Association of white matter hyperintensities with long-term EGFR-TKI treatment and prediction of progression risk.
The purpose of this study was to test the hypothesis that brain white matter hyperintensities (WMH) are more common in patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and identify clinical risk factors associated with WMH. This multiple-center, prospective cohort study was conducted from March 2017 to July 2020. Two groups of patients with non-small cell lung cancer (NSCLC) who received or did not receive EGFR-TKI were included and followed up for more than 24 months. The progression of WMH was defined as an increase of ≥1 point on the Fazekas visual rating scale between the baseline and at the 2-year follow-up. A modified Poisson regression model was performed to evaluate risk factors on increased WMH load. Among 286 patients with NSCLC, 194 (68%) patients with NSCLC who received EGFR-TKI and 92 (32%) patients with NSCLC without EGFR-TKI treatment were analyzed. Modified Poisson regression analysis showed that EGFR-TKI treatment was independently associated with the WMH progression (EGFR-TKI: aRR 2.72, 95% confidence interval [CI] 1.46-5.06, p = .002). Interleukin (IL)-2, IL-4, and IL-10 were associated with increased WMH in the adjusted model (IL-2: aRR 1.55 [95% CI 1.06-2.25], p = .023; IL-4: aRR 1.66 [95% CI 1.13-2.43], p = .010; IL-10: aRR 1.48 [95% CI 1.06-2.06], p = .020). Patients with NSCLC who received EGFR-TKI may be at higher risk of developing WMH or worsening of WMH burden. The impact of increased WMH lesions in these patients is to be further assessed. IL-2, IL-4, and IL-10 may be used as potential biomarkers to monitor the risk of increased WMH burden.


The plasma membrane flattens out to fuel cell-surface growth during Drosophila cellularization.
Cell-shape change demands cell-surface growth, but how growth is fueled and choreographed is still debated. Here we use cellularization, the first complete cytokinetic event in Drosophila embryos, to show that cleavage furrow ingression is kinetically coupled to the loss of surface microvilli. We modulate furrow kinetics with RNAi against the Rho1-GTPase regulator slam and show that furrow ingression controls the rate of microvillar depletion. Finally, we directly track the microvillar membrane and see it move along the cell surface and into ingressing furrows, independent of endocytosis. Together, our results demonstrate that the kinetics of the ingressing furrow regulate the utilization of a microvillar membrane reservoir. Because membranes of the furrow and microvilli are contiguous, we suggest that ingression drives unfolding of the microvilli and incorporation of microvillar membrane into the furrow. We conclude that plasma membrane folding/unfolding can contribute to the cell-shape changes that promote embryonic morphogenesis.


A pilot study to investigate the feasibility and cardiac effects of pegylated liposomal doxorubicin (PL-DOX) as adjuvant therapy in medically fit elderly breast cancer patients.
In this pilot study, we examined the feasibility and toxicity in 16 elderly women age > or =65 receiving six cycles of pegylated liposomal doxorubicin (PL-DOX) cyclophosphamide as adjuvant chemotherapy for breast cancer. An extensive cardiologic assessment was also performed including echocardiographic Doppler-based strain rate imaging (SRI), a promising new sensitive technique to assess cardiac function. All but one patient finished the six planned cycles without major dose reductions or delay, and with limited serious toxicity showing the feasibility of this regimen. Significant decreases in radial strain and strain rate were found after six cycles of treatment while left ventricle ejection fraction remained unchanged. SRI may be a useful tool in the follow-up of elderly patients treated with anthracyclines, allowing early initiation of preventive measures in order to prevent further irreversible cardiac damage.


Detecting outliers in non-redundant diffraction data.
Outliers are observations which are very unlikely to be correct, as judged by independent observations or other prior information. Such unexpected observations are treated, effectively, as being more informative about possible models, so they can seriously impede the course of structure determination and refinement. The best way to detect and eliminate outliers is to collect highly redundant data, but it is not always possible to make multiple measurements of every reflection. For non-redundant data, the prior expectation given either by a Wilson distribution of intensities or model-based structure-factor probability distributions can be used to detect outliers. This captures mostly the excessively strong reflections, which dominate the features of electron-density maps or, even more so, Patterson maps. The outlier rejection tests have been implemented in a program, Outliar.


Use of Royal Darwin Hospital emergency department by immigration detainees in 2011.
To describe the number and nature of emergency department (ED) attendances by immigration detainees in Darwin, in the Northern Territory, over a 12-month period. Retrospective observational study of immigration detainees attending the Royal Darwin Hospital ED during the 2011 calendar year. Number of ED attendances and primary diagnoses. In 2011, there were 770 ED attendances by 518 individual detainees at Royal Darwin Hospital. Those who attended the ED had a mean (SD) age of 27.6 (12.2) years, and 112 of them (21.6%) were children. Most (413, 79.7%) were male, and Iran and Afghanistan were the two most common countries of birth. We estimate that 50.1% (95% CI, 47.0%-53.2%) of immigration detainees in Darwin (mean, 776 per month; total, 1034), attended the Royal Darwin Hospital ED at least once in 2011. The most common primary diagnosis was psychiatric problems (187 attendances, 24.3%), including self-harm (138 attendances, 17.9%). In 2011, asylum seekers in immigration detention in Darwin had a high prevalence of unmet health needs and substantial levels of psychiatric morbidity. The primary health care provided to them was inadequate.


Purposeful Engagement, Healthy Aging, and the Brain.
Research on psychological well-being in later life has identified strengths and vulnerabilities that occur with aging. We review the conceptual and philosophical foundations of a eudaimonic model of well-being and its empirical translation into six key dimensions of positive functioning. We also consider its implications for health, broadly defined. Numerous findings from national longitudinal samples of U.S. adults are described. They show declining scores on purpose in life and personal growth with aging, but also underscore the notable variability among older persons in these patterns. Recently, health benefits have been identified among older adults who maintain high levels of a particular aspect of well-being, namely, purposeful life engagement. These benefits include extended longevity, reduced risk for various disease outcomes, reduced physiological dysregulation, and gene expression linked to better inflammatory profiles. The brain mechanisms that underlie such outcomes are also examined via a focus on affective style. Adults with higher levels of purpose in life show more rapid recovery from negative stimulus provocation, whereas those with higher well-being overall show sustained activation of reward circuitry in response to positive stimuli, and this pattern is associated with lower diurnal cortisol output. Volumetric findings (right insular gray matter volume) have also been linked with eudaimonic well-being. Eudaimonic well-being predicts better health and longer lives, and thus constitutes an important direction for future research and practice. Intervention studies designed to promote well-being, including among those suffering from psychological disorders, are briefly described.


Peritonitis from starch glove powder.
Contamination of surgical wounds by starch glove powders has produced peritoneal inflammation and adhesions in many patients. Some have required surgical operation because of possible infection, others because of obstruction of the intestine. Resolving granulomas and fibrosis have been observed as incidental asymptomatic lesions in some patients during reoperation for other conditions. Starch granules are probably capable of producing inflammation in any patient, and the degree is believed to be related to the amount of starch present. Care in removing glove powder from gloves before they are worn in an operation will diminish or eliminate the problem. Removal can be accomplished by rubbing the gloves with a moist sterile towel or laparotomy tape.


Immobilization of alpha-amylase to a composite temperature-sensitive membrane for starch hydrolysis.
A composite membrane was made by casting hydrogel onto a nonwoven polyester support and used for enzyme immobilization. The hydrogel consists of N-isopropylacrylamide, cross-linker N, N'-methylenebis(acrylamide), 2-hydroxyethyl methacrylate, soluble starch, and N-(acryloxy)succinimide (NAS). The composite membrane is temperature-sensitive with a lower critical solution temperature (LCST) around 35 degreesC. It responds to temperature change by swelling below the LCST and shrinking above the LCST, corresponding to opening and closing of the membrane pores. alpha-Amylase was immobilized to the membrane by covalent bonds through reacting with the high reactive ester groups in NAS. The membrane-immobilized enzyme retained 32% of specific activity toward soluble starch when compared with that of free enzyme, and its properties were characterized and compared with those of the free enzyme. The immobilized enzyme was more thermally stable than the free enzyme. Kinetic constants, (Km) and the activation energy of the immobilized enzyme were both larger than those of the free enzyme. Starch hydrolysis with the immobilized enzyme was investigated in two-compartment permeation cells with a composite membrane between the cells. Reaction was carried out by hydrolyzing soluble starch in the donor side and collecting the hydrolyzed products in the receptor side. This reactor could be operated with temperature cycling to enhance the reaction and facilitate separation of products from the substrate. The best operating condition is cycling the temperature between 50 and 20 degrees C every 5 min. The membrane reactor was operated up to eight times for successive starch hydrolysis.


Laser-assisted vitrification of large equine embryos.
The major difficulty in providing the benefits of embryo cryopreservation for equine agriculture is the mismatch between the optimal embryo age for collection from the mare (7-8 days after ovulation was detected) and the optimal age for freezing under current methods (6.5 days after ovulation). To overcome this limitation, we tested a method to enhance penetration of cryopreservative across the capsule and trophoblast of day 7 and 8 embryos combined with rapid freezing by vitrification. Six small embryos (<300 μm in diameter) were collected on day 6-7 after ovulation and twelve larger embryos were recovered on day 7-8. In the treatment group, replacement of blastocoelic fluid with cryopreservative solution was facilitated by a laser system used to create a small opening in the embryonic capsule and trophectoderm. All embryos were vitrified using a CryoLeaf freezing support. After recovery from freezing and embryo transfer, three of four small untreated embryos (<300 μm in diameter, 75%) and four of nine large blastocysts in the treatment group (>300 μm in diameter, 44%) resulted in a vesicle as detected by ultrasonography approximately one week after transfer. However, only one recipient mare was still pregnant on day 23, and she delivered a live foal. Further investigation is required to determine why most of the embryos in this experiment were lost between day 13 and day 23 of gestation.


Basement membrane antigen in Wilms' tumor.
A basement membrane antigen was prepared from renal cortical basement membranes by partial reduction and alkylation. The antigen was partially purified by gel filtration chromatography. By indirect immunofluorescence, the antigen was found within five Wilms' tumors adjacent to tumor cells. The location and configuration of antigen was similar to that of flocculent electron-dense material observed ultrastructurally. The localization of this antigen provides immunohistochemical evidence for the production of basement membrane components by Wilms' tumors.


The role of the data coordinating center in the IRB review and approval process: the DIG trial experience.
Before any clinical trial can begin to recruit patients, participating clinical centers must obtain approval from their institutional review board (IRB). When studies are federally funded, such as by the U.S. Department of Health and Human Services (DHHS), centers must also have or obtain a federal compliance agreement from the Office of Human Research Protections (formerly the Office for Protection from Research Risks [OPRR]). The Digitalis Investigation Group trial was a large, international, double-blind, DHHS-funded randomized trial on the effect of digoxin on mortality in heart failure. Due to the anticipated number of centers (>200), the study's data coordinating center (DCC) was requested to assume additional responsibilities that included: (1) acting as a liaison between the OPRR and all study centers; (2) reviewing and correcting all assurance statements before submission to the OPRR; (3) reviewing and approving all centers' informed consent forms; and (4) helping the many research-inexperienced centers to establish IRBs or to locate an IRB in their region that would accept IRB responsibility for them. Although a heavy burden was placed on the DCC, the IRB and OPRR approval process was probably shortened by many weeks at those centers not already possessing a federal compliance agreement. This enabled the study to be completed on schedule and within budget.


In vivo interaction of acrylonitrile and 2-cyanoethylene oxide with DNA in rats.
Several approaches were used to probe aspects of the mechanism of acrylonitrile carcinogenicity in rats. Acrylonitrile did not appear to increase the rate of DNA synthesis resulting from tissue injury and regeneration in liver or brain, the latter being a target organ. The chemical did cause unscheduled DNA synthesis in rat liver but not brain. The epoxide of acrylonitrile, 2-cyanoethylene oxide, was formed in perfused rat liver; this metabolite accumulated in the perfusate as long as acrylonitrile was available to the organ. When 2-cyano[2,3-14C]ethylene oxide was administered to rats i.p., covalent binding to both liver and brain protein was found, but no covalent binding to nucleic acids could be detected at the level of 0.3 alkylations per 10(6) bases. No 1,N6-ethenoadenosine or 1,N6-ethenodeoxyadenosine was found in liver nucleic acids after administration of either acrylonitrile or 2-cyanoethylene oxide to rats, with the limits of detection being 0.3 alkylations per 10(6) RNA bases and 1 alkylation per 10(6) DNA bases. However, low levels of N7-(2-oxoethyl)guanine were detected in the livers of these rats by means of a radiometric derivative assay (0.014-0.032 alkylations per 10(6) DNA bases). In the brains of the treated rats the levels of N7-(2-oxoethyl)guanine were not above the limit of detection. These results show that acrylonitrile has some limited potential for genotoxicity in vivo and that the epoxide, with its ability to leave the liver and possibly to enter the brain, can interact with nucleic acids to a limited degree.


Extended endoscopic transphenoidal approach for tuberculum sellae meningiomas.
Removal of tuberculum sella (TS) meningiomas is traditionally performed through transcranial approaches. Wide use of the endoscope in transphenoidal pituitary surgery is recently accessible through the tuberculum sellae with an endoscope-assisted or purely endoscopic technique. Extended endoscopic approach is an important and alternative route for meningiomas, which are located on the midline originating from the tuberculum sella. However, cerebrospinal fluid (CSF) leakage is an important problem in extended endoscopic approaches. In this report, we discuss surgical limitations and nuances of endoscopic transphenoidal approach from a retrospective analysis of nine patients with TS meningiomas. Endoscopic transphenoidal approach was performed for seven women and two men (mean age, 51.1 years; age range, 32-78 years) with TS meningiomas between July 2007 and March 2010 in the Department of Neurosurgery, Kocaeli, Turkey. Total removal was achieved in six of nine patients. An improvement of the preoperative visual deficits was observed in six of the nine patients. Multilayer closure was performed for reconstruction, and lumbar external drainage was used for all patients for 3-5 days. CSF leakage was not seen in any of the patients after the operation and removal of the drainage. Endoscopic extended transphenoidal approach is still not a standardized procedure for TS meningiomas, but it may be considered as an alternative procedure in selected cases.


Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA.
A new lidocaine derivative (Astra, GEA 968) depresses excitability of myelinated frog nerve in a manner which depends upon the rate of use of the nerve. This phenomenon has been shown, under voltage clamp conditions, to involve "frequency-" or "use-dependent" inhibition of the transient inward sodium currents at the node of Ranvier. With 0.6 mM GEA 968 in the solution bathing the node, the inward sodium currents produced by 5-msec depolarizing pulses to -20 mV are reduced to 40% of control values if the node is rested for a few hundred seconds prior to the test pulse. Repetitive opening of the sodium channels by depolarizing pulses enhances this inhibition, for example, currents are eventually reduced to 10 to 20% of control with repetitive depolarization at 2 sec-1. If the preparation is then allowed to rest, this use-dependent increment in inhibition gradually declines with a time constant of about 10 seconds. Repetitive opening of the sodium channels by depolarizing pulses preceded by large hyperpolarizing prepulses reverses the inhibition caused by application of depolarizing pulses alone. It is hypothesized that the GEA 968 molecule binds to open sodium channels and, in doing so, simultaneously blocks the channel and shifts the curve relating sodium inactivation to membrane potential by 20 to 40 mV in the hyperpolarizing direction. Several kinds of evidence supporting this molecular hypothesis are presented. Lidocaine, procaine, procaine amide and a quaternary lidocaine derivative QX-314 also cause use-dependent depression of sodium currents in this preparation. This common mode of action of tertiary and quaternary anesthetics implies that the cationic form of tertiary anesthetics is active.


Strategies for validation.
The easy-to-use statistical package has imposed a new hardship on the clinical researcher: too much complicated analysis. The problem is most acute in the interpretation of multivariate results that select a combination of several factors that "best" predict or explain medical outcomes. For example, these methods give rise to formulas that 1) weigh together the risk factors of smoking, blood pressure, and lipid levels as determinants of heart disease, or 2) construct from pathologic and clinical evidence a prognostic profile for disease-free rectal cancer patients. To help the clinician apply these methods, we propose that, on request, statistical packages also produce two sets of calculations that validate the primary analysis: 1) a set of simple tabulations that show how the factors and outcomes used in the primary analysis relate to one another, and 2) the results of alternative analyses that show factors which every analysis selects, factors which only appear in the primary analysis, and those which tend to substitute for one another.


Evaluation of guidelines for initiation of highly active antiretroviral therapy in a longitudinal cohort of HIV-infected individuals.
Expert panels have developed several guidelines for initiating highly active antiretroviral therapy (HAART) in patients with HIV infection. To evaluate these guidelines, we simulated their application in a cohort of HIV-infected patients established and followed before HAART was available, and determined how long such patients survived without disease progression in the absence of HAART. Longitudinal data was used that had been collected from 1982 to 1995 on a prospective cohort of 133 homosexual men with known or closely approximated dates of HIV-1 seroconversion and negligible antiretroviral exposure. The main definition of disease progression was CD4 cell count < or = 300x10(6)/l or development of clinical AIDS diagnosis within 12 months. The mean number of years between the recommended initiation of therapy and when disease progression occurred in the absence of HAART were as follows: initiation of treatment at first visit, 4.81 years [median, 3.78 years; interquartile range (IQR), 1.85-6.59 years]; CD4 cell count <500x10(6)/l or serum RNA >5000 copies/ml (at least 10000 copies/ml fresh plasma), 4.35 years (median, 3.22 years; IQR, 1.56-6.19 years); CD4 cells <500x10(6)/l or serum RNA >20000 copies/ml (at least 40000 copies/ml fresh plasma), 3.61 years (median, 2.70 years; IQR, 1.40-5.11 years); and CD4 cells <500x10(6)/l, 2.72 years (median, 2.17 years; IQR, 0.81-4.25 years). The percentage of patients who had disease progression before HAART would have been recommended was 0.8, 1.6, 3.2 and 13.6% with each of these four approaches, respectively. Implementation of recommended treatment guidelines will result in a substantial proportion of patients being treated for long periods before immunologic or clinical disease progression would have occurred in the absence of HAART. These findings should be considered in the clinical care of HIV-infected patients and in future recommendations for the initiation of HAART.


Stoichiometric reactions of methylparathion with a palladium aryl oxime metallacycle.
The reaction of [Pd(3)(OAc)(6)] with (E)-acetophenone oxime and pyridine in CHCl(3) under reflux affords the metallacycle [Pd(OAc)[C,N-(C(6)H(4)C(CH(3))=NOH)-2](py)] (1) as a yellow air-stable complex. The same reaction carried out at room temperature in the absence of pyridine affords the trinuclear oximato complex [Pd(mu-(E)-ON=C(CH(3))Ph)(mu-OAc)](3) (2), which can be converted into 1 upon heating in the presence of pyridine. As indicated by (1)H and (31)P NMR spectroscopy, complex 1 reacts with methylparathion in acetone-d(6)-D(2)O solutions to afford [Pd(SP(=O)(OCH(3))(2))[C,N-(C(6)H(4)C(CH(3))=NOH)-2](py)] (3) and [Pd(mu-SP(=O)(OCH(3))(2))[C,N-(C(6)H(4)C(CH(3))=NOH)-2]](2) (4) as well as free p-nitrophenol. Compounds 1-4 have been characterized by single-crystal X-ray analysis, NMR and EA. Compounds 1 and 3 are mononuclear complexes with the acetate and dimethylthiophosphate ligand, respectively, trans from the phenyl group. Compound 2 is a trinuclear complex whose structure can be derived from that of [Pd(3)(OAc)(6)] by replacing three of the acetate ligands on one side of Pd(3) plane by three N,O-coordinated oximate ligands. Complex 4 is a dinuclear complex in which the two square-planar palladium moieties are linked by the sulfur atoms of the bridging dimethylthiophosphate ligands.


Establishing authenticity of hay milk: Detection of silage feeding through cyclopropane fatty acids analysis using 1H NMR spectroscopy.
Cyclopropane fatty acids (CPFAs) serve as indicators of silage feeding, verifying the authenticity of hay milk where silage feeding is forbidden. In this study, the authenticity of hay milk was determined by detecting CPFAs using proton nuclear magnetic resonance (1H NMR) spectroscopy. 245 milk samples were collected in South Tyrol (Italy), categorized as follows: 98 from grass silage-fed cows, 98 from maize silage-fed cows, and 49 authentic hay milk. The limit of detection of CPFAs was 12 µM, corresponding to 70 mg/kg of freeze-dried milk. The CPFAs were absent in all of the hay milk samples, verifying their authenticity. In contrast, 97 % of maize silage and 77 % of grass silage samples exhibited distinct CPFAs signals. These findings were further corroborated by gas chromatography-mass detector (GC-MS) analysis. The study highlights 1H NMR as a robust, and rapid technique for hay milk authentication, supporting alpine dairy production and increasing consumer trust in food authenticity.


Maternal Diarrhea and Antibiotic Use are Associated with Increased Risk of Diarrhea among HIV-Exposed, Uninfected Infants in Kenya.
HIV-exposed, uninfected (HEU) children are a growing population at particularly high risk of infection-related death in whom preventing diarrhea may significantly reduce under-5 morbidity and mortality in sub-Saharan Africa. A historic cohort (1999-2002) of Kenyan HEU infants followed from birth to 12 months was used. Maternal and infant morbidity were ascertained at monthly clinic visits and unscheduled sick visits. The Andersen-Gill Cox model was used to assess maternal, environmental, and infant correlates of diarrhea, moderate-to-severe diarrhea (MSD; diarrhea with dehydration, dysentery, or related hospital admission), and prolonged/persistent diarrhea (> 7 days) in infants. HIV-exposed, uninfected infants (n = 373) experienced a mean 2.09 (95% CI: 1.93, 2.25) episodes of diarrhea, 0.47 (95% CI: 0.40, 0.55) episodes of MSD, and 0.34 (95% CI: 0.29, 0.42) episodes of prolonged/persistent diarrhea in their first year. Postpartum maternal diarrhea was associated with increased risk of infant diarrhea (Hazard ratio [HR]: 2.09; 95% CI: 1.43, 3.06) and MSD (HR: 2.89; 95% CI: 1.10, 7.59). Maternal antibiotic use was a risk factor for prolonged/persistent diarrhea (HR: 1.63; 95% CI: 1.04, 2.55). Infants living in households with a pit latrine were 1.44 (95% CI: 1.19, 1.74) and 1.49 (95% CI: 1.04, 2.14) times more likely to experience diarrhea and MSD, respectively, relative to those with a flush toilet. Current exclusive breastfeeding was protective against MSD (HR: 0.30; 95% CI: 0.15, 0.58) relative to infants receiving no breast milk. Reductions in maternal diarrhea may result in substantial reductions in diarrhea morbidity among HEU children, in addition to standard diarrhea prevention interventions.


In vitro activity of Peltophorum africanum Sond. (Fabaceae) extracts on the egg hatching and larval development of the parasitic nematode Trichostrongylus colubriformis.
Trichostrongylus colubriformis is an important cause of parasitic gastroenteritis in ruminants, where it causes protracted diarrhoea, rapid loss of weight, loss of production and death. The in vitro efficacy of extracts of Peltophorum africanum was determined against this parasitic nematode. Eggs and larvae of T. colubriformis were incubated at 23 degrees C in the extracts of the leaf, bark and root of P. africanum at concentrations of 0.008-25 mg ml-1 for 2 and 5 days, respectively. Thiabendazole and water were used as positive and negative controls, respectively. Inhibition of egg hatching and larval development increased significantly (P<0.05) with increasing concentrations of the extracts. Concentrations of 0.2-1.0 mg ml-1 of the extracts of leaf, stem bark, and root bark of P. africanum completely inhibited the hatching of eggs and development of larvae. No eggs and larvae of T. colubriformis could be observed in wells incubated with all the three extracts at concentrations of 5 and 25 mg ml-1. The in vitro model results support the traditional use of P. africanum against nematode parasites. Further research is required to isolate and structurally identify the active anthelmintic compounds, and to improve methods of plant extraction of the effective anthelmintic components that will be readily adaptable for use by rural communities against helminthosis.


No-reference quality assessment of natural stereopairs.
We develop a no-reference binocular image quality assessment model that operates on static stereoscopic images. The model deploys 2D and 3D features extracted from stereopairs to assess the perceptual quality they present when viewed stereoscopically. Both symmetric- and asymmetric-distorted stereopairs are handled by accounting for binocular rivalry using a classic linear rivalry model. The NSS features are used to train a support vector machine model to predict the quality of a tested stereopair. The model is tested on the LIVE 3D Image Quality Database, which includes both symmetric- and asymmetric-distorted stereoscopic 3D images. The experimental results show that our proposed model significantly outperforms the conventional 2D full-reference QA algorithms applied to stereopairs, as well as the 3D full-reference IQA algorithms on asymmetrically distorted stereopairs.


Substituent Position of Iminocyclitols Determines the Potency and Selectivity for Gut Microbial Xenobiotic-Reactivating Enzymes.
Selective inhibitors of gut bacterial β-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (2-7) for the GUSs. Complex structures of Ruminococcus gnavus GUS with 2-7 explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine (2) made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition (Ki ≥ 11 nM). C6-propyl analogue of 2 (6) displayed 700-fold selectivity for opportunistic bacterial GUSs (Ki = 74 nM for E. coli GUS and 51.8 μM for RgGUS). In comparison with 2, there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.


What is the explanation for the changes to cobalt-60 tissue-air ratios in BJR Supplement 25?
Values of tissue-air ratio (TAR) in the recent British Journal of Radiology (BJR) Supplement 25 have been increased by nearly 2% over the values which have been accepted for the past 30 years. The need for this was shown by analysis of previous data using scaling laws, together with Monte Carlo calculations and careful re-measurement. However, it was not clear why previous determinations of TAR were in error: it was not, as some workers argued, because scattered radiation had been included in the absorbed dose in the miniphantom, because TAR data in BJR Supplement 17 had been derived from peak scatter factor (PSF), which is not based on the miniphantom concept. The purpose of this paper is to find the real explanation of why the PSF and, therefore, TAR were underestimated for so long. Two definitions of PSF are considered: one based on kerma and one based on dose. This paper relates PSF of either definition to measurements of air kerma by including in the derivation the scatter in the plug which replaces the chamber when it has been removed from the surface of the water phantom. The kerma-based PSF is found to be 2% higher than the simple ratio of chamber readings in phantom and in air. The value of the dose-based definition agrees with that of the kerma-based definition to within 0.2%. It is the scatter in the replacement plug in the surface of the water phantom which was effectively ignored by previous workers, and which explains the underestimates of around 2% in PSF and TAR. The value of the dose-based PSF differs slightly from that of the kerma-based PSF because of the different distributions of primary and scatter photon fluence.


The effectiveness of primary care based risk stratification for targeted latent tuberculosis infection screening in recent immigrants to the UK: a retrospective cohort study.
Most UK tuberculosis (TB) cases occur in immigrants from high TB incidence areas, implicating reactivation of imported latent TB infection (LTBI). Strategies to identify and treat immigrant LTBI in primary care at the time of first registration (coded Flag-4) may be effective. This was an 11-year retrospective cohort study to evaluate effectiveness of LTBI screening in recent immigrants to Leicestershire at their time of primary care registration. We examined the temporal relationship between dates of Flag-4 primary care registration (n=59 007) and foreign-born TB (FB-TB) cases (n=857), for immigrants arriving to the UK after 1999. TB diagnosed >6 months after registration was considered potentially preventable with screening. Primary outcomes were the potentially preventable proportion of FB-TB and the number needed to screen (NNS) of immigrants to identify one potentially preventable case, stratified by age and region of origin. 250 cases (29%) were potentially preventable in Flag-4-registered immigrants. Overall, 511 cases (60%) were potentially preventable among primary-care registered immigrants, implying a significant proportion without Flag-4 status. Prospective TB incidence (95% CI) after Flag-4 registration was 183 (163 to 205) cases/100 000 person-years, with a NNS (95% CI) of 145 (130 to 162). Targeted screening was most effective for 16-35 year olds from TB incidence regions 150-499/100 000 (NNS (95% CI)=65 (57 to 74), preventing 159 (18.7%) cases). Unpreventable TB risk increased with delayed primary care registration after UK entry (p<0.001) and was associated with HIV seropositivity (relative risk (95% CI)=1.89 (1.25 to 2.84), p=0.003). LTBI screening at primary care registration offers an effective strategy for potentially identifying immigrants at high risk of developing TB.


Carbamazepine treatment of a patient with Klüver-Bucy syndrome.
A 20-year-old man developed Klüver-Bucy syndrome with rage attacks following a motor vehicle accident. Several symptoms, including the attacks, responded dramatically to carbamazepine. Carbamazepine may be a useful agent in the treatment of this unusual syndrome.


High Performing Ternary Solar Cells through Förster Resonance Energy Transfer between Nonfullerene Acceptors.
Nonradiative Förster resonance energy transfer (FRET) is an important mechanism of organic solar cells, which can improve the exciton migration over a long distance, resulting in improvement of efficiency of solar cells. However, the current observations of FRET are very limited, and the efficiencies are less than 9%. In this study, FRET effect was first observed between two nonfullerene acceptors in ternary solar cells, which improved both the absorption range and exciton harvesting, leading to the dramatic enhancement in the short circuit current and power conversion efficiency. Moreover, this strategy is proved to be a versatile platform for conjugated polymers with different bandgaps, resulting in a remarkable efficiency of 10.4%. These results demonstrated a novel method to enhance the efficiency of organic soar cells.


From fish to amphibians to mammals: in search of novel strategies to optimize cardiac regeneration.
Different vertebrate species have different cardiac regeneration rates: high in teleost fish, moderate in urodele amphibians, and almost negligible in mammals. Regeneration may occur through stem and progenitor cell differentiation or via dedifferentiation with residual cardiomyocytes reentering the cell cycle. In this review, we will examine the ability of zebrafish and newts to respond to cardiac damage with de novo cardiogenesis, whereas rodents and humans respond with a marked fibrogenic response and virtually no cardiomyocyte regeneration. Concerted strategies are needed to overcome this evolutionarily imposed barrier and optimize cardiac regeneration in mammals.


Prevalence and Risk Factors for Chronic Venous Disease in the General Russian Population.
The aim was to establish the prevalence of chronic venous disease (CVD) and its risk factors in the general population. This was a population based, cross sectional study. In total, 703 residents aged > 18 years from the rural community of Kryukovo (Central Russia) were enrolled. Medical history was taken and clinical examination performed, documenting venous signs/symptoms. The CEAP classification of the most affected limb was used. Duplex ultrasound was performed to register morphological changes and reflux in deep and superficial veins. There were 63% women and 37% men (mean age 53.5 years). CVD was found in 69.3%. Of all participants 4.7% were C0S and 34.3% were C1. Chronic venous insufficiency (C3-C6) was found in 8.2% and venous ulcers (C5-C6) in 1.1%. Venous pain, heaviness, fatigue, itching, and the sensation of swelling were documented in 14.8%, 36.3%, 32.8%, 7.0% and 29.1% of patients respectively. Family history was the significant risk factor for both CVD (hazard ratio [HR] 1.3) and primary varicose vein disease (HR 1.6; p < .01). Female sex was a risk factor only for CVD (HR 1.3; p < .01) but not for varicose veins. Age was a risk factor for CVD (HR 1.01) and for varicose veins (HR 1.02; p < .01). For women, number of births (HR 1.05; p < .05) and menopause (HR 1.3; p < .01) were risk factors for CVD. Menopause was a risk factor for varicose veins (HR 2.0; p < .05). This study provides data on the prevalence of CVD, venous abnormalities and risk factors in Russia. The results contribute to already established data, giving a more complete outlook on the global prevalence of CVD.


Correction of sampling errors due to laser tuning rate fluctuations in swept-wavelength interferometry.
The frequency-sampling method is widely used to accommodate nonlinear laser tuning in swept-wavelength interferometric techniques such as optical frequency domain reflectometry (OFDR) and swept-wavelength optical coherence tomography (OCT). In this paper we analyze the frequency-sampling method and identify two sources of sampling errors. One source of error is the limit of an underlying approximation for long interferometer path mismatches and fast laser tuning rates. A second source of error is transmission delays in data acquisition hardware. We show that the measurement system can be configured such that the two error sources cancel to second order. We present experimental verification of sampling error correction using a general swept-wavelength interferometer with a significantly nonlinear laser sweep.


Image-based calculation of perfusion and oxyhemoglobin saturation in skeletal muscle during submaximal isometric contractions.
The relative oxygen saturation of hemoglobin and the rate of perfusion are important physiological quantities, particularly in organs such as skeletal muscle, in which oxygen delivery and use are tightly coupled. The purpose of this study was to demonstrate the image-based calculation of the relative oxygen saturation of hemoglobin and quantification of perfusion in skeletal muscle during isometric contractions. This was accomplished by establishing an empirical relationship between the rate of radiofrequency-reversible dephasing and near-infrared spectroscopy-observed oxyhemoglobin saturation (relative oxygen saturation of hemoglobin) under conditions of arterial occlusion and constant blood volume. A calibration curve was generated and used to calculate the relative oxygen saturation of hemoglobin from radiofrequency-reversible dephasing changes measured during contraction. Twelve young healthy subjects underwent 300 s of arterial occlusion and performed isometric contractions of the dorsiflexors at 30% of maximal contraction for 120 s. Muscle perfusion was quantified during contraction by arterial spin labeling and measures of muscle T(1). Comparisons between the relative oxygen saturation of hemoglobin values predicted from radiofrequency-reversible dephasing and that measured by near-infrared spectroscopy revealed no differences between methods (P = 0.760). Muscle perfusion reached a value of 34.7 mL 100 g(-1) min(-1) during contraction. These measurements hold future promise in measuring muscle oxygen consumption in healthy and diseased skeletal muscle.


Spectral shift of a light wave on scattering from an ellipsoidal particle with arbitrary orientation.
Within the accuracy of the first-order Born approximation, a general expression for the far-zone spectrum of a light wave on scattering from an arbitrarily orientated ellipsoidal particle is derived. We show that the spectrum of the scattered field, in general, changes with the scattering azimuthal angle, displaying rotational nonsymmetry. The influence of the orientation of the particle on the spectrum of the scattered field is discussed, and the relationship between the orientation of scattering particle and the distribution of the relative spectral shift of the scattered field is investigated.


Operative vs nonoperative management for blunt pancreatic transection in children: multi-institutional outcomes.
The management of traumatic pancreatic transection remains controversial. A multi-institutional review from 1995 to 2012 was conducted comparing operative with nonoperative management for grades II and III blunt pancreatic injuries in patients younger than 18 years. Fourteen pediatric trauma centers participated, yielding 167 patients; 57 underwent distal pancreatectomy and 95 were managed nonoperatively. Fifteen patients treated with operative drain placement only were studied separately. Patients undergoing resection had a shorter time to goal oral feeds (7.8 ± 0.7 days vs 15.1 ± 2.5 days; p = 0.007) and a lower rate of pseudocyst formation (0% vs 18%; p = 0.001). Pseudocyst formation resulted in a greater need for endoscopic and interventional radiologic procedures (26% vs 2%; p = 0.002) in the nonoperative group, as well as a longer time to complete resolution (38.6 ± 6.4 days vs 22.6 ± 5.0 days; p = 0.05) compared with resection. When looking at those patients with clear evidence of main duct injury at presentation, those undergoing resection also had fewer complications (33% vs 61%; p = 0.05) and fewer total days in-hospital (12.6 ± 8.4 days vs 17.5 ± 9.7 days; p = 0.04) compared with nonoperative management. In children with blunt pancreatic injury, distal pancreatectomy is superior to nonoperative management with more rapid resumption of diet, fewer repeat interventions, and a shorter period to complete resolution. When the main duct is involved, the benefits to operative resection also include lower morbidity and fewer days of hospitalization. Therefore, assessing the status of the pancreatic duct is paramount in determining management.


Opioid peptide receptor studies. 15. Relative efficacy of 4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide and related compounds at the cloned human delta-opioid receptor.
Previous data obtained from both binding and functional assays demonstrated that (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide [(-)-RTI5989-54] displays selective binding and full agonist activity relative to (+/-)-RTI5989-54 for the delta opioid receptor. The present study was conducted to evaluate the activities of structurally diverse opioid receptor delta ligands in the [(35)S]GTP-gamma-S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned human delta receptors, demonstrated that (-)-RTI5989-54 behaves like the highly selective delta agonist SNC80. Addition of the hydroxyl group to RTI5989-54 (RTI5989-61) or replacement of the allyl group with the trans-crotyl group on the piperidine nitrogen of RTI-5989-61 (RTI5989-62) increased binding affinity, produced full agonist activity, and decreased intrinsic efficacy at the delta opioid receptor. The order of potency for the EC(50) (GTP-gamma-S) was RTI5989-62 (0.20 nM) > RTI5989-61 (0.43 nM) > SNC80 (1.92 nM) > DPDPE (3.50 nM) > (-)-RTI5989-54 (17.6 nM) > (+/-)-RTI5989-54 (65.6 nM) > (+)-RTI5989-54 (483 nM). RTI5989-61 and RTI5989-62 were fully efficacious, but had intrinsic efficacy values that were 2.2-3.1 times lower than that of DPDPE and SNC80. Comparison of the binding K(i) in competitively inhibiting [(125)I]IOXY binding to the functional K(i) for delta antagonists [Ki (IOXY)/Ki (GTP-gamma-S)] shows that antagonists might antagonize agonist-evoked neurochemical effects with equal magnitude while occupying different proportions of target receptors.


[Student - centered teaching: evolvement of the initial phase of the basic Pediatric Nursing Course].
The authors present a description of the evolvement of the initial phase of the Pediatric Nursing I Course, which, since 1979, utilizes the student - centered teaching methodology at the Nursing School of the São Paulo University.


Examining the Relationship Between the Testate Amoeba Hyalosphenia papilio (Arcellinida, Amoebozoa) and its Associated Intracellular Microalgae Using Molecular and Microscopic Methods.
Symbiotic relationships between heterotrophic and phototrophic partners are common in microbial eukaryotes. Among Arcellinida (Amoebozoa) several species are associated with microalgae of the genus Chlorella (Archaeplastida). So far, these symbioses were assumed to be stable and mutualistic, yet details of the interactions are limited. Here, we analyzed 22 single-cell transcriptomes and 36 partially-sequenced genomes of the Arcellinida morphospecies Hyalosphenia papilio, which contains Chlorella algae, to shed light on the amoeba-algae association. By characterizing the genetic diversity of associated Chlorella, we detected two distinct clades that can be linked to host genetic diversity, yet at the same time show a biogeographic signal across sampling sites. Fluorescence and transmission electron microscopy showed the presence of intact algae cells within the amoeba cell. Yet analysis of transcriptome data suggested that the algal nuclei are inactive, implying that instead of a stable, mutualistic relationship, the algae may be temporarily exploited for photosynthetic activity before being digested. Differences in gene expression of H. papilio and Hyalosphenia elegans demonstrated increased expression of genes related to oxidative stress. Together, our analyses increase knowledge of this host-symbiont association and reveal 1) higher diversity of associated algae than previously characterized, 2) a transient association between H. papilio and Chlorella with unclear benefits for the algae, 3) algal-induced gene expression changes in the host.


Chronic PKC-beta2 activation in HT-29 Cl.19a colonocytes prevents cAMP-mediated ion secretion by inhibiting apical membrane CFTR targeting.
We investigated the effects of chronically applied PKC-stimulating phorbol esters on subcellular CFTR expression and localization in polarized HT-29 Cl.19A monolayers. Modulation of PKC activity with the PKC-beta-specific agonist 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPA) or nonisoform-selective PMA altered monolayer CFTR immunofluorescence. A decrease in the CFTR signal within the luminal cellular pole was noted with both phorbol esters. Volumetric analysis of the intracellular CFTR signal revealed that both compounds promoted CFTR accumulation into punctate vesicle-like structures found adjacent to the cellular tight junction [labeled with zona occludens (ZO)-1 antibody], extending basally (DOPPA) into the cell. Puncta were more frequent with DOPPA and larger in size with PMA. DOPPA also promoted ZO-1 accumulation at tricellular corners associated with enhanced CFTR puncta number. The observed loss of CFTR immunofluorescence signal induced by low-dose PMA was related to CFTR sequestration into fewer cytoplasmic puncta and correlated with larger increases in PKC substrate phosphorylation. Both phorbol esters downregulated steady-state cellular CFTR mRNA levels by 70%. However, the effects of DOPPA and PMA were largely independent of CFTR biosynthesis: expression levels were 80-85% of control, and the glycosylation status of immunoprecipitated protein remained largely unchanged. Thus changes in cellular CFTR localization correlated with our companion study showing that PMA-induced inhibition of transcellular cAMP-dependent short-circuit current (ISC) was accompanied by cytoplasmic PKC-beta2 accumulation and modest activation of PKC-beta1 and PKC-epsilon. The inhibitory effect of DOPPA on ISC was related solely to increased cytoplasmic PKC-beta2 levels. Thus PKC-beta2 is hypothesized to participate in the regulation of CFTR apical plasma membrane targeting within the constitutive cellular biosynthetic pathway.


A new technique for the study of vascular presynaptic receptors in freely moving rats.
A technique is described in which a silicon catheter is utilized for permanent catheterization of the portal vein, and curved platinum stimulation electrodes around this vein are used for the stimulation of the local nervous plexus. The method has a success ratio of over 70% during a period of more than 2 mo. Five animals were used in experiments over a period longer than 5 mo. Using this technique, we investigated the influence of variation of current density, pulse duration, and frequency of stimulation on the electrically evoked release of norepinephrine in portal blood. Enhancement of all stimulation parameters proportionally increased the evoked norepinephrine release. The alpha 2-adrenoceptor antagonist yohimbine was found to increase basal norepinephrine levels 4.43-fold and facilitated the evoked release additionally with a factor of 4.70. The results show that noradrenergic neurotransmission in the portal vein nervous plexus is controlled presynaptically by a strong local alpha 2-adrenergic autoinhibition. The method offers the means to explore locally the presynaptic modulation of endogenous neurotransmitter release in unrestrained unanesthetized animals.


Studies on shigella isolated in southern Taiwan.
During 1969, a total of 1,476 fecal and rectal swab specimens was collected from children with diarrhea and 249 strains of shigella were isolated. The incidence was 16.9%. The serotypes of 249 strains were: Shigella dysenteriae, 1.6% (4 strains); S. flexneri, 73.1% (182 strains); S. boydii, 3.2 (8 strains) and S. sonnei, 22.1% (55 strains). There was no marked difference of the isolation rate throughout the whole year. The susceptibility of shigella isolates to chemotherapeutic agents were also investigated. The percentage of the strains susceptible to gentamicin was 97.2%; to cephaloridine, 93.2%; to kanamycin, 91.9%; to colistin, 91.6%; to hetacillin, 88.4%; to ampicillin, 82.4% and to nalidixic acid, 79.9%. The other tested chemotherapeutic agents were less effective.


Allorhizobium terrae sp. nov., isolated from paddy soil, and reclassification of Rhizobium oryziradicis (Zhao et al. 2017) as Allorhizobium oryziradicis comb. nov.
A polyphasic taxonomic approach was used to characterize a nitrogen-fixing bacterium, designated strain CC-HIH110T, isolated from paddy soil in Taiwan. Cells of strain CC-HIH110T were Gram-stain-negative, rod-shaped, motile with polar flagella, catalase-positive and oxidase-positive. Optimal growth occurred at 30 °С, pH 7 and 1 % NaCl. Phylogenetic analyses based on 16S rRNA genes revealed a distinct taxonomic position attained by strain CC-HIH110T associated with Rhizobium oryziradicis (98.4 % sequence identity), Allorhizobium vitis (97.8 %), Allorhizobium taibaishanense (97.7 %) and Allorhizobium undicola (96.0 %), and lower sequence similarity to other species. Average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain CC-HIH110T and the type strains of other closely related species were 71.5-88.6 % and 19.6-35.5 %, respectively. Strain CC-HIH110T contained C16 : 0 3-OH, C14 : 0 3-OH/iso C16 : 1 I and C18 : 1 ω7c/C18 : 1 ω6c as the predominant fatty acids. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine, phosphatidylcholine, three unknown aminophospholipids, two unknown phospholipids and an unknown lipid. The major polyamine was homospermidine. The DNA G+C content was 55.0 mol% and the predominant quinone was ubiquinone (Q-10). Based on its distinct phylogenetic, phenotypic and chemotaxonomic traits together with results of comparative 16S rRNA gene sequence, ANI and dDDH analyses, strain CC-HIH110T is proposed to represent a novel Allorhizobium species, for which the name Allorhizobium terrae sp. nov. (type strain CC-HIH110T=BCRC 80932T=JCM 31228T). In addition, Rhizobium oryziradicis is reclassified as Allorhizobium oryziradicis (type strain N19T=ACCC 19962T=KCTC 52413T) comb. nov.


Increased sensitivity to alprazolam in females with a paternal history of alcoholism.
Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.


Traditional food patterns are associated with better diet quality and improved dietary adequacy in Aboriginal peoples in the Northwest Territories, Canada.
Traditionally, the Arctic diet has been derived entirely from locally harvested animal and plant species; however, in recent decades, imported foods purchased from grocery stores have become widely available. The present study aimed to examine Inuvialuit, traditional or nontraditional dietary patterns; nutrient density of the diet; dietary adequacy; and main food sources of energy and selected nutrient intakes. This cross-sectional study used a culturally appropriate quantitative food frequency questionnaire to assess diet. Traditional and nontraditional eaters were classified as those consuming more or less than 300 g of traditional food daily. Nutrient densities per 4184 kJ (1000 kcal) were determined. Dietary adequacy was determined by comparing participants' nutrient intakes with the Dietary Reference Intakes. The diet of nontraditional eaters contained, on average, a lower density of protein, niacin, vitamin B12 , iron, selenium, zinc, omega-3 fatty acids (P ≤ 0.0001), vitamin B6 , potassium, thiamin, pantothenic acid (P ≤ 0.001), riboflavin and magnesium (P ≤ 0.05). Inadequate nutrient intake was more common among nontraditional eaters for calcium, folate, vitamin C, zinc, thiamin, pantothenic acid, vitamin K, magnesium, potassium and sodium. Non-nutrient-dense foods (i.e. high fat and high sugar foods) contributed to energy intake in both groups, more so among nontraditional eaters (45% versus 33%). Traditional foods accounted for 3.3% and 20.7% of total energy intake among nontraditional and traditional eaters, respectively. Diet quality and dietary adequacy were better among Inuvialuit who consumed more traditional foods. The promotion of traditional foods should be incorporated in dietary interventions for this population.


Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease.
Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.


MPV17 does not control cancer cell proliferation.
MPV17 is described as a mitochondrial inner membrane channel. Although its function remains elusive, mutations in the MPV17 gene result in hepato-cerebral mitochondrial DNA depletion syndrome in humans. In this study, we show that MPV17 silencing does not induce depletion in mitochondrial DNA content in cancer cells. We also show that MPV17 does not control cancer cell proliferation despite the fact that we initially observed a reduced proliferation rate in five MPV17-silenced cancer cell lines with two different shRNAs. However, shRNA-mediated MPV17 knockdown performed in this work provided misguiding results regarding the resulting proliferation phenotype and only a rescue experiment was able to shed definitive light on the implication of MPV17 in cancer cell proliferation. Our results therefore emphasize the caution that is required when scientific conclusions are drawn from a work based on lentiviral vector-based gene silencing and clearly demonstrate the need to systematically perform a rescue experiment in order to ascertain the specific nature of the experimental results.


The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.
Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features. We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC). The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ± 6.8 mm) than in wild-type BRAF cases (20.9 ± 10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis. The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.


An ischemia-guided approach for risk stratification in patients with acute coronary syndromes.
The optimal management approach for patients with non-ST-segment elevation acute coronary syndromes continues to be an issue of debate. An ischemia-guided strategy appears to be effective as an alternative to either a very conservative "wait-and-see" approach or a very aggressive routine revascularization approach. The need for another approach is supported by the lack of conclusive evidence-based results favoring an early routine invasive treatment strategy. In the Thrombolysis in Myocardial Infarction (TIMI) IIIB trial, there were no differences in the incidence of death or myocardial infarction (MI) between patients treated with an early invasive approach and those treated with a conservative approach to treatment. Significantly worse outcomes were shown in patients assigned to an early invasive strategy in the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial at 1-year follow-up (111 clinical events in the invasive group vs 85 in the conservative group; p = 0.05). Registry information, including that from the Organization to Assess Strategies for Ischemic Syndromes (OASIS), which included approximately 8,000 patients with unstable angina or suspected MI, has even suggested an excess hazard with a routine invasive approach. Patients with non-ST-segment elevation MI observed in the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO)-IIB and Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trials also fared better with an ischemia-guided strategy. Even the recent FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC II) trial investigators had to be very selective relative to eliminating high-risk patients in the first week and treating with intense anti-ischemic therapy and 5-7 days of low-molecular-weight heparin therapy to show an advantage for assigned revascularization. A careful clinical evaluation with attention to early risk stratification is essential in the ischemia-guided approach. The Braunwald classification for unstable angina helps identify independent clinical predictors of a poor outcome; high risk is clearly associated with Braunwald class III and type C. Electrocardiographic and biochemical markers for myocardial necrosis (cardiac troponin T or I) are important tools for assessing the presence and degree of ischemia and associated risk for adverse outcome. Noninvasive evaluation of left ventricular ejection fraction is essential for identifying those at high risk due to impaired contractile function. When these conventional markers do not provide conclusive information, noninvasive stress testing is most helpful to further identify those at highest risk for revascularization.


Characterization of a new multigene family encoding isomaltases in the yeast Saccharomyces cerevisiae, the IMA family.
It has been known for a long time that the yeast Saccharomyces cerevisiae can assimilate alpha-methylglucopyranoside and isomaltose. We here report the identification of 5 genes (YGR287c, YIL172c, YJL216c, YJL221c and YOL157c), which, similar to the SUCx, MALx, or HXTx multigene families, are located in the subtelomeric regions of different chromosomes. They share high nucleotide sequence identities between themselves (66-100%) and with the MALx2 genes (63-74%). Comparison of their amino acid sequences underlined a substitution of threonine by valine in region II, one of the four highly conserved regions of the alpha-glucosidase family. This change was previously shown to be sufficient to discriminate alpha-1,4- to alpha-1,6-glucosidase activity in YGR287c (Yamamoto, K., Nakayama, A., Yamamoto, Y., and Tabata, S. (2004) Eur. J. Biochem. 271, 3414-3420). We showed that each of these five genes encodes a protein with alpha-glucosidase activity on isomaltose, and we therefore renamed these genes IMA1 to IMA5 for IsoMAltase. Our results also illustrated that sequence polymorphisms among this family led to interesting variability of gene expression patterns and of catalytic efficiencies on different substrates, which altogether should account for the absence of functional redundancy for growth on isomaltose. Indeed, deletion studies revealed that IMA1/YGR287c encodes the major isomaltase and that growth on isomaltose required the presence of AGT1, which encodes an alpha-glucoside transporter. Expressions of IMA1 and IMA5/YJL216c were strongly induced by maltose, isomaltose, and alpha-methylglucopyranoside, in accordance with their regulation by the Malx3p-transcription system. The physiological relevance of this IMAx multigene family in S. cerevisiae is discussed.


Structural properties of an engineered outer membrane protein G mutant, OmpG-16SL, investigated with infrared spectroscopy.
The structural and functional differences between wild type (WT) outer membrane protein G and its two mutants are investigated with Fourier transform infrared spectroscopy. Both mutants have a long extension to the primary sequence to increase the number of β-strands from 14 (wild type) to 16 in an attempt to enlarge the pore diameter. The comparison among proteins is made in terms of pH-dependent conformational changes and thermal stability. Results show that all proteins respond to pH change but at different degrees. At acidic environment, all proteins contain the same number of residues participated in β-sheet structure. However, at neutral pH, the mutants have less ordered structure compared to WT porin. Thermal stability tests show that mutants differ significantly from WT porin at neutral pH. Although the transition temperature is directly proportional with the amount of β-sheet content, the changes in the pre-transition phase that pave the way to structural breakdown are shown to involve interactions among charged residues by two-dimensional correlation spectroscopy analysis. Results of the analysis show that side chain interactions play an active role under increasing temperature. Both mutants have more unordered secondary structure but they respond to pH change in tertiary structure level. Findings of this study provided deeper insight on the active players in structural stability of the WT porin.Communicated by Ramaswamy H. Sarma [Formula: see text].


Spotlight on peginterferon-alpha-2a (40KD) in chronic hepatitis C.
Peginterferon-alpha-2a (40KD) is a new 'pegylated' subcutaneous formulation of interferon-alpha-2a that has been developed to improve on the pharmacokinetic profile and therapeutic efficacy of interferon-alpha-2a. Peginterferon-alpha-2a (40KD) is produced by the covalent attachment of recombinant interferon-alpha-2a to a branched mobile 40KD polyethylene glycol moiety, which shields the interferon-alpha-2a molecule from enzymatic degradation, reduces systemic clearance and enables once-weekly administration. Peginterferon-alpha-2a (40KD) was significantly more effective than interferon-alpha-2a in interferon-alpha therapy-naive adults with chronic hepatitis C in three nonblind, randomised, multicentre trials. Virological responses (intention-to-treat results) were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-alpha-2a (40KD) 180 microg/week; sustained virological responses 24 weeks after the end of treatment occurred in 30 to 39% of patients. Virological responses at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-alpha-2a. Peginterferon-alpha-2a (40KD) was significantly more effective than interferon-alpha in patients with or without cirrhosis infected with HCV genotype 1. Sustained biochemical responses achieved with peginterferon-alpha-2a (40KD) 180 microg/week ranged from 34 to 45% and were significantly higher than with interferon-alpha-2a. Recipients of peginterferon-alpha-2a (40KD) also experienced histological improvements; 24 weeks after discontinuation of treatment with peginterferon-alpha-2a (40KD) 180 microg/week, 54% to 63% of patients had a >/=2-point improvement in histological activity index score. Peginterferon-alpha-2a (40KD) produced histological responses in patients (with or without cirrhosis) with or without a sustained virological response. Peginterferon-alpha-2a (40KD) produced better results than interferon-alpha-2a alone or interferon-alpha-2b plus oral ribavirin on various measures of quality of life in patients with chronic hepatitis C. The tolerability profile of peginterferon-alpha-2a (40KD) is broadly similar to that of interferon-alpha-2a in patients with chronic hepatitis C with or without cirrhosis. Headache, fatigue and myalgia are among the most common adverse events. In conclusion, peginterferon-alpha-2a (40KD) administered once weekly produces significantly higher sustained responses, without compromising tolerability, than interferon-alpha-2a administered thrice weekly in noncirrhotic or cirrhotic patients with chronic hepatitis C, including those infected with HCV genotype 1 - a group in whom interferon-alpha treatment has usually been unsuccessful. Peginterferon-alpha-2a (40KD) is a valuable new treatment option and appears poised to play an important role in the first-line treatment of patients with chronic hepatitis C, including difficult-to-treat patients such as those with compensated cirrhosis and/or those infected with HCV genotype 1.


Variation on a theme: vibrational signaling in caterpillars of the rose hook-tip moth, Oreto rosea.
Vibrational communication in hook-tip moth caterpillars is thought to be widely used and highly variable across species, but this phenomenon has been experimentally examined in only two species to date. The purpose of this study is to characterize and describe the function of vibrational signaling in a species, Oreta rosea Walker 1855 (Lepidoptera: Drepanidae), that differs morphologically from previously studied species. Caterpillars of this species produce three distinct types of vibrational signals during territorial encounters with conspecifics--mandible drumming, mandible scraping and lateral tremulation. Signals were recorded using a laser-doppler vibrometer and characterized based on temporal and spectral components. Behavioural encounters between a leaf resident and a conspecific intruder were staged to test the hypothesis that signaling functions as a territorial display. Drumming and scraping signals both involve the use of the mandibles, being hit vertically on, or scraped laterally across, the leaf surface. Lateral tremulation involves quick, short, successive lateral movements of the anterior body region that vibrates the entire leaf. Encounters result in residents signaling, with the highest rates observed when intruders make contact with the resident. Residents signal significantly more than intruders and most conflicts are resolved within 10 minutes, with residents winning 91% of trials. The results support the hypothesis that vibrational signals function to advertise leaf occupancy. Signaling is compared between species, and evolutionary origins of vibrational communication in caterpillars are discussed.


A novel deterministic forecast model for COVID-19 epidemic based on a single ordinary integro-differential equation.
In this paper, we present a new approach to deterministic modelling of COVID-19 epidemic. Our model dynamics is expressed by a single prognostic variable which satisfies an integro-differential equation. All unknown parameters are described with a single, time-dependent variable R(t). We show that our model has similarities to classic compartmental models, such as SIR, and that the variable R(t) can be interpreted as a generalized effective reproduction number. The advantages of our approach are the simplicity of having only one equation, the numerical stability due to an integral formulation and the reliability since the model is formulated in terms of the most trustable statistical data variable: the number of cumulative diagnosed positive cases of COVID-19. Once this dynamic variable is calculated, other non-dynamic variables, such as the number of heavy cases (hospital beds), the number of intensive-care cases (ICUs) and the fatalities, can be derived from it using a similarly stable, integral approach. The formulation with a single equation allows us to calculate from real data the values of the sample effective reproduction number, which can then be fitted. Extrapolated values of R(t) can be used in the model to make reliable forecasts, though under the assumption that measures for reducing infections are maintained. We have applied our model to more than 15 countries and the ongoing results are available on a web-based platform [1]. In this paper, we focus on the data for two exemplary countries, Italy and Germany, and show that the model is capable of reproducing the course of the epidemic in the past and forecasting its course for a period of four to five weeks with a reasonable numerical stability.


Radiolabeled Cyclic RGD Peptides as Radiotracers for Imaging Tumors and Thrombosis by SPECT.
The integrin family is a group of transmembrane glycoprotein comprised of 19 α- and 8 β-subunits that are expressed in 25 different α/β heterodimeric combinations on the cell surface. Integrins play critical roles in many physiological processes, including cell attachment, proliferation, bone remodeling, and wound healing. Integrins also contribute to pathological events such as thrombosis, atherosclerosis, tumor invasion, angiogenesis and metastasis, infection by pathogenic microorganisms, and immune dysfunction. Among 25 members of the integrin family, the α(v)β(3) is studied most extensively for its role of tumor growth, progression and angiogenesis. In contrast, the α(IIb)β(3 )is expressed exclusively on platelets, facilitates the intercellular bidirectional signaling ("inside-out" and "outside-in") and allows the aggregation of platelets during vascular injury. The α(IIb)β(3) plays an important role in thrombosis by its activation and binding to fibrinogen especially in arterial thrombosis due to the high blood flow rate. In the resting state, the α(IIb)β(3) on platelets does not bind to fibrinogen; on activation, the conformation of platelet is altered and the binding sites of α(IIb)β(3 )are exposed for fibrinogen to crosslink platelets. Over the last two decades, integrins have been proposed as the molecular targets for diagnosis and therapy of cancer, thrombosis and other diseases. Several excellent review articles have appeared recently to cover a broad range of topics related to the integrin-targeted radiotracers and their nuclear medicine applications in tumor imaging by single photon emission computed tomography (SPECT) or a positron-emitting radionuclide for positron emission tomography (PET). This review will focus on recent developments of α(v)β(3)-targeted radiotracers for imaging tumors and the use of α(IIb)β(3)-targeted radiotracers for thrombosis imaging, and discuss different approaches to maximize the targeting capability of cyclic RGD peptides and improve the radiotracer excretion kinetics from non-cancerous organs. Improvement of target uptake and target-to-background ratios is critically important for target-specific radiotracers.


AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells.
The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.


Improved quantification and mapping of anomalous pulmonary venous flow with four-dimensional phase-contrast MRI and interactive streamline rendering.
Cardiac MRI is routinely performed for quantification of shunt flow in patients with anomalous pulmonary veins, but can be technically-challenging to perform. Four-dimensional phase-contrast (4D-PC) MRI has potential to simplify this exam. We sought to determine whether 4D-PC may be a viable clinical alternative to conventional 2D phase-contrast MR imaging. With institutional review board approval and HIPAA-compliance, we retrospectively identified all patients with anomalous pulmonary veins who underwent cardiac MRI at either 1.5 Tesla (T) or 3T with parallel-imaging compressed-sensing (PI-CS) 4D-PC between April, 2011 and October, 2013. A total of 15 exams were included (10 male, 5 female). Algorithms for interactive streamline visualization were developed and integrated into in-house software. Blood flow was measured at the valves, pulmonary arteries and veins, cavae, and any associated shunts. Pulmonary veins were mapped to their receiving atrial chamber with streamlines. The intraobserver, interobserver, internal consistency of flow measurements, and consistency with conventional MRI were then evaluated with Pearson correlation and Bland-Altman analysis. Triplicate measurements of blood flow from 4D-PC were highly consistent, particularly at the aortic and pulmonary valves (cv 2-3%). Flow measurements were reproducible by a second observer (ρ = 0.986-0.999). Direct measurements of shunt volume from anomalous veins and intracardiac shunts matched indirect estimates from the outflow valves (ρ = 0.966). Measurements of shunt fraction using 4D-PC using any approach were more consistent with ventricular volumetric displacements than conventional 2D-PC (ρ = 0.972-0.991 versus 0.929). Shunt flow may be reliably quantified with 4D-PC MRI, either indirectly or with detailed delineation of flow from multiple shunts. The 4D-PC may be a more accurate alternative to conventional MRI.


Punctate Inner Choroidopathy and Choroidal Neovascularization in Korean Patients.
Purpose: To describe the clinical features and outcomes of punctate inner choroidopathy (PIC) in Korean patientsMethods: We retrospectively reviewed the medical records of patients with PIC between 2004 and 2015. The main outcome measures included best-corrected visual acuity (BCVA), presence of choroidal neovascularization (CNV), and optical coherence tomography findings. Patients with and without CNV were compared.Results: Forty eyes of 26 patients were included. The final BCVA was better than 20/40 in 33 eyes (82.5%). CNV was initially present in 12 eyes (30.0%). The mean initial and final logMAR BCVA was poorer for eyes with CNV than for eyes without CNV. Eyes with CNV exhibited a larger myopic refractive error, inflammatory lesions confined within the posterior pole, and a decreased final subfoveal choroidal thickness compared with eyes without CNV.Conclusion: PIC in the Korean population generally exhibits favorable visual outcomes, and eyes with CNV show more abnormalities and poorer outcomes.


[Professional practices in public dental healthcare: case study of two municipal districts, Bahia State, Brazil].
This paper examines the working facilities and processes of dentists in the primary healthcare systems of two towns in Bahia State, Brazil, striving to analyze the extent to which factors related to dental care, training, placement and professional profiles influence their practices. Semi-structured interviews were conducted with nine dentists in both towns, with work process organization patterns in Municipality C being closer to the structuring principles of Brazil's National Health System than in Municipality E. This seems to be related to management characteristics, with networking links among individual, collective, and preventive clinical activities and planning noted in Municipality C. Despite these differences, the practitioners presented similarities in terms of dual militancy and perceptions of the public and private healthcare fields. The hegemony of the private sector seems to be influencing the professional practices of dentists in the public health system.


Development of dot-ELISA for the detection of venoms of major Indian venomous snakes.
India remained an epicenter for the snakebite-related mortality and morbidities due to widespread agricultural activities across the country and a considerable number of snakebites offended by Indian cobra (Naja naja), common krait (Bungarus caeruleus), Russell's viper (Daboia russelii), and saw-scaled viper (Echis carinatus). Presently, there is no selective test available for the detection of snake envenomation in India before the administration of snake antivenin. Therefore, the present study aimed to develop rapid, sensitive assay for the management of snakebite, which can detect venom, responsible snake species and serve as a tool for the reasonable administration of snake antivenin, which have scarcity across the world. The selective envenomation detection assay needs venom specific antibodies (VSAbs) for that monovalent antisera was prepared by hyperimmunization of rabbits with specific venom. However, obtained antibodies exhibit maximum activity towards homologous venom as well as quantifiable degree of cross-reactivity with heterologous venoms. Use of these antibodies for development of selective envenomation detection assay may create ambiguity in results, therefore needs to isolate VSAbs from monovalent antisera. The cross-reacting antibodies were specifically removed by immunoaffinity chromatography to obtain VSAbs. For the development of venom detection ELISA test (VDET), two different species of antibodies were used that offers enhanced sensitivity along with selective identification of the venoms of the responsible snakes. In conclusion, the developed VDET is rapid, specific, yet sensitive to detect venoms of offending snake species, and its venom concentration down to 1.0 ng/ml. However, the device observed with lowest venom concentration detection ability in the range <1.0 ng/ml from experimentally envenomated samples. The implementation of VDET will help in avoiding unnecessary usage and adverse reactions of snake antivenin. The test has all the merits to become a choice of method in envenomation diagnosis from medically important snakes of India.


An electronic trigger based on care escalation to identify preventable adverse events in hospitalised patients.
Methods to identify preventable adverse events typically have low yield and efficiency. We refined the methods of Institute of Healthcare Improvement's Global Trigger Tool (GTT) application and leveraged electronic health record (EHR) data to improve detection of preventable adverse events, including diagnostic errors. We queried the EHR data repository of a large health system to identify an 'index hospitalization' associated with care escalation (defined as transfer to the intensive care unit (ICU) or initiation of rapid response team (RRT) within 15 days of admission) between March 2010 and August 2015. To enrich the record review sample with unexpected events, we used EHR clinical data to modify the GTT algorithm and limited eligible patients to those at lower risk for care escalation based on younger age and presence of minimal comorbid conditions. We modified the GTT review methodology; two physicians independently reviewed eligible 'e-trigger' positive records to identify preventable diagnostic and care management events. Of 88 428 hospitalisations, 887 were associated with care escalation (712 ICU transfers and 175 RRTs), of which 92 were flagged as trigger-positive and reviewed. Preventable adverse events were detected in 41 cases, yielding a trigger positive predictive value of 44.6% (reviewer agreement 79.35%; Cohen's kappa 0.573). We identified 7 (7.6%) diagnostic errors and 34 (37.0%) care management-related events: 24 (26.1%) adverse drug events, 4 (4.3%) patient falls, 4 (4.3%) procedure-related complications and 2 (2.2%) hospital-associated infections. In most events (73.1%), there was potential for temporary harm. We developed an approach using an EHR data-based trigger and modified review process to efficiently identify hospitalised patients with preventable adverse events, including diagnostic errors. Such e-triggers can help overcome limitations of currently available methods to detect preventable harm in hospitalised patients.


Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure.
The X-linked muscle wasting disease Duchenne muscular dystrophy is caused by the lack of dystrophin in muscle. Protein structure predictions, patient mutations, in vitro binding studies and transgenic and knockout mice suggest that dystrophin plays a mechanical role in skeletal muscle, linking the subsarcolemmal cytoskeleton with the extracellular matrix through its direct interaction with the dystrophin-associated protein complex (DAPC). Although a signaling role for dystrophin has been postulated, definitive data have been lacking. To identify potential non-mechanical roles of dystrophin, we tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and the dystrophin-related protein utrophin. We show that restoration of the DAPC with Dp71 does not prevent the structural abnormalities of the post-synaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In marked contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, is able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. These experiments provide the first direct evidence that in addition to a mechanical role and relocalization of the DAPC, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle. In addition, these mice provide unique insights into skeletal muscle fiber type composition.


[Study of stabilized erythrocytes in the direct hemagglutination reaction with influenza viruses by the method of multifactorial planning of experiments].
It was demonstrated that human, chicken and guinea pig erythrocytes stabilized with acrolein, glutaraldehyde and formalin could be used for titration of influenza A1, A2 and B viruses. For this purpose, a four-factor experiment of the type of 3X4X3X2 was planned. All the factors under study (the erythrocyte species, stabilization, erythrocyte concentration and virus type), and some dual interactions (erythrocyte species and stabilization, erythrocyte species and virus type, stabilization and virus type) were found to be significant. Planning of a multifactorial experiment permits a composite investigation of the infleunce of the factors under study and their interactions on influenza virus titers with a reduction of the total number of tests and to obtain more significant answers to preset tasks.


Morphometric analysis of particulate debris extracted by four different embolic protection devices from coronary arteries, aortocoronary saphenous vein conduits, and carotid arteries.
Different embolic protection devices have been introduced for endovascular interventions: filters or balloon occlusion and aspiration systems. Despite widening use in a variety of vascular beds and clinical syndromes, little is known about the particulate burden liberated from different vascular beds and caught by different protection devices. We performed histologic and morphometric analyses of particulate debris captured during stenting of degenerated saphenous vein bypass grafts and native coronary arteries during acute myocardial infarction or during elective intervention and carotid arteries to assess the relative performance of different protection devices. We analyzed 232 interventions (90 saphenous vein bypass grafts, 77 native coronary arteries, and 65 carotid arteries) with 4 different devices (65 FilterWires, 99 Interceptors, 41 GuardWires, and 27 Proxis catheters) using the RapidVue particle analyzer. No difference in embolic volume retrieved was demonstrated between devices in saphenous vein bypass grafts and carotid interventions. A smaller volume of particulate debris was retrieved by the GuardWire compared with the FilterWire and the Proxis catheter in native coronary artery interventions. The Interceptor and the GuardWire captured more smaller particles than did the FilterWire or Proxis catheter. During saphenous vein bypass graft or carotid intervention, different embolic protection strategies were performed similarly. In native coronary artery stenting, however, proximal embolic protection retrieved larger amounts of debris than did distal filters or occlusion devices. These data may allow greater tailoring of embolic protection device development and application in specific anatomic locales.


Ethical problems in clinical practice.
Ethics is about judgment, which is rarely black and white. This paper highlights some of the ethical dilemmas that face practising clinicians in their everyday life and restates how useful the General Medical Council guidance is to make appropriate decisions. The authors have faced all eight of the clinical scenarios in this paper in their routine clinical practice.


A quantitative analysis of biodiversity and the recreational value of potential national parks in Denmark.
Denmark has committed itself to the European 2010 target to halt the loss of biodiversity. Currently, Denmark is in the process of designating larger areas as national parks, and 7 areas (of a possible 32 larger nature areas) have been selected for pilot projects to test the feasibility of establishing national parks. In this article, we first evaluate the effectiveness of the a priori network of national parks proposed through expert and political consensus versus a network chosen specifically for biodiversity through quantitative analysis. Second, we analyze the potential synergy between preserving biodiversity in terms of species representation and recreational values in selecting a network of national parks. We use the actual distribution of 973 species within these 32 areas and 4 quantitative measures of recreational value. Our results show that the 7 pilot project areas are not significantly more effective in representing species than expected by chance and that considerably more efficient networks can be selected. Moreover, it is possible to select more-effective networks of areas that combine high representation of species with high ranking in terms of recreational values. Therefore, our findings suggest possible synergies between outdoor recreation and biodiversity conservation when selecting networks of national parks. Overall, this Danish case illustrates that data-driven analysis can not only provide valuable information to guide the decision-making process of designating national parks, but it can also be a means to identify solutions that simultaneously fulfill several goals (biodiversity preservation and recreational values).


Therapeutic potentials of Houttuynia cordata Thunb. against inflammation and oxidative stress: A review.
Houttuynia cordata Thunb. (Family: Saururaceae) is an herbaceous perennial plant that grows in moist and shady places. The plant is well known among the people of diverse cultures across Japan, Korea, China and North-East India for its medicinal properties. Traditionally the plant is used for its various beneficial properties against inflammation, pneumonia, severe acute respiratory syndrome, muscular sprain, stomach ulcer etc. Oxidative stress and inflammation were found to be linked with most of the diseases in recent times. Many ancient texts from Chinese Traditional Medicine, Ayurveda and Siddha, and Japanese Traditional medicine have documented the efficacy of H. cordata against oxidative stress and inflammation. This review aims to provide up-to-date and comprehensive information on the efficacy of H. cordata extracts as well as its bioactive compounds both in vitro and in vivo, against oxidative stress and inflammation MATERIALS AND METHODS: Relevant information on H. cordata against oxidative stress and inflammation were collected from the established scientific databases such as NCBI, Web of Science, ScienceDirect, Elsevier, and Springer. Additionally, a few books and magazines were also consulted to get the important information. Herbal medicines or plant products were traditionally being used for treating the oxidative stress and inflammation related diseases in diverse communities across the world. Scientifically, H. cordata has shown to target several signaling pathways and found to effectively reduce the oxidative stress and inflammation. Phyto-constituents such as afzelin, hyperoside and quercitrin have shown to reduce inflammation both in vitro and in vivo models. These molecules were also shown to have strong antioxidant properties both in vivo and in vitro models. H. cordata extracts and its bioactive molecules were shown to have both anti-inflammatory and anti-oxidative properties. As both in vitro and in vivo studies were shown that H. cordata did not have any toxicity on the various model systems used, future clinical studies will hopefully make an impact on the future direction of treating inflammation-related diseases.


Cumulative inactivation of N-type CaV2.2 calcium channels modified by alternative splicing.
The Ca(V)2 family of voltage-gated calcium channels, present in presynaptic nerve terminals, regulates exocytosis and synaptic transmission. Cumulative inactivation of these channels occurs during trains of action potentials, and this may control short-term dynamics at the synapse. Inactivation during brief, repetitive stimulation is primarily attributed to closed-state inactivation, and several factors modulate the susceptibility of voltage-gated calcium channels to this form of inactivation. We show that alternative splicing of an exon in a cytoplasmic region of the Ca(V)2.2 channel modulates its sensitivity to inactivation during trains of action potential waveforms. The presence of this exon, exon 18a, protects the Ca(V)2.2 channel from entry into closed-state inactivation specifically during short (10 ms to 3 s) and small depolarizations of the membrane potential (-60 mV to -50 mV). The reduced sensitivity to closed-state inactivation within this dynamic range likely underlies the differential responsiveness of Ca(V)2.2 splice isoforms to trains of action potential waveforms. Regulated alternative splicing of Ca(V)2.2 represents a possible mechanism for modulating short-term dynamics of synaptic efficacy in different regions of the nervous system.


Intake of cruciferous vegetables is associated with reduced risk of ovarian cancer: a meta-analysis.
Epidemiological studies on the association between cruciferous vegetable (CV) consumption and the risk of ovarian cancer have demonstrated inconsistent results. We conducted a meta-analysis on CV consumption and ovarian cancer risk. The relevant studies were identified by searching the Medline (Pubmed), Embase and Web of Science databases. The references of related articles and reviews up to October 2013 were also screened. The pooled relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest CV consumption levels were calculated using a random-effects model. The heterogeneity and publication bias were also evaluated. Eight studies (4 case-control studies and 4 cohort studies) were identified and included in this meta-analysis. When all studies were pooled together, there was a significantly inverse association between CV consumption and the risk of ovarian cancer (RR: 0.89; 95% CI: 0.81-0.99). No significant heterogeneity or publication bias was found. The findings from this study suggest that the consumption of CVs may reduce the risk of ovarian cancer. Further investigations are needed to confirm the clinical effect of CVs on ovarian cancer.


A novel method to detect mutation in DNA by utilizing exponential amplification reaction triggered by the CRISPR-Cas9 system.
We, herein, describe a novel method to detect mutation in DNA by utilizing exponential amplification reaction (EXPAR) triggered by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, called CRISPR-EXPAR. The CRISPR system consisting of two Cas9/sgRNA complexes was designed to cut out a specific mutation region within the target DNA, which would consequently promote EXPAR by continuously repeated extension and nicking reactions. As a consequence, a large number of final EXPAR products, which can be monitored through duplex-specific fluorescent staining, are produced. Based on this design principle, we successfully identified a model target mutation within the human epidermal growth factor receptor 2 (HER2) gene down to 437 aM with excellent specificity. The practical capability of this method was verified by reliably identifying the target mutation directly from the genomic DNA (gDNA) extracted from the lung cancer cell line, NCI-H1781 (H1781), and its universal applicability was further confirmed by identifying another EFGF L858R mutation. This technique could serve as a new isothermal platform to identify various mutations by rationally redesigning single guide RNA (sgRNA) according to the target mutation site.