.
Financial and legal entities (e.g. banks, casinos, notaries etc.) have to report money laundering suspicions. Countries' engagement in fighting money laundering is evaluated-among others-with statistics on how often these suspicions are reported. Lack of compliance can result in economically harmful blacklisting. Nevertheless, these blacklists repeatedly become empty-in what is known as the emptying blacklist paradox. We develop a principal-agent model with intermediate agents and show that non-harmonized statistics can lead to strategic reporting to avoid blacklisting, and explain the emptying blacklist paradox. We recommend the harmonization of the standards to report suspicion of money laundering.


Treatment by specialist surgical neurooncologists improves survival times for patients with malignant glioma.
Surgeries for CNS tumors are frequently performed by general neurosurgeons and by those who specialize in surgical neurooncology. Subspecialization in neurosurgical practice has become common and may improve patient morbidity and mortality rates. However, the potential benefits for patients of having their surgeries performed by surgical neurooncologists remain unclear. Recently, a shift in patient care to those who practice predominantly surgical neurooncology has been promoted. Evidence for this practice is lacking and therefore requires fundamental investigation. The authors conducted a case-control study of neurooncology patients who underwent surgery for glioblastoma and anaplastic astrocytoma during 2006-2009. Outcomes were compared for patients whose surgery was performed by general neurosurgeons (generalists) or by specialist neurooncology neurosurgeons (specialists). An electronic record database and a picture archiving and communication system were used to collect data and assess the extent of tumor resection. Mortality rates and survival times were compared. Patient comorbidity and postoperative morbidity were assessed by using the Waterlow, patient handling, and falls risk assessment scores. Effects of case mix were adjusted for by using Cox regression and a hazards model. Outcomes for 135 patients (65 treated by generalists and 70 by specialists) were analyzed. Survival times were longer for patients whose surgery was performed by specialists (p=0.026) and after correction for case mix (p=0.019). Extent of tumor resection was greater when performed by specialists (p=0.005) and correlated with increased survival times (p=0.004). There was a trend toward reduced surgical deaths when surgery was performed by specialists (2.8%) versus generalists (7%) (p=0.102), and inpatient stays were significantly shorter when surgery was performed by specialists (p=0.008). The prognosis for glioblastoma multiforme remains dire, and improved treatments are urgently needed. This study provides evidence for a survival benefit when surgery is performed by specialist neurooncology neurosurgeons. The benefit might be attributable to increased tumor resection. Furthermore, specialist neurooncology surgical care may reduce the number of surgical patient deaths and length of inpatient stay. These findings support the recommendations for subspecialization within surgical neurooncology and advocate for care of these patients by specialists.


[Effect of antithyroid medication on the effective half-life and uptake of 131-iodine following radioiodine therapy].
A radioiodine therapy (RIT) in thyrotoxic patients receiving antithyroid drugs (ATD) leads in comparison to nonpretreated patients either to higher therapeutic doses or to higher treatment failure rates. Aim of this study was to optimize the effect of RIT in patients pretreated with ATD. Therefore, the influence of ATD was assessed in 109 patients with shortened effective half-life of 131I. RIT was performed under stationary conditions. Radioiodine activity of the thyroid gland was measured twice a day. In 77 patients antithyroid medication was stopped three days after RIT. The progress of the first RIT and of a second radioiodine application, which still was necessary in 29 patients, was compared to 32 patients receiving ATD, continuously. Values of effective half-life for 131I rose significantly from 3.2 +/- 0.2 to 5.7 +/- 0.2 days (Graves' disease: 3.4 to 5.7 days; toxic goiters' disease: multifocal autonomy 3.2 to 6.2 days; unifocal autonomy 2.5 auf 5.0 days) 2-3 days after stopping ATD. There was an increase of the 131I-uptake of a second after stopping ATD, too. In contrast, 131I-uptake of a second RIT decreased significantly in patients receiving ATD, continuously. Effective half-life and uptake of 131I was affected significantly by ATD. The stop taking of ATD after RIT is useful to improve an apparent insufficient RIT in thyrotoxic patients receiving ATD.


Directed Self-Assembly of Topological Defects of Liquid Crystals.
One of the alluring aspects of liquid crystals (LCs) is their readily controllable self-assembly behavior, leading to comprehension of complex topological structures and practical patterning applications. Here, we report on manipulating various kinds of topological defects by adopting an imprinted polymer-based soft microchannel that simultaneously imposes adjustable surface anchoring, confinement, and uniaxial alignment. Distinctive molecular orientation could be achieved by varying the surface anchoring conditions at the sidewall polymer and the rubbing directions on the bottom layer. On this pioneering platform, a common LC material, 8CB (4'-n-octyl-4-cyano-biphenyl), was placed where various topological defect domains were generated in a periodic arrangement. The experimental results showed that our platform can change the packing behavior and even the shape of topological defects by varying the rubbing condition. We believe that this facile tool to modulate surface boundary conditions combined with topographic confinement can open a way to use LC materials in potential optical and patterning applications.


An updated phylogeny and morphological study of the Phymaturus vociferator clade (Iguania: Liolaemidae).
Species delimitation in Phymaturus has been a difficult task due to the highly conserved morphological and ecological features present in this genus. Almost all species of Phymaturus have been described without DNA data or lacking statistical analyses which makes even more difficult to compare species. Although two molecular phylogenetic studies have been recently published, here we provide the first multilocus phylogenetic reconstruction including all Chilean species, with samples from all type localities and some previously unsampled populations. We also estimate pairwise distances among the Chilean species of Phymaturus (P. vociferator and P. mallimaccii clades) and compare our results with the P. payuniae clade, where previous studies have used multiple lines of evidence. Additionally, we performed univariate and multivariate morphological analyses and skeletal comparisons (clavicle) for the species of the P. vociferator clade. As a result of this integrative approach, we describe a new species.


Comparative analysis of RNA secondary structure accuracy on predicted RNA 3D models.
RNA structure is conformationally dynamic, and accurate all-atom tertiary (3D) structure modeling of RNA remains challenging with the prevailing tools. Secondary structure (2D) information is the standard prerequisite for most RNA 3D modeling. Despite several 2D and 3D structure prediction tools proposed in recent years, one of the challenges is to choose the best combination for accurate RNA 3D structure prediction. Here, we benchmarked seven small RNA PDB structures (40 to 90 nucleotides) with different topologies to understand the effects of different 2D structure predictions on the accuracy of 3D modeling. The current study explores the blind challenge of 2D to 3D conversions and highlights the performances of de novo RNA 3D modeling from their predicted 2D structure constraints. Our results show that conformational sampling-based methods such as SimRNA and IsRNA1 depend less on 2D accuracy, whereas motif-based methods account for 2D evidence. Our observations illustrate the disparities in available 3D and 2D prediction methods and may further offer insights into developing topology-specific or family-specific RNA structure prediction pipelines.


Alterations induced by E-cadherin and beta-catenin antibodies during the development of Bufo arenarum (Anura-Bufonidae).
E(epithelial)-cadherin is a member of a calcium-dependent family of cell surface glycoproteins involved in cell-cell adhesion and morphogenesis. Catenins are a large family of proteins that connect the cadherins to the cytoskeleton. They are important for cadherin function and for transducing signals involved in specification of cell fate during embryogenesis. The best characterized catenins include alpha-, beta-, gamma-, and p120-catenin. Using specific antibodies, we studied the expression and distribution of E-cadherin, and alpha- and beta-catenin in developmental stages of Bufo arenarum toad. The three proteins were found co-localized in stages 19 to 41 of development. Surprisingly, E-cadherin was the only of these three proteins found earlier than stage 19. To test whether E-cadherin and beta-catenin have a functional role in Bufo arenarum embryogenesis, stage 17 whole embryos were incubated with anti-E-cadherin and beta-catenin antibodies. Both anti-E-cadherin and anti-beta-catenin antibodies induced severe morphological alterations. However, while alterations produced by the anti-beta-catenin antibody, showed some variability from the most severe (neural tube and notochord duplication) to a simple delay in development, the alterations with anti-E-cadherin were homogeneous. These observations suggest a critical role for E-cadherin and beta-catenin in the early embryonic development of the Bufo arenarum toad. Our results are consistent with the developmental role of these proteins in other species. One of the most surprising findings was the blockage with the anti-beta-catenin antibodies on later embryo stages, and we hypothesize that the partial axes duplication could be mediated by the notochord induction.


Difficulty in distinguishing radiation-induced prostate sarcoma from radiation mucositis in a patient with persistent urinary retention and hematuria after prostate cancer radiotherapy.
Urinary retention and hematuria owing to radiation-induced mucositis are occasional late adverse events in patients with prostate cancer. Moreover, radiation-induced secondary malignancies are late adverse events, although they are extremely rare. Herein, we describe a case of radiation-induced secondary malignancy of the prostate that was initially difficult to distinguish from radiation mucositis. A 74-year-old man with prostate cancer underwent brachytherapy and external beam radiotherapy 9 years ago. Twenty-eight months after irradiation, he presented with urinary retention and hematuria owing to radiation mucositis and underwent transurethral resection of the prostate. At 89 months after irradiation, the patient again showed urinary retention and hematuria. The cause of urinary retention and hematuria could not be identified on cystoscopy. Despite receiving medications, the patient's symptoms did not improve. Therefore, transurethral fulguration was performed, and prostate biopsy revealed spindle cell sarcoma. A diagnosis of radiation-induced undifferentiated pleomorphic/spindle cell sarcoma was made, and the patient underwent total cystectomy and construction of the ileal conduit. Two weeks after the surgery, computed tomography revealed peritoneal dissemination. The patient died 5 weeks after the surgery. The case findings indicate that clinicians should consider the possibility of radiation-induced secondary malignancy; moreover, thorough pathological examination of the prostate with CT and MRI is important to distinguish RISM from radiation mucositis even if no tumors are found on cystoscopy.


Beta-actinin-like protein from plasmodium.
A beta-actinin-like protein was isolated from plasmodia of the slime mold. The chain weight was the same as that of actin (43,000), but the amino acid composition was significantly different. The action of plasmodium beta-actinin on actin was the same as that of beta-actinin from rabbit skeletal muscle: inhibition of the recombination of F-actin fragments; formation of Mg polymer; inhibition of interfilamental interaction of F-actin and retardation of depolymerization of F-actin. The only difference observed was its sensitivity to trypsin: plasmodium actinin was less quickly digested by trypsin than rabbit beta-actinin.


Efficacy and Safety of Nintedanib Plus Docetaxel in Patients with Advanced Lung Adenocarcinoma: Complementary and Exploratory Analyses of the Phase III LUME-Lung 1 Study.
Nintedanib is a triple angiokinase inhibitor approved with docetaxel for adenocarcinoma non-small cell lung cancer after first-line chemotherapy (FLT). In the phase III LUME-Lung 1 study, overall survival (OS) was significantly longer with nintedanib/docetaxel than with placebo/docetaxel in all adenocarcinoma patients and those with time from start of FLT (TSFLT) <9 months. This study sought to extend analyses from the LUME-Lung 1 study, specifically for adenocarcinoma patients, to explore the impact of clinically relevant characteristics on outcomes such as time to progression after FLT. Exploratory analyses were conducted of the overall and European LUME-Lung 1 adenocarcinoma population according to age, prior therapy, and tumor dynamics. Analyses also used TSFLT and time from end of FLT (TEFLT). Treatment with nintedanib/docetaxel significantly improved OS in European patients independently of age or prior therapy. Analyses of several patient subgroups showed improvements in median OS: TSFLT <6 months, 9.5 versus 7.5 months (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.55-0.98); chemorefractory to FLT, 9.1 versus 6.9 months (HR 0.72, 95% CI 0.52-0.99); progressive disease (PD) as best response to FLT, 9.8 versus 6.3 months (HR 0.62, 95% CI 0.41-0.94); TEFLT ≤6 months, 11.3 versus 8.2 months (HR 0.75, 95% CI 0.61-0.92); and TEFLT <3 months, 11.0 versus 8.0 months (HR 0.74, 95% CI 0.58-0.94). Nintedanib/docetaxel demonstrated significant OS benefits in adenocarcinoma patients, which were more pronounced in patients with shorter TSFLT or TEFLT, or with PD as best response to FLT. This study was registered at ClinicalTrials.gov: NCT00805194.


Corneal Posterior Curvature Changes After Phacoemulsification Cataract Surgery with 2.75 mm Corneal Incision.
The aim of this study was to evaluate the corneal posterior curvature changes after phacoemulsification cataract surgery, with intraocular lens implantation, with a temporal limbal self-sealing 2.75 millimeters (mm) corneal incision, using a Placido-dual rotating Scheimpflug device. In this prospective intervention study, corneal posterior curvature changes were evaluated in fifty-six patients (56 eyes). All patients underwent corneal tomography using the Galilei G2 (Ziemer Ophthalmic System AG, Port, Switzerland) preoperatively (PRE) and with two weeks (RP15), one month (RP30), and three months (RP90) after phacoemulsification cataract surgery with a temporal limbal self-sealing 2.75 mm incision. Tomographic parameters analyzed in the posterior cornea were the steep curvature (K2), flat curvature (K1), mean curvature (average K), and posterior corneal astigmatism. We did not observe any statistically significant change in the K2, K1, average K, and posterior corneal astigmatism in any postoperative follow-up measurements (RP15, RP30, RP90), showing that the postoperative values tend to be the same as the preoperative ones when measured with the Galilei G2 tomography. In conclusion, the 2.75 mm temporal limbal self-sealing corneal incision in phacoemulsification cataract surgery does not induce significant changes in the posterior corneal curvature parameters of K2, K1, average K, and astigmatism.


Dual effects of mesenteric lymph isolated from rats with burn injury on contractile function in rat ventricular myocytes.
Gut-derived factors in intestinal lymph have been shown to trigger myocardial contractile dysfunction. However, the underlying cellular mechanisms remain unclear. We examined the effects of physiologically relevant concentrations of mesenteric lymph collected from rats with 40% burn injury (burn lymph) on excitation-contraction coupling in rat ventricular myocytes. Burn lymph (0.1-5%), but not control mesenteric lymph from sham-burn animals, induced dual positive and negative inotropic effects depending on the concentrations used. At lower concentrations (<0.5%), burn lymph increased the amplitude of myocyte contraction (1.6 +/- 0.3-fold; n = 12). At higher concentrations (>0.5%), burn lymph initially enhanced myocyte contraction, which was followed by a block of contraction. These effects were partially reversible on washout. The initial positive inotropic effect was associated with a prolongation of action potential duration (measured at 90% repolarization, 2.5 +/- 0.6-fold; n = 10), leading to significant increases in the net Ca2+ influx (1.7 +/- 0.1-fold; n = 8). There were no significant changes in the resting membrane potential. The negative inotropic effect was accompanied by a decrease in the action potential plateau (overshoot decrease by 69 +/- 10%; n = 4) and membrane depolarization. Voltage-clamp experiments revealed that the positive inotropic effects of burn lymph were due to an inhibition of the transient outward K+ currents that prolong action potential duration, and the inhibitory effects were due to a concentration-dependent inhibition of Ca2+ currents that lead to a reduction of action potential plateau. These burn lymph-induced changes in cardiac myocyte Ca2+ handling can contribute to burn-induced contractile dysfunction and ultimately to heart failure.


Gross mosaic pattern of mitochondrial DNA deletions in skeletal muscle tissues of an individual adult human subject.
Using polymerase chain reaction techniques, the patterns of mitochondrial DNA deletions (which characteristically occur at low abundance during ageing) were compared in different skeletal muscle samples of an adult human subject. In one particular section of the biceps muscle, an unusual pattern of mitochondrial DNA deletions was detected; the common 4977 bp deletion was absent, but other deletions were observed. In pectoralis (chest) muscle, deletions commonly seen in normal adults were readily detected, including the 4977 bp deletion. Significantly, different patterns of mtDNA deletions were found in two adjacent parts of the same biceps muscle sample: one was the unusual pattern mentioned above, but the other part clearly contained the 4977 bp deletion. The results therefore demonstrate a gross mosaic pattern of mtDNA deletions in the skeletal muscle tissues of an individual human subject.


Hybrid Electro-Optical Pumping of Active Plasmonic Nanostructures.
Surface plasmon polaritons (SPPs) offer a unique opportunity to overcome the diffraction limit of light. However, this opportunity comes at the cost of the strong absorption of the SPP field in a metal, which unavoidably limits the SPP propagation length to a few tens of micrometers in nanostructures with deep-subwavelength mode confinement. The only possibility to avoid the propagation losses is to compensate for them by optical gain in the adjacent active medium. Different approaches for surface plasmon amplification by stimulated emission of radiation have been proposed based on either optical or electrical pumping. However, each has its own disadvantages caused by the selected type of pumping scheme. Here, we study, for the first time, hybrid electro-optical pumping of active plasmonic waveguide structures, and by using comprehensive self-consistent numerical simulations, demonstrate that this hybrid approach can outperform both pure electrical pumping and pure optical pumping. The SPP modal gain is higher than under pure optical pumping, while one can precisely and locally adjust it by tuning the electric current, which allows the reduction of amplification noise and provides additional functionalities. We believe that our findings lay a solid foundation for the development of a new generation of active plasmonic devices and stimulate further research in this area.


Using Chemoinformatics, Bioinformatics, and Bioassay to Predict and Explain the Antibacterial Activity of Nonantibiotic Food and Drug Administration Drugs.
Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure.


Mechanical and tribological characterization of TiB2 thin films.
Titanium Diboride (TiB2) presents high mechanical and physical properties. Some wear studies were also carried out in order to evaluate its tribological properties. One of the most popular wear tests for thin films is the ball-cratering configuration. This work was focused on the study of the tribological properties of TiB2 thin films using micro-abrasion tests and following the BS EN 1071-6: 2007 standard. Due to high hardness usually patented by these films, diamond was selected as abrasive on micro-abrasion tests. Micro-abrasion wear tests were performed under five different durations, using the same normal load, speed rotation and ball. Films were deposited by unbalanced magnetron sputtering Physical Vapour Deposition (PVD) technique using TiB2 targets. TiB2 films were characterized using different methods as Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS), Atomic Force Microscopy (AFM), X-ray Diffraction (XRD), Electron Probe Micro-Analyser (EPMA), Ultra Micro Hardness and Scratch-test Analysis, allowing to confirm that TiB2 presents adequate mechanical and physical properties. Ratio between hardness (coating and abrasive particles), wear resistance and wear coefficient were studied, showing that TiB2 films shows excellent properties for tribological applications.


Prolonged Integration Site Selection of a Lentiviral Vector in the Genome of Human Keratinocytes.
BACKGROUND Lentiviral vectors have been successfully used for human skin cell gene transfer studies. Defining the selection of integration sites for retroviral vectors in the host genome is crucial in risk assessment analysis of gene therapy. However, genome-wide analyses of lentiviral integration sites in human keratinocytes, especially after prolonged growth, are poorly understood. MATERIAL AND METHODS In this study, 874 unique lentiviral vector integration sites in human HaCaT keratinocytes after long-term culture were identified and analyzed with the online tool GTSG-QuickMap and SPSS software. RESULTS The data indicated that lentiviral vectors showed integration site preferences for genes and gene-rich regions. CONCLUSIONS This study will likely assist in determining the relative risks of the lentiviral vector system and in the design of a safe lentiviral vector system in the gene therapy of skin diseases.


Dietary nutrient intakes and skin-aging appearance among middle-aged American women.
Nutritional factors play a key role in normal dermatologic functioning. However, little is known about the effects of diet on skin-aging appearance. We evaluated the associations between nutrient intakes and skin-aging appearance. Using data from the first National Health and Nutrition Examination Survey, we examined associations between nutrient intakes and skin aging in 4025 women (40-74 y). Nutrients were estimated from a 24-h recall. Clinical examinations of the skin were conducted by dermatologists. Skin-aging appearance was defined as having a wrinkled appearance, senile dryness, and skin atrophy. Higher vitamin C intakes were associated with a lower likelihood of a wrinkled appearance [odds ratio (OR) 0.89; 95% CI: 0.82, 0.96] and senile dryness (OR: 0.93; 95% CI: 0.87, 0.99). Higher linoleic acid intakes were associated with a lower likelihood of senile dryness (OR: 0.75; 95% CI: 0.64, 0.88) and skin atrophy (OR: 0.78; 95% CI 0.65, 0.95). A 17-g increase in fat and a 50-g increase in carbohydrate intakes increased the likelihood of a wrinkled appearance (OR: 1.28 and 1.36, respectively) and skin atrophy (OR: 1.37 and 1.33, respectively). These associations were independent of age, race, education, sunlight exposure, income, menopausal status, body mass index, supplement use, physical activity, and energy intake. Higher intakes of vitamin C and linoleic acid and lower intakes of fats and carbohydrates are associated with better skin-aging appearance. Promoting healthy dietary behaviors may have additional benefit for skin appearance in addition to other health outcomes in the population.


Species-dependent metabolism of a novel selective α7 neuronal acetylcholine receptor agonist ABT-107.
Metabolism of ABT-107 was investigated in in vitro hepatic systems, in rat and monkey receiving [¹⁴C]ABT-107, and in vivo plasma in rat, dog, monkey and human. In in vitro hepatic systems, ABT-107 was primarily cleared via oxidative metabolism, and proceeded via two parallel pathways. Pathway 1, ABT-107 was oxidized at the nitrogen of quinuclidine moiety to form M1. Pathway 2, oxidation occurred at indole-containing moiety to form M2. Metabolism via N-oxidation was predominant in dog and rat, while in monkey and human, metabolism proceeded primarily via oxidation of indole-containing moiety. ABT-107 was extensively metabolized in vivo in rat and monkey. M1 was primarily found in rat urine and bile; whereas, M2 was the major metabolite in monkey urine and feces. M1 was the predominant circulating metabolite in dog and rat. M2 was the primary circulating metabolite in monkey and human. Enzymatic studies suggested M1 formation was primarily mediated by renal FMO1. CYP3A4, 1A2, 2J2 and 2D6 were primary enzymes catalyzing M2 formation. Biotransformation of ABT-107 in human and monkey is markedly different from that in dog and rat, suggesting that monkey is an appropriate model for predicting human biotransformation and toxicology of ABT-107.


The role of n-3 polyunsaturated fatty acids in the prevention and treatment of breast cancer.
Breast cancer (BC) is the most common cancer among women worldwide. Dietary fatty acids, especially n-3 polyunsaturated fatty acids (PUFA), are believed to play a role in reducing BC risk. Evidence has shown that fish consumption or intake of long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for inhibiting mammary carcinogenesis. The evidence regarding α-linolenic acid (ALA), however, remains equivocal. It is essential to clarify the relation between ALA and cancer since ALA is the principal source of n-3 PUFA in the Western diet and the conversion of ALA to EPA and DHA is not efficient in humans. In addition, the specific anticancer roles of individual n-3 PUFA, alone, have not yet been identified. Therefore, the present review evaluates ALA, EPA and DHA consumed individually as well as in n-3 PUFA mixtures. Also, their role in the prevention of BC and potential anticancer mechanisms of action are examined. Overall, this review suggests that each n-3 PUFA has promising anticancer effects and warrants further research.


Enantioselective construction of tetrasubstituted stereogenic carbons through Brønsted base catalyzed michael reactions: α'-hydroxy enones as key enoate equivalent.
Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α'-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α'-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α'-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.


Loke zupa decoction attenuates bronchial EMT-mediated airway remodelling in chronic asthma through the PI3K-Akt/HIF-1α signaling pathway.
Loke zupa decoction (Lok) is a well-established classic Chinese folk remedy for asthma. We sought to investigate the effect and mechanism of Lok on asthma airway remodelling and provide novel insights for the prevention and treatment of asthma. For in vitro experiments, BEAS-2B cells were assigned into six groups: Control, TGF-β1 (10 μM), TGF-β1 + Lok-20, TGF-β1 + Lok-40, TGF-β1 + Lok-80 μg/mL and TGF-β1 + SB431542 (5 μM). CCK8 and wound healing assays were performed. For in vivo experiments, 60 female BALB/c mice were randomly divided into 5 groups: Control, model, Lok-4.55, Lok-9.1, and DEX group. Lok was administrated by gavage during the challenge stage for 8 consecutive weeks (4.55 and 9.1 g/kg/day). We investigated airway inflammation and airway remodelling in the lungs and verified the activation status of EMT-related markers and the PI3K-Akt/HIF-1α signalling pathway. In vitro, Lok efficiently inhibited TGF-β1-induced BEAS-2B cell proliferation ability (cell viability 165% vs. 105%) and migration (migration areas 85% vs. 35%) without affecting their normal growth (IC50 274.2 µg/mL at 48 h). In vivo, Lok effectively protected mice from asthma, as evidenced by decreased histological damage and level of cytokines in BALF (IL-4, IL-13 and TGF-β1) by 17%-77%. Mechanistic research revealed that Lok reduced the levels of EMT-related molecules and significantly downregulated the PI3K-Akt/HIF-1α signalling pathway. Our findings provide novel insights into the protective effect of Lok on asthma and the underlying mechanisms, providing a theoretical basis and potential treatment possibilities for this patient population.


Prognostic significance of CD44v6 and nm23 protein immunoexpression in laryngeal squamous cell carcinoma.
In several tumours expression of CD44 and nm23 protein has been linked to tumour progression and metastasis. The aim of this study was to determine if there is any relationship between CD44v6 and nm23 protein immunoreactivity in squamous cancer cells and prognosis in patients with laryngeal carcinoma. The samples of human larynx cancer from patients with lymph node metastases and without lymph node involvement were analysed for CD44v6 and nm23 protein expression by immunohistochemistry using monoclonal antibodies. There was no significant difference in CD44v6 immunoexpression in cancer cells in patients with and without metastases. The statistical analysis did not reveal difference in survival time between patients with high and low CD44v6 immunoreactivity. The expression of nm23 protein in laryngeal cancer in patients with lymph node metastases was significantly decreased in comparison with patients without metastases. Analysis of survival revealed that patients with lower expression of nm23 protein in tumour tissue had significantly shorter survival than patients with higher nm23 immunoreactivity. The results suggest that nm23 protein immunoreactivity can be useful in predicting tumour behaviour in laryngeal cancer patients and indicate a lack of association between CD44v6 immunoexpression and tumour progression in those patients.


Development of biomonitoring equivalents for barium in urine and plasma for interpreting human biomonitoring data.
The objectives of the present work were: (1) to assemble population-level biomonitoring data to identify the concentrations of urinary and plasma barium across the general population; and (2) to derive biomonitoring equivalents (BEs) for barium in urine and plasma in order to facilitate the interpretation of barium concentrations in the biological matrices. In population level biomonitoring studies, barium has been measured in urine in the U.S. (NHANES study), but no such data on plasma barium levels were identified. The BE values for plasma and urine were derived from U.S. EPA's reference dose (RfD) of 0.2 mg/kg bw/d, based on a lower confidence limit on the benchmark dose (BMDL05) of 63 mg/kg bw/d. The plasma BE (9 μg Ba/L) was derived by regression analysis of the near-steady-state plasma concentrations associated with the administered doses in animals exposed to barium chloride dihydrate in drinking water for 2-years in a NTP study. Using a human urinary excretion fraction of 0.023, a BE for urinary barium (0.19 mg/L or 0.25 mg/g creatinine) was derived for US EPA's RfD. The median and the 95th percentile barium urine concentrations of the general population in U.S. are below the BE determined in this study, indicating that the population exposure to inorganic barium is expected to be below the exposure guidance value of 0.2 mg/kg bw/d.


Unravelling the electromechanical coupling in a graphene/bulk h-BN heterostructure.
The stacking heterostructure of graphene on bulk h-BN produces a moiré pattern with topographic corrugation. The corrugation of the moiré pattern expectantly induces a considerable curvature and a flexoelectric response, which calls for a detailed study. In this work, we used lateral force microscopy, a scanning technique to locally observe the moiré pattern and topographic corrugation. The curvature and flexoelectric potentials are derived from the measured topographic corrugation, revealing a huge curvature of ∼107 m-1 and a flexoelectric potential of ∼10 mV in the hexagonal domain wall region (∼3-4 nm) of the moiré pattern. In addition, the domain walls of the moiré pattern also generate a clear electromechanical and frictional response, arising from the corrugation-induced flexoelectric response. In summary, the results of this work provide insights into the understanding of the flexoelectricity in the graphene/bulk h-BN and its associated electromechanical coupling behavior in the moiré pattern of a van der Waals stacking heterostructure.


Radiographic prognostic factors determining spontaneous space closure after loss of the permanent first molar.
Permanent first molars (PFM) with a poor prognosis are routinely extracted in children throughout the United Kingdom. National guidelines suggest that to achieve spontaneous closure for the mandibular arch, the PFM should be extracted at 8 to 10 years of age, during bifurcation formation of the second molar. The literature is of limited quality and has suggested alternative variables that may be associated with successful space closure. Our aim was to investigate the radiographic prognostic factors associated with space closure after extraction of PFM. Two objectives of the research are reported in this article: to determine factors that might predict space closure of the second molar after extraction of the PFM, and to develop a tool kit to aid clinical decision making. We assessed 148 maxillary and 153 mandibular PFM extracted from 81 participants retrospectively. Dental age, second molar developmental stage, second premolar and second molar angulations, and presence or absence of the third molar were assessed on the preextraction orthopantomograms. Outcome was assessed via visual examination, study models, or radiographs. Closure occurred in 89.9% of the maxillary and 49.0% of the mandibular quadrants. Dental age was statistically, but not clinically, significant in the maxillary arch (P <0.05). For the mandibular arch, presence or absence of the third molar and second molar angulation were statistically and clinically significant (P <0.01 and P <0.05, respectively). A tool kit was developed in relation to the mandibular arch variables. These findings are contradictory to the Royal College of Surgeons guidelines and suggest that the presence of the third molar and a mesially angulated second molar are favorable for space closure. The developed tool kit requires further validity testing.


Formulation and characterization of amphotericin B-chitosan-dextran sulfate nanoparticles.
A new nanoparticulate delivery system for amphotericin B (AmB) has been developed by means of the polyelectrolyte complexation technique. Two opposite charged polymers were used to form nanoparticles through electrostatic interaction, chitosan (CH) as a positively charged polymer and dextran sulfate (DS) as a polymer with a negative charge, together with zinc sulfate as a crosslinking and hardening agent. The AmB nanoparticles obtained possessed a mean particle size of 600-800 nm with a polydispersity index of 0.2, indicating a narrow size distribution. The measured zeta potential of the nanoparticle surface was approximately -32 mV indicating a strong negative charge at the particle's surface. Scanning electron microscopy revealed spherical particles with a smooth surface. Drug association efficacy of up to 65% was achieved. Dissolution studies demonstrated a fast release behavior suggesting that AmB exhibits only moderate interaction with the weakly crosslinked polymers of the nanoparticles. Although, electronic absorbance spectra showed that the aggregation state of AmB was modified within the nanoparticles, a reduction of nephrotoxicity was observed in an in vivo renal toxicity study.