Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show?
Endometriosis is a gynecologic disorder that can lead to debilitating chronic pelvic pain and infertility. Gonadotropin-releasing hormone agonists (GnRHa) have emerged as a primary medical therapy for patients with symptomatic disease, but secondary hypoestrogenic side effects may limit compliance. Add-back therapy is a means of surmounting this problem. Progestins such as norethindrone acetate may be administered with or without addition of low doses of estrogens to safely and effectively extend GnRHa therapy while minimizing side effects. Recent studies have demonstrated that the use of add-back enhances compliance and duration of therapy. The initiation of an add-back should not be deferred given evidence demonstrating an increase in vasomotor symptoms and bone loss if not administered concomitantly. The subset of adolescents with endometriosis who require GnRHa therapy should be administered an add-back, but require careful monitoring of bone mineral density. Implementation of an appropriately selected add-back will significantly reduce hypoestrogenic side effects, enhance compliance, and allow for prolongation of therapy without interfering with the efficacy of GnRHa in treating symptomatic endometriosis.


Evaluation of rifampicin and isoniazid susceptibility testing of Mycobacterium tuberculosis by a mycobacteriophage D29-based assay.
Conventional methods for determining drug susceptibility of Mycobacterium tuberculosis require several weeks to obtain results, limiting their usefulness; automated methods and those based on molecular biology techniques have been able to reduce the turnaround time, but their high cost and need for sophisticated equipment restrict their use in developing countries. The goal of the present study was to evaluate the diagnostic accuracy of a rapid (3-4 days) low-cost test based on the use of mycobacteriophage D29 to determine the susceptibility of strains of M. tuberculosis to rifampicin (RIF) and isoniazid (INH). Results obtained show that susceptibility testing for RIF has a high diagnostic accuracy as compared to the standard indirect proportion method on Löwenstein-Jensen medium (sensitivity 100% and specificity 98%). Given the association between the resistance to RIF and INH, which define multidrug resistance (MDR), this test seems suitable for rapid detection of MDR tuberculosis strains (kappa=0.978). Susceptibility testing for INH using mycobacteriophage D29 had a good but lower diagnostic accuracy as compared to the standard method (sensitivity 80.4% and specificity 80.8%); the test would then be of limited usefulness in the management of tuberculosis patients. Further studies to determine the relationship of mycobacteriophage D29 tests to in vivo correlates of sensitivity to specific antituberculosis drugs are warranted.


Characterization of indole-positive Proteus mirabilis.
Thirteen indole-producing, swarming strains of Proteus were identified by additional biochemical testing as being Proteus mirabilis. These strains were characterized by 40 biochemical tests and by susceptibility testing to 11 antibiotics. All produced ornithine decarboxylase and were susceptible to members of the penicillin-cephalosporin groups of antibiotics. These indole-positive strains are similar to indole-negative P. mirabilis and are distinctly different from P. vulgaris. For greatest accuracy and to insure greatest clinical relevancy, P. mirabilis and P. vulgaris should be distinguished from one another in the laboratory by performing both the indole and ornithine decarboxylase tests.


Nonclassical Photon Number Distribution in a Superconducting Cavity under a Squeezed Drive.
A superconducting qubit in the strong dispersive regime of circuit quantum electrodynamics is a powerful probe for microwave photons in a cavity mode. In this regime, a qubit excitation spectrum is split into multiple peaks, with each peak corresponding to an individual photon number in the cavity (discrete ac Stark shift). Here, we measure the qubit spectrum in a cavity that is driven continuously with a squeezed vacuum generated by a Josephson parametric amplifier. By fitting the obtained spectrum with a model which takes into account the finite qubit excitation power, we determine the photon number distribution, which reveals an even-odd photon number oscillation and quantitatively fulfills Klyshko's criterion for nonclassicality.


Can We Just Say: Transcription Second?
The striking correlation between genome topology and transcriptional activity has for decades made researchers revisit the question, "Does form follow function, or does function follow form?" In a new study, Hug et al. address this question by comparing the timing of zygotic genome activation to the emergence of genome structures during Drosophila embryogenesis.


The role of somatosensory input in target localization during binocular and monocular viewing while performing a high precision reaching and placement task.
Binocular vision provides the most accurate and precise depth information; however, many people have impairments in binocular visual function. It is possible that other sensory inputs could be used to obtain reliable depth information when binocular vision is not available. However, it is currently unknown whether depth information from another modality improves target localization in depth during action execution. Therefore, the goal of this study was to assess whether somatosensory input improves target localization during the performance of a precision placement task. Visually normal young adults (n = 15) performed a bead threading task during binocular and monocular viewing in two experimental conditions where needle location was specified by 1) vision only, or 2) vision and somatosensory input, which was provided by the non-dominant limb. Performance on the task was assessed using spatial and temporal kinematic measures. In accordance with the hypothesis, results showed that the interval spent placing the bead on the needle was significantly shorter during monocular viewing when somatosensory input was available in comparison to a vision only condition. In contrast, results showed no evidence to support that somatosensory input about the needle location affects trajectory control. These findings demonstrate that the central nervous system relies predominately on visual input during reach execution, however, somatosensory input can be used to facilitate the performance of the precision placement task.


Echocardiography in shock management.
Echocardiography is pivotal in the diagnosis and management of the shocked patient. Important characteristics in the setting of shock are that it is non-invasive and can be rapidly applied.In the acute situation a basic study often yields immediate results allowing for the initiation of therapy, while a follow-up advanced study brings the advantage of further refining the diagnosis and providing an in-depth hemodynamic assessment. Competency in basic critical care echocardiography is now regarded as a mandatory part of critical care training with clear guidelines available. The majority of pathologies found in shocked patients are readily identified using basic level 2D and M-mode echocardiography. A more comprehensive diagnosis can be achieved with advanced levels of competency, for which practice guidelines are also now available. Hemodynamic evaluation and ongoing monitoring are possible with advanced levels of competency, which includes the use of colour Doppler, spectral Doppler, and tissue Doppler imaging and occasionally the use of more recent technological advances such as 3D or speckled tracking.The four core types of shock-cardiogenic, hypovolemic, obstructive, and vasoplegic-can readily be identified by echocardiography. Even within each of the main headings contained in the shock classification, a variety of pathologies may be the cause and echocardiography will differentiate which of these is responsible. Increasingly, as a result of more complex and elderly patients, the shock may be multifactorial, such as a combination of cardiogenic and septic shock or hypovolemia and ventricular outflow obstruction.The diagnostic benefit of echocardiography in the shocked patient is obvious. The increasing prevalence of critical care physicians experienced in advanced techniques means echocardiography often supplants the need for more invasive hemodynamic assessment and monitoring in shock.


Series: Practical Evaluation of Clinical Image Quality (4): Determination of Image Quality in Digital Radiography System.
Recently, for medical imaging, digital radiography systems are widely used in clinical practices. However, a study in the past reported that a patient radiation exposure level by digital radiography is in fact not lower than that by analog radiography system. High level of attention needs to be paid for over-exposure when using the conventional analog radiography with a screen and a film, as it results in high density of the film. However, for digital radiography systems, since the automatic adjusting function of image density is equipped with them, no attention for radiation dose need to be paid. Thus technologists tend to be careless and results in higher chance for over-exposure. Current digital radiography systems are high-performance in the image properties and capable of patient dose reduction. Especially, the image quality of the flat panel detector system is recognized, higher than that of the computed radiography system by imaging plates, in both objective and subjective evaluations. Therefore, we technologists are responsible for optimizing the balance between the image quality of the digital radiogram and the radiation dose required for each case. Moreover, it is also required for us as medical technologists to make effective use of such evaluation result of medical images for patients.


On forward inferences of fast and slow readers. An eye movement study.
Unimpaired readers process words incredibly fast and hence it was assumed that top-down processing, such as predicting upcoming words, would be too slow to play an appreciable role in reading. This runs counter the major postulate of the predictive coding framework that our brain continually predicts probable upcoming sensory events. This means, it may generate predictions about the probable upcoming word during reading (dubbed forward inferences). Trying to asses these contradictory assumptions, we evaluated the effect of the predictability of words in sentences on eye movement control during silent reading. Participants were a group of fluent (i.e., fast) and a group of speed-impaired (i.e., slow) readers. The findings indicate that fast readers generate forward inferences, whereas speed-impaired readers do so to a reduced extent - indicating a significant role of predictive coding for fluent reading.


Feasibility of telephone follow-up after medical abortion.
This study was conducted to assess the feasibility of using telephone calls combined with high-sensitivity urine pregnancy testing as a primary method of follow-up after medical abortion. We enrolled 139 women up to 63 days of gestation to receive mifepristone 200 mg orally and misoprostol 800 mcg vaginally or buccally, per their choice. Participants were contacted by phone one week after mifepristone administration and interviewed using standardized questions. If the subject or clinician thought the pregnancy was not expelled, the subject returned for an ultrasound examination. Otherwise, subjects performed high-sensitivity home urine pregnancy testing 30 days after the mifepristone and were called within 3 days of the test. Those with positive pregnancy tests returned for an ultrasound examination. Those with negative tests required no further follow-up. Six of the 139 (4.3%, 95% CI 1.6-9.1%) subjects presented prior to Phone Call 1 for an in-person visit. All 133 (100%, 95% CI 97.8-100%) subjects eligible for their first telephone follow-up were contacted. Eight of the 133 (6.1%, 95% CI 2.6-11.5%) women were asked to return for evaluation and all did so (100%, 95% CI 63.1-100%). Eight of the 133 women eligible for the 30 day phone call presented for an interim visit prior to the call. After 30 days, 116 of the 117 (99.1%, 95% CI 97.5-100%) eligible subjects were contacted. One subject was not reached for the day 30 phone call. Twenty-seven of the 116 (23.3%, 95% CI 15.6-31.0%) subjects had a positive pregnancy test and required follow-up. Two of these subjects (7.4%, 95% CI 1.0-24.2%) did not return for in-person follow-up. Two of the 116 (1.7%, 95% CI 0.2-6.1%) subjects had inconclusive pregnancy tests and were asked to return for follow-up. One of these subjects (50%, 95% CI 1.2-98.7%) did not return. Complete follow-up was achieved in 135 of the 139 subjects (97.1%, 95% CI 94.3-99.9%). None of the 26 women evaluated for a positive or inconclusive pregnancy test had a gestational sac or continuing pregnancy. Telephone follow-up combined with urine pregnancy testing after medical abortion is a feasible alternative to routine ultrasonography or serial serum hCG measurements.


Local Electric Fields as a Natural Switch of Heme-Iron Protein Reactivity.
Heme-iron oxidoreductases operating through the high-valent FeIVO intermediates perform crucial and complicated transformations, such as oxidations of unreactive saturated hydrocarbons. These enzymes share the same Fe coordination, only differing by the axial ligation, e.g., Cys in P450 oxygenases, Tyr in catalases, and His in peroxidases. By examining ~200 heme-iron proteins, we show that the protein hosts exert highly specific intramolecular electric fields on the active sites, and there is a strong correlation between the direction and magnitude of this field and the protein function. In all heme proteins, the field is preferentially aligned with the Fe-O bond ( Fz ). The Cys-ligated P450 oxygenases have the highest average Fz of 28.5 MV cm-1, i.e., most enhancing the oxyl-radical character of the oxo group, and consistent with the ability of these proteins to activate strong C-H bonds. In contrast, in Tyr-ligated proteins, the average Fz is only 3.0 MV cm-1, apparently suppressing single-electron off-pathway oxidations, and in His-ligated proteins, Fz is -8.7 MV cm-1. The operational field range is given by the trade-off between the low reactivity of the FeIVO Compound I at the more negative Fz , and the low selectivity at the more positive Fz . Consequently, a heme-iron site placed in the field characteristic of another heme-iron protein class loses its canonical function, and gains an adverse one. Thus, electric fields produced by the protein scaffolds, together with the nature of the axial ligand, control all heme-iron chemistry.


A perspective for sequencing familial hypercholesterolaemia in African Americans.
African Americans suffer disproportionately from poor cardiovascular health outcomes despite similar proportions of African Americans and Americans of European ancestry experiencing elevated cholesterol levels. Some of the variation in cardiovascular outcomes is due to confounding effects of other risk factors, such as hypertension and genetic influence. However, genetic variants found to contribute to variation in serum cholesterol levels in populations of European ancestry are less likely to replicate in populations of African ancestry. To date, there has been limited follow-up on variant discrepancies or on identifying variants that exist in populations of African ancestry. African and African-American populations have the highest levels of genetic heterogeneity, which is a factor that must be considered when evaluating genetic variants in the burgeoning era of personalised medicine. Many of the large published studies identifying genetic variants associated with disease risk have evaluated populations of mostly European ancestry and estimated risk in other populations based on these findings. The purpose of this paper is to provide a perspective, using familial hypercholesterolaemia as an exemplar, that studies evaluating genetic variation focused within minority populations are necessary to identify factors that contribute to disparities in health outcomes and realise the full utility of personalised medicine.


Infertility in a Maltese poodle as a result of a sperm midpiece defect.
A 2 1/2-year-old Maltese poodle was examined for breeding soundness following a series of unsuccessful matings to fertile bitches. He was found to have only 8% normal sperm in his ejaculate when Spermac-stained smears were examined under the light microscope. The defect most frequently encountered involved the midpiece attachment, and the various manifestations of disintegration found in this region are described and illustrated. Transmission and scanning electron microscopy confirmed light microscopical findings.


Psychometric properties of the multidimensional assessment of interoceptive awareness (MAIA) in a Chilean population.
The multidimensional assessment of interoceptive awareness (MAIA) is an instrument designed to assess interoceptive awareness. The aim of this study was to adapt the original MAIA scale to Spanish and to analyze its psychometric properties in a Chilean population. The MAIA was administered to 470 adults, aged 18-70 years, 76.6% women and 23.4% men, residents of the provinces of Valparaíso and Concepción, Chile. Exploratory factor analysis reduced the scale from 32 to 30 items. Confirmatory factor analysis supports a structure of eight interrelated factors (Noticing, Not-Distracting, Not-Worrying, Attention Regulation, Emotional Awareness, Self- Regulation, Body Listening, and Trusting), similar to the original scale (χ(2) (371) = 659.78, p = 0.0001; CFI = 0.92, TLI = 0.91, RMSEA = 0.056 and SRMR = 0.059). The Spanish version showed appropriate indicators of construct validity and reliability, with a Cronbach's α of 0.90 for the total scale, and values between 0.40 and 0.86 for the different subscales. Similar to previous studies, low reliability was observed in two of the eight scales (Not-Distracting and Not-Worrying), thus further revision of these subscales is suggested. The Spanish version of MAIA proved to be a valid and reliable tool to investigate interoceptive awareness in the Chilean population.


Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the Aβ42-Treated Forebrain Spheroids Derived from Human Stem Cells.
Extracellular matrix (ECM) components of the brain play complex roles in neurodegenerative diseases. The study of microenvironment of brain tissues with Alzheimer's disease revealed colocalized expression of different ECM molecules such as heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), matrix metal-loproteinases (MMPs), and hyaluronic acid. In this study, both cortical and hippocampal populations were generated from human-induced pluripotent stem cell-derived neural spheroids. The cultures were then treated with heparin (competes for Aβ affinity with HSPG), heparinase III (digests HSPGs), chondroitinase (digests CSPGs), hyaluronic acid, and an MMP-2/9 inhibitor (SB-3CT) together with amyloid β (Aβ42) oligomers. The results indicate that inhibition of HSPG binding to Aβ42 using either heparinase III or heparin reduces Aβ42 expression and increases the population of β-tubulin III+ neurons, whereas the inhibition of MMP2/9 induces more neurotoxicity. The results should enhance our understanding of the contribution of ECMs to the Aβ-related neural cell death.


LncRNA SNHG15 promotes proliferation and migration of lung cancer via targeting microRNA-211-3p.
To investigate whether lncRNA (long non-coding RNA) SNHG15 could regulate the proliferation and migration of lung cancer via microRNA-211-3p and its underlying mechanism. SNHG15 expression in 55 LC (lung cancer) tissues and 30 normal lung tissues was detected by qRT-PCR (quantitative Real Time-Polymerase Chain Reaction). The relationship between SNHG15 expression and pathological characteristics of LC patients was analyzed the by Kaplan-Meier method. The target microRNA of SNHG15 was predicted by bioinformatics and verified by dual-luciferase reporter gene assay. Viability, cell cycle and migration of LC cells after altering expressions of SNHG15 or microRNA-211-3p were detected by cell counting kit-8 (CCK-8), flow cytometry and transwell assay, respectively. SNHG15 was highly expressed in LC tissues than that of normal lung tissues. Besides, LC patients with stage I-II presented lower expression of SNHG15 than those with stage III-IV. SNHG15 expression was correlated to tumor size, TNM stage, and lymph node metastasis, whereas not correlated to age and sex of LC patients. For in vitro studies, SNHG15 knockdown resulted in viability reduction, cell cycle arrest and reduced migration of LC cells, which were reversed by the microRNA-211-3p knockdown. SNHG15 is highly expressed in LC tissues, which promotes the occurrence and progression of LC via regulating proliferation and migration of LC cells by targeting microRNA-211-3p.


Modelling for the inheritance of multiple births and fertility in endangered equids: Determining risk factors and genetic parameters in donkeys (Equus asinus).
Multiple births or twinning in equids are dangerous, undesirable situations that compromise the life of the dam and resulting offspring. However, embryo vitrification and freezing techniques take advantage of individuals whose multiple ovulations allow flushing more fertilised embryos from the oviduct to be collected, increasing the productivity and profitability of reproductive techniques. Embryo preservation is especially important in highly endangered populations such as certain donkey (Equus asinus) breeds; for which conventional reproductive techniques have previously been deemed inefficient. For instance, becoming an effective alternative to artificial insemination with frozen semen to preserve the individuals' genetic material. The objective of this study was to examine the historical foaling records of Andalusian donkeys to estimate prevalence, risk factors, phenotypic and genetic parameters for multiple births, assessing the cumulative foal number born per animal, maximum foal number per birth and multiple birth number per animal. We designed a Bayesian General Animal Mixed Model with single records considering the 'fixed' effects of birth year, birth season, birth month, sex, farm, location, and husbandry system. Age was considered and included as a linear and quadratic covariate. Gibbs sampling reported heritability estimates ranging from 0.18 ± 0.101 to 0.24 ± 0.078. Genetic and phenotypic correlations ranged from 0.496 ± 0.298 to 0.846 ± 0.152 and 0.206 ± 0.063 to 0.607 ± 0.054, respectively. Predicted breeding values obtained enable the potential selection against/for these traits, offering a new perspective for donkey breeding and conservation.


Core/Shell PEGS/HA Hybrid Nanoparticle Via Micelle-Coordinated Mineralization for Tumor-Specific Therapy.
Nanomicelles, by virtue of their prominent biocompatibility, degradability, and ability to solubilize hydrophobic drugs, have been widely used as the most effective delivery platform for anticancer drugs. However, undesirable drug-loading capacity, unfeasible modification, poor in vivo stability, and intratumoral penetration remain to be addressed. Herein, we introduce a novel core/shell PEGylated poly(glycerol sebacate) (PEGS)/hydroxyapatite (HA) hybrid nanomicelle based on a unique triblock PEGS substrate with functional carboxyls in terminals and free hydroxyls as pendant groups. The hydrophobic doxorubicin (DOX) can be controllably encapsulated in the core of nanomicelles via hydrogen bonding, and ensuing in situ mineralization of HA occurs as a shell layer with the electrostatic effect between the carboxylate radical (COO-) and calcium ion (Ca2+). Through optimizing the coordination of PEGS nanomicelles and HA mineralization, 20-30 nm spherical nanoparticles can be formed with considerable drug loading (0.38 mg DOX/1 mg nanoparticles) and a sensitive pH-responsive release (about 50% release amount at pH 5.6 while <5% release amount at pH 7.4 in 24 h). In further in vitro studies, this PEGS/HA hybrid nanoparticle system exhibits excellent selective tumor inhibitory efficacy, while in in vivo studies, high efficacy of tumor suppression and low incidence of toxicity can be evidenced in a DOX-loaded PEGS/HA group (71.7% decrease in average tumor volume compared to a control group after 15 day hypodermic treatment). The core/shell PEGS/HA nanoparticle coordinated with PEGS nanomicelles and in situ HA mineralization represents high drug-loading capacity, multifunctional possibility, and tumor-selective and responsive release profiles and could offer a highly promising platform for tumor therapy in clinical application.


Thinking and drinking: alcohol-related cognitions across stages of adolescent alcohol involvement.
Alcohol-related cognitions, particularly expectancies for drinking and nondrinking and motives for nondrinking, are involved in the initiation, maintenance, and cessation of alcohol use and are hypothesized to play key roles in adolescent decision making. This study explored (a) the relationships between alcohol use expectancies, nondrinking expectancies, and nondrinking motives; (b) the roles of these cognitions across hypothesized developmental stages of adolescent alcohol use; and (c) the relationships between these cognitions and recent or intended future changes in drinking behavior in a cross-sectional sample. Surveys assessing alcohol use behaviors and attitudes were administered to 1,648 high school students. Heavier drinkers reported more positive alcohol use expectancies and fewer nondrinking motives than did lighter drinkers or nondrinkers; however, nondrinking expectancies only differed between nondrinkers and rare drinkers and all subsequent drinking classes. Alcohol use expectancies, nondrinking expectancies, and nondrinking motives differentiated students who recently initiated alcohol from those who had not, while nondrinking expectancies and nondrinking motives differentiated binge-drinking students who had made recent efforts to reduce/stop their drinking from those who had not. Intentions to initiate or reduce drinking in the coming month were also associated with these alcohol-related cognitions. Drinking and nondrinking expectancies and motives for not drinking may play critical roles in decisions to alter alcohol-use behavior during adolescence. Future exploration of temporal relationships between changes in alcohol-related cognitions and behavioral decision making will be useful in the refinement of effective prevention and intervention strategies.


Growth inhibitory and antimetastatic effect of green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems.
Breast cancer is the second leading cause of cancer-related deaths among females. Dietary habits may have a role in breast cancer risk and prevention as well. Here, we examined the effect of green tea polyphenols (GTP) on growth and metastasis of highly metastatic mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. 4T1 cells were treated with (-)-epigallocatechin-3-gallate (EGCG), and the effect was determined on cellular proliferation, induction of apoptosis, proapoptosis, and antiapoptotic proteins of Bcl-2 family, and caspase 3 and poly(ADP-ribose) polymerase activation following 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Western blot analysis. Anticarcinogenic and antimetastatic effect of GTP in 4T1 cells was assessed in immunocompetent BALB/c mice. Treatment of 4T1 cells with EGCG resulted in inhibition of cell proliferation, induction of apoptosis in dose- and time-dependent manner. The increase in apoptosis was accompanied with decrease in the protein expression of Bcl-2 concomitantly increase in Bax, cytochrome c release, Apaf-1, and cleavage of caspase 3 and PARP proteins. Treatment of EGCG-rich GTP in drinking water to 4T1 cells bearing BALB/c mice resulted in reduction of tumor growth accompanied with increase in Bax/Bcl-2 ratio, reduction in proliferating cell nuclear antigen and activation of caspase 3 in tumors. Metastasis of tumor cells to lungs was inhibited and survival period of animals was increased after green tea treatment. This study suggests that GTP have the ability to prevent the development of breast cancer and its metastasis; however, further in vivo studies are required to identify the molecular targets.


Characterization of a Hank's type serine/threonine kinase and serine/threonine phosphoprotein phosphatase in Pseudomonas aeruginosa.
Pseudomonas aeruginosa is an opportunistic pathogen that causes infections in eye, urinary tract, burn, and immunocompromised patients. We have cloned and characterized a serine/threonine (Ser/Thr) kinase and its cognate phosphoprotein phosphatase. By using oligonucleotides from the conserved regions of Ser/Thr kinases of mycobacteria, an 800-bp probe was used to screen P. aeruginosa PAO1 genomic library. A 20-kb cosmid clone was isolated, from which a 4.5-kb DNA with two open reading frames (ORFs) were subcloned. ORF1 was shown to encode Ser/Thr phosphatase (Stp1), which belongs to the PP2C family of phosphatases. Overlapping with the stp1 ORF, an ORF encoding Hank's type Ser/Thr kinase was identified. Both ORFs were cloned in pGEX-4T1 and expressed in Escherichia coli. The overexpressed proteins were purified by glutathione-Sepharose 4B affinity chromatography and were biochemically characterized. The Stk1 kinase is 39 kDa and undergoes autophosphorylation and can phosphorylate eukaryotic histone H1. A site-directed Stk1 (K86A) mutant was shown to be incapable of autophosphorylation. A two-dimensional phosphoamino acid analysis of Stk1 revealed strong phosphorylation at a threonine residue and weak phosphorylation at a serine residue. The Stp1 phosphatase is 27 kDa and is an Mn(2+)-, but not a Ca(2+)- or a Mg(2+)-, dependent Ser/Thr phosphatase. Its activity is inhibited by EDTA and NaF, but not by okadaic acid, and is similar to that of PP2C phosphatase.


Plantago campestris (Plantaginaceae), a rare new species from southern Brazil, supported by phylogenomic and morphological evidence.
High-throughput sequencing, when combined with taxonomic expertise, is a powerful tool to refine and advance taxonomic classification, including at the species level. In the present work, a new species, Plantago campestris, is described out of the P. commersoniana species complex, based on phylogenomic and morphological evidence. The main morphological characters that distinguish the new species from P. commersoniana are the glabrous posterior sepals and the slightly broader leaves. The new species is known from only three localities, all in natural high-elevation grasslands in Paraná and Santa Catarina states, southern Brazil. According to the IUCN criteria new species should be assessed as Endangered (EN). We present field photographs of P. campestris and related species, and we provide an identification key to the species previously included within the circumscription of P. commersoniana.


Reactivity of the beta-AlF(3)(100) surface: defects, fluorine mobility and catalysis of the CCl(2)F(2) dismutation reaction.
Hybrid exchange density functional theory is used to model defects on the beta-AlF(3) (100) surface. The stability of the surface with respect to the diffusion of surface F ions is investigated. It is shown that under typical reaction conditions (600 K) the surface is not kinetically hindered from reaching thermodynamic equilibrium. A reaction mechanism for the catalysis of 2CCl(2)F(2)--> CClF(3) + CCl(3)F is proposed. The mechanism and corresponding reaction barriers are calculated using a double-ended transition state search method. It is predicted that the processes that determine the overall reaction rate occur at defect sites.


Why did you come back to the hospital? A qualitative analysis of 72-hour readmissions.
Readmissions occurring within a few days of discharge are more likely due to a problem from the patient's original admission and may be preventable by interventions in the hospital setting. As part of a quality improvement project intended to reduce readmissions within 72 hours of discharge our objective was to explore patient and physician perspectives of reasons for readmissions and to identify potential indicators of readmission during the index admission. A retrospective chart review of all readmissions within 72 hours between 2/1/2019 and 6/7/2019 in our healthcare system comprised of an academic medical center and 2 smaller community hospitals. As part of a hospital protocol, patients readmitted within 30 days were interviewed by a social worker regarding reasons for readmission and their perspective on what might have prevented it. These answers, physician notes relevant to the reason for readmission and the clinical course of the index admission were abstracted from patient charts. For the subset of patients identified by themselves or their physicians as potentially benefitting from a longer hospitalization, their index admission was reviewed for indicators of readmission. Reasons for readmission, potential preventive measures, and indicators of readmission were independently reviewed by two authors then grouped into common themes by consensus. One hundred and thirty-one patients readmitted within 72 hours were identified. Most patients were readmitted for infection related, cardiac or pulmonary reasons. Extending the initial admission was the most common factor suggested by both patients and physicians to prevent readmission. Focusing on 70 patients who may have benefited from a longer admission, indicators included patients not returning to their baseline health status, inadequate management of a known issue, or new symptoms developing during the index admission. Patients should be evaluated for indicators of readmission, which may help guide decisions to discharge patients and decrease rates of 72-hour readmissions.


Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.
Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. Randomized, double-blind, placebo, and active-controlled 12-month study. Forty-seven university and private rheumatology practices in the United States and Canada. Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.


Full-genome sequences of hepatitis B virus subgenotype D3 isolates from the Brazilian Amazon Region.
The Brazilian Amazon Region is a highly endemic area for hepatitis B virus (HBV). However, little is known regarding the genetic variability of the strains circulating in this geographical region. Here, we describe the first full-length genomes of HBV isolated in the Brazilian Amazon Region; these genomes are also the first complete HBV subgenotype D3 genomes reported for Brazil. The genomes of the five Brazilian isolates were all 3,182 base pairs in length and the isolates were classified as belonging to subgenotype D3, subtypes ayw2 (n = 3) and ayw3 (n = 2). Phylogenetic analysis suggested that the Brazilian sequences are not likely to be closely related to European D3 sequences. Such results will contribute to further epidemiological and evolutionary studies of HBV.


Research ethics committees at work: the experience of one multi-location study.
To report the outcome of applications to 43 research ethics committees. Four regional health authorities in England. The research ethics committees varied considerably in their practices. The time lapse until notification of the outcome of the approval ranged from just under one week to 23 weeks with a mean of 8.6 weeks. Four research ethics committees failed to notify the research team of an outcome of their request for approval. A national research ethics committee is needed to review national and multi-location research studies in the light of the fragmented and variable practice of local research ethics committees.


Mechanisms of action of the principal prolific genes and their application to sheep production.
The prolificacy variation in sheep makes it an excellent animal model to understand the mechanisms regulating ovulation rate. Identification of mutations responsible for the increased prolificacy of the Inverdale, Booroola, Javanese, Cambridge and Belclare sheep open new avenues of investigation for the paracrine control of folliculogenesis. To date, all known mutations are in genes from ligands or receptors of the transforming growth factor beta superfamily, and point to the bone morphogenetic protein family of peptides as local regulators of ovarian follicle growth. The mechanism of action of the mutated genes is not fully understood, but results in the ovulation of a higher number of follicles with smaller diameter and fewer granulosa cells than that of the wildtype, thus speeding the differentiation of ovulatory follicles. Comparisons of the performance of Booroola-crossed flocks in different countries showed that carriers of the prolificacy mutation have higher ewe productivity but also higher perinatal mortality and lighter weight lambs. Their economic impact on the sheep industry depends on farm environment and management. Nevertheless, the diagnostic tests now available to identify the genetic mutations resulting in increased ovulation rate, will simplify the introduction of these mutations and their monitoring in flocks for research and commercial purposes.


Adding Vision to Concussion Testing: A Prospective Study of Sideline Testing in Youth and Collegiate Athletes.
Sports-related concussion commonly affects the visual pathways. Current sideline protocols test cognition and balance but do not include assessments of visual performance. We investigated how adding a vision-based test of rapid number naming could increase our ability to identify concussed athletes on the sideline at youth and collegiate levels. Participants in this prospective study included members of a youth ice hockey and lacrosse league and collegiate athletes from New York University and Long Island University. Athletes underwent preseason baseline assessments using: 1) the King-Devick (K-D) test, a <2-minute visual performance measure of rapid number naming, 2) the Standardized Assessment of Concussion (SAC), a test of cognition, and 3) a timed tandem gait test of balance. The SAC and timed tandem gait are components of the currently used Sport Concussion Assessment Tool, 3rd Edition (SCAT3 and Child-SCAT3). In the event of a concussion during the athletic season, injured athletes were retested on the sideline/rink-side. Nonconcussed athletes were also assessed as control participants under the same testing conditions. Among 243 youth (mean age 11 ± 3 years, range 5-17) and 89 collegiate athletes (age 20 ± 1 years, range 18-23), baseline time scores for the K-D test were lower (better) with increasing participant age (P < 0.001, linear regression models). Among 12 athletes who sustained concussions during their athletic season, K-D scores worsened from baseline by an average of 5.2 seconds; improvement by 6.4 seconds was noted for the nonconcussed controls (n = 14). The vision-based K-D test showed the greatest capacity to distinguish concussed vs control athletes based on changes from preseason baseline to postinjury (receiver operating characteristic [ROC] curve areas from logistic regression models, accounting for age = 0.92 for K-D, 0.87 for timed tandem gait, and 0.68 for SAC; P = 0.0004 for comparison of ROC curve areas). Adding a vision-based performance measure to cognitive and balance testing enhances the detection capabilities of current sideline concussion assessment. This observation in patients with mild traumatic brain injury reflects the common involvement and widespread distribution of brain pathways dedicated to vision.


Nucleotide variation in Sabin type 2 poliovirus from an immunodeficient patient with poliomyelitis.
The molecular and antigenic properties of a Sabin-like type 2 poliovirus, isolated from the stool samples of a 2-year-old agammaglobulinaemic child who developed paralysis 1 year after receiving the third dose of oral poliovirus vaccine, were analysed. The virus revealed 0.88 % genome variation in the VP1 region compared with the standard reference strain, compatible with replication of the virus in the intestine over approximately 1 year. The typical mutations in the 5'NCR and VP1 associated with reversion to neurovirulence for Sabin type 2 poliovirus were found. Despite this, the virus was characterized by both PCR and ELISA tests as Sabin-like and showed temperature sensitivity and neurovirulence in transgenic mice typical of the Sabin type 2 vaccine strain. Gammaglobulin replacement therapy led rapidly to virus clearance, which, when combined with treatment with the antiviral drug pleconaril, stopped virus excretion; no further virus shedding occurred. This is the first case of poliomyelitis and long-term excretion from an immunodeficient patient to be reported in Italy through the active 'Acute Flaccid Paralysis' surveillance system.


Asparagine preserves intestinal barrier function from LPS-induced injury and regulates CRF/CRFR signaling pathway.
Stress causes intestinal inflammation and barrier dysfunction. Corticotrophin-releasing factor (CRF)/CRF receptor (CRFR) signaling pathway has been shown to be important for stress-induced intestinal mucosal alteration. L-Asparagine (ASN) is a powerful stimulator of ornithine decarboxylase and cell proliferation in a variety of cell types, including colonic cells. In the present study, we investigated whether dietary ASN supplementation could alleviate the damage of intestinal barrier function caused by LPS through modulation of CRF/CRFR signaling pathway. Twenty-four weaned pigs were randomly divided into one of four treatments: (1) non-challenged control; (2) Escherichia coli LPS challenged control; (3) LPS + 0.5% ASN; (4) LPS + 1.0% ASN. LPS stress induced villous atrophy, intestinal morphology disruption and decreased claudin-1 expression. ASN supplementation increased intestinal claudin-1 protein expression and alleviated villous atrophy and intestinal morphology impairment caused by LPS stress. In addition, ASN supplementation increased the number of intestinal intraepithelial lymphocytes and reversed the elevations of intestinal mast cell number and neutrophil number induced by LPS stress. Moreover, ASN decreased the mRNA expression of intestinal CRF, glucocorticoid receptors and tryptase. These results indicate that ASN attenuates intestinal barrier dysfunction induced by LPS stress, and regulates CRF/CRFR1 signaling pathway and mast cell activation.


Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins.
Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. How can the leukemic cells disrupt this barrier and invasive the CNS, even if many of the currently available chemotherapies can not cross the BBB? Tight junction in endothelial cells occupies a central role in the function of the BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we show matrix metalloproteinase (MMP)-2 and -9, secreted by leukemic cells, mediate the BBB opening by disrupting tight junction proteins in the CNS leukemia. We demonstrated that leukemic cells impaired tight junction proteins ZO-1, claudin-5 and occludin resulting in increased permeability of the BBB. However, these alterations reduced when MMP-2 and -9 activities were inhibited by RNA interference strategy or by MMP inhibitor GM6001 in an in vitro BBB model. We also found that the disruption of the BBB in company with the down-regulation of ZO-1, claudin-5 and occludin and the up-regulation of MMP-2 and -9 in mouse brain tissues with leukemic cell infiltration by confocal imaging and the assay of in situ gelatin zymography. Besides, GM6001 protected all mice against CNS leukemia. Our findings suggest that the degradation of tight junction proteins ZO-1, claudin-5 and occludin by MMP-2 and -9 secreted by leukemic cells constitutes an important mechanism in the BBB breakdown which contributes to the invasion of leukemic cells to the CNS in acute leukemia.


Coexpression of complementary fragments of ClC-5 and restoration of chloride channel function in a Dent's disease mutation.
The human hereditary disorder Dent's disease is linked to loss-of-function mutations of the chloride channel ClC-5. Many of these mutations involve insertion of premature stop codons, resulting in truncation of the protein. We determined whether the functional activity of ClC-5 could be restored by coexpression of the truncated protein (containing the NH2-terminal region) with its complementary "missing" COOH-terminal region. Split channel constructs for ClC-5, consisting of complementary N and C protein regions, were created at an arbitrary site in the COOH-terminal region (V655) and at four Dent's disease mutation sites (R347, Y617, R648, and R704). Coexpression of complementary fragments for the split channel at V655 produced currents with anion and pH sensitivity similar to those of wild-type ClC-5. Channel activity was similarly restored when complementary split channel constructs made for Dent's mutation R648 were coexpressed, but no ClC-5 currents were found when split channels for mutations R347, Y617, or R704 were coexpressed. Immunoblot and immunofluorescence studies of COS-7 cells revealed that N or C protein fragments could be transiently expressed and detected in the plasma membrane, even in split channels that failed to show functional activity. The results suggest that ClC-5 channel activity can be restored for specific Dent's mutations by expression of the missing portion of the ClC-5 molecule.


Distribution of Viral Antigen and Inflammatory Lesions in the Central Nervous System of Cockatiels ( Nymphicus hollandicus) Experimentally Infected with Parrot Bornavirus 2.
Neurotropism is a striking characteristic of bornaviruses, including parrot bornavirus 2 (PaBV-2). Our study evaluated the distribution of inflammatory foci and viral nucleoprotein (N) antigen in the brain and spinal cord of 27 cockatiels ( Nymphicus hollandicus) following experimental infection with PaBV-2 by injection into the pectoral muscle. Tissue samples were taken at 12 timepoints between 5 and 114 days post-inoculation (dpi). Each experimental group had approximately 3 cockatiels per group and usually 1 negative control. Immunolabeling was first observed within the ventral horns of the thoracic spinal cord at 20 dpi and in the brain (thalamic nuclei and hindbrain) at 25 dpi. Both inflammation and viral antigen were restricted to the central core of the brain until 40 dpi. The virus then spread quickly at 60 dpi to both gray and white matter of all analyzed sections of the central nervous system (CNS). Encephalitis was most severe in the thalamus and hindbrain, while myelitis was most prominent in the gray matter and equally distributed in the cervical, thoracic, and lumbosacral spinal cord. Our results demonstrate a caudal to rostral spread of virus in the CNS following experimental inoculation of PABV-2 into the pectoral muscle, with the presence of viral antigen and inflammatory lesions first in the spinal cord and progressing to the brain.


[Functional limitations associated with lumbosacral spine pain in pregnant women].
Lower back pain affects most pregnant women. Pain is often associated with varying degrees of functional limitations, causing a problem for pregnant women in the performance of many everyday activities. The aim of the study was to assess the extent to which lumbosacral spine pain caused limitations in the daily functioning of pregnant women, and the relationship between reported restrictions and analysed variables. The study was conducted in the city of Szczecin in Poland among 81 pregnant women. Data were collected using a standardized Oswestry questionnaire survey (The Oswestry Lower Back Pain Disability Questionnaire). Results were analysed using the χ² test of independence. The signi􀏐icance level was adopted at p < 0.05. The majority of women pregnant for the second time (n = 38) had mild disability. The relationship between the degree of disability and the order of pregnancies was statistically signi 􀏐icant (χ² = 40.457, p = 0.0000000085). The majority of pregnant women had minor functional limitations due to pain in the lumbosacral spine region. The degree of functional limitations depends on the trimester of pregnancy and the order of pregnancies.


The comparative preemptive analgesic efficacy of addition of vitamin B complex to gabapentin versus gabapentin alone in women undergoing cesarean section under spinal anesthesia: A prospective randomized double-blind study.
Development of new multimodal analgesic regimens have led to substantial improvement in postoperative pain relief. We designed this study to compare the effect of combined vitamin B complex-gabapentin versus gabapentin alone on postoperative pain in women undergoing cesarean section under spinal anesthesia. One hundred twenty-eight women who underwent cesarean section under spinal anesthesia were randomized to receive orally 300 mg gabapentin (group G) or 300 mg of gabapentin plus 2 vitamin B complex (group GB) tablets 30 minutes before surgery. Postoperative pain intensity and total analgesic consumption during 12 hours after surgery, vomiting, and drowsiness during recovery were assessed. The pain intensity in the gabapentin plus vitamin B complex group was lower than gabapentin group during 12 hours after surgery (95% CI: 1.4-2.2; P < .001). Meanwhile, the total analgesic consumption in this group was less than gabapentin alone (95% CI: 1.07-1.24; P = 0.034). The incidence of vomiting in patients who receive combined gabapentin-vitamin B complex group was similar to gabapentin alone (P = .206). The difference of the distribution of the relative frequency of sedation according to Ramsay sedation scores in patients between 2 groups were insignificant (P = .82). All newborns in our study were free of any adverse effects. Addition of vitamin B complex to gabapentin reduced intensity of postoperative pain and also the total amount of analgesic consumption within the first 12 hours postoperative following cesarean section.


A simplified surgical approach to the incomplete form of testicular feminization.
A simplified surgical approach to the intersex child with the incomplete form of testicular feminization is presented. The procedure is particularly useful in patients where the gonadal tissue is located in the scrotolabial folds and eliminates the necessity for exploratory laparotomy. Representative drawings of the procedure are shown.


Correlates of kyphosis in older women. The Fracture Intervention Trial Research Group.
To determine the association between kyphosis (degree of forward curvature of the thoracic spine) and measures of spinal osteoporosis (height loss and vertebral fractures) and chronic back pain and disability in older women. A cross-sectional study. Eleven clinical centers in the United States. A total of 6439 community-dwelling osteoporotic women aged 55-80 enrolled in the Fracture Intervention Trial (FIT), a multicenter clinical trial of alendronate. Thoracic curvature was measured at baseline using a Debreuner Kyphometer. Height loss was determined by subtracting current height measured with a Harpenden stadiometer from self-reported height at age 25. Vertebral fractures were defined by morphometry and semiquantitative reading of lateral thoracic and lumbar spine radiographs, and chronic back pain and back-related disability were assessed by questionnaire. After adjustment for age, a 15 degrees increase in kyphosis was associated with losing more than 4 cm of height (OR, 1.88; 95% CI, 1.79-2.03) and having a vertebral fracture (OR, 1.57; 95% CI, 1.46-1.69). Kyphosis was more strongly related to thoracic fractures than to lumbar fractures, and kyphosis was most prominent in women with multiple thoracic wedge fractures. Kyphosis was also associated with upper back pain (OR per 15 degrees increase, 1.62; 95% CI 1.47-1.79) and middle back pain (OR per 15 degrees increase, 1.24; 95% CI 1.12-1.36), but it was not related to lower back pain (OR per 15 degrees increase, 0.98; 95% CI 0.90-1.05). Women with greater degrees of kyphosis were only slightly more likely to report back-related disability (OR per 15 degrees increase, 1.18; 95% CI 1.03-1.35) and poorer health status (OR per 15 degrees increase, 1.19; 95% CI 1.03-1.37). Older women with greater degrees of kyphosis are likely to have other manifestations of spinal osteoporosis such as height loss and thoracic fractures and to suffer chronic upper and middle back pain. Measurement of kyphosis may be useful in assessing the severity of spinal osteoporosis.


High Entropy Oxides Modulate Atomic-Level Interactions for High-Performance Aqueous Zinc-Ion Batteries.
The strong electrostatic interaction between high-charge-density zinc ions (112 C mm-3 ) and the fixed crystallinity of traditional oxide cathodes with delayed charge compensation hinders the development of high-performance aqueous zinc-ion batteries (AZIBs). Herein, to intrinsically promote electron transfer efficiency and improve lattice tolerance, a revolutionary family of high-entropy oxides (HEOs) materials with multipath electron transfer and remarkable structural stability as cathodes for AZIBs is proposed. Benefiting from the unique "cock-tail" effect, the interaction of diverse type metal-atoms in HEOs achieves essentially broadened d-band and lower degeneracy than monometallic oxides, which contribute to convenient electron transfer and one of the best rate-performances (136.2 mAh g-1 at 10.0 A g-1 ) in AZIBs. In addition, the intense lattice strain field of HEOs is highly tolerant to the electrostatic repulsion of high-charge-density Zn2+ , leading to the outstanding cycling stability in AZIBs. Moreover, the super selectability of elements in HEOs exhibits significant potential for AZIBs.


Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.
Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.


Exercise-induced changes in insulin and glucagon are not required for enhanced hepatic glucose uptake after exercise but influence the fate of glucose within the liver.
To test whether pancreatic hormonal changes that occur during exercise are necessary for the postexercise enhancement of insulin-stimulated net hepatic glucose uptake, chronically catheterized dogs were exercised on a treadmill or rested for 150 min. At the onset of exercise, somatostatin was infused into a peripheral vein, and insulin and glucagon were infused in the portal vein to maintain basal levels (EX-Basal) or simulate the response to exercise (EX-Sim). Glucose was infused as needed to maintain euglycemia during exercise. After exercise or rest, somatostatin infusion was continued in exercised dogs and initiated in dogs that had remained sedentary. In addition, basal glucagon, glucose, and insulin were infused in the portal vein for 150 min to create a hyperinsulinemic-hyperglycemic clamp in EX-Basal, EX-Sim, and sedentary dogs. Steady-state measurements were made during the final 50 min of the clamp. During exercise, net hepatic glucose output (mg x kg(-1) x min(-1)) rose in EX-Sim (7.6 +/- 2.8) but not EX-Basal (1.9 +/- 0.3) dogs. During the hyperinsulinemic-hyperglycemic clamp that followed either exercise or rest, net hepatic glucose uptake (mg x kg(-1) x min(-1)) was elevated in both EX-Basal (4.0 +/- 0.7) and EX-Sim (4.6 +/- 0.5) dogs compared with sedentary dogs (2.0 +/- 0.3). Despite this elevation in net hepatic glucose uptake after exercise, glucose incorporation into hepatic glycogen, determined using [3-3H]glucose, was not different in EX-Basal and sedentary dogs, but was 50 +/- 30% greater in EX-Sim dogs. Exercise-induced changes in insulin and glucagon, and consequent glycogen depletion, are not required for the increase in net hepatic glucose uptake after exercise but result in a greater fraction of the glucose consumed by the liver being directed to glycogen.


Chemical reactivity and long-range transport potential of polycyclic aromatic hydrocarbons--a review.
Polycyclic aromatic hydrocarbons (PAHs) are of considerable concern due to their well-recognised toxicity and especially due to the carcinogenic hazard which they present. PAHs are semi-volatile and therefore partition between vapour and condensed phases in the atmosphere and both the vapour and particulate forms undergo chemical reactions. This article briefly reviews the current understanding of vapour-particle partitioning of PAHs and the PAH deposition processes, and in greater detail, their chemical reactions. PAHs are reactive towards a number of atmospheric oxidants, most notably the hydroxyl radical, ozone, the nitrate radical (NO3) and nitrogen dioxide. Rate coefficient data are reviewed for reactions of lower molecular weight PAH vapour with these species as well as for heterogeneous reactions of higher molecular weight compounds. Whereas the data for reactions of the 2-3-ring PAH vapour are quite extensive and generally consistent, such data are mostly lacking for the 4-ring PAHs and the heterogeneous rate data (5 and more rings), which are dependent on the substrate type and reaction conditions, are less comprehensive. The atmospheric reactions of PAH lead to the formation of oxy and nitro derivatives, reviewed here, too. Finally, the capacity of PAHs for long range transport and the results of numerical model studies are described. Research needs are identified.


Effect of Topical Nonsteroidal Anti-inflammatory Drugs on Pupillary Size During Uncomplicated Cataract Surgery.
To compare the effectiveness of three different topical nonsteroidal anti-inflammatory drugs (NSAIDs) in inhibiting surgically induced miosis during uncomplicated cataract phacoemulsification. Prospective, randomized, double-masked comparative study of patients aged 40 years or older with grades II to III cataracts (Lens Opacities Classification System) and no other comorbidities. Participants were randomized into four groups: 0.1% nepafenac, 0.03% flurbiprofen, 0.4% ketorolac, or lubricant (control group). Medications were applied three times, starting 90 minutes before surgery at 30-minute intervals. Phacoemulsification was performed by the same surgeon using the stop-and-chop technique. Pupillary area and vertical and horizontal pupil diameters were measured at five surgical stages and analyzed with a computerized image system. Multiple comparison tests were performed to analyze intergroup differences. A P value of less than .05 was considered statistically significant. A total of 88 eyes were included in the study (22 eyes per group). Maximum pupillary area at the end of surgery was observed in the nepafenac group (62.72 ± 9.75 mm2) versus the ketorolac, flurbiprofen, and control groups (P = .003, P =.001, and P < .001, respectively). The percentage of pupillary area loss at the end of surgery was 7.50% with nepafenac, 9.84% with flurbiprofen, 10.09% with ketorolac, and 13.83% with control. A trend to larger pupillary area and diameters was found in the nepafenac, flurbiprofen, and ketorolac groups compared with the control group, with better performance in maintaining larger pupil diameters and area in the nepafenac group at all surgical stages. All NSAIDs were effective in maintaining intraoperative mydriasis during uncomplicated cataract phacoemulsification compared to the control group. [J Refract Surg. 2017;33(4):236-242.].


Oral diabetes medication monotherapy and short-term mortality in individuals with type 2 diabetes and coronary artery disease.
To determine whether sulfonylurea use, compared with non-sulfonylurea oral diabetes medication use, was associated with 2-year mortality in individuals with well-controlled diabetes and coronary artery disease (CAD). We studied 5352 US veterans with type 2 diabetes, obstructive CAD on coronary angiography, hemoglobin A1c ≤7.5% at the time of catheterization, and taking zero or one oral diabetes medication (categorized as no medications, non-sulfonylurea medication, or sulfonylurea). We estimated the association between medication category and 2-year mortality using inverse probability of treatment-weighted (IPW) standardized mortality differences and IPW multivariable Cox proportional hazards regression. 49%, 35%, and 16% of the participants were on no diabetes medications, non-sulfonylurea medications, and sulfonylureas, respectively. In individuals on no medications, non-sulfonylurea medications, and sulfonylureas, the unadjusted mortality rates were 6.6%, 5.2%, and 11.9%, respectively, and the IPW-standardized mortality rates were 5.9%, 6.5%, and 9.7%, respectively. The standardized absolute 2-year mortality difference between non-sulfonylurea and sulfonylurea groups was 3.2% (95% CI 0.7 to 5.7) (p=0.01). In Cox proportional hazards models, the point estimate suggested that sulfonylurea use might be associated with greater hazard of mortality than non-sulfonylurea medication use, but this finding was not statistically significant (HR 1.38 (95% CI 1.00 to 1.93), p=0.05). We did not observe significant mortality differences between individuals on no diabetes medications and non-sulfonylurea users. Sulfonylurea use was common (nearly one-third of those taking medications) and was associated with increased 2-year mortality in individuals with obstructive CAD. The significance of the association between sulfonylurea use and mortality was attenuated in fully adjusted survival models. Caution with sulfonylurea use may be warranted for patients with well-controlled diabetes and CAD, and metformin or newer diabetes medications with cardiovascular safety data could be considered as alternatives when individualizing therapy.


Cognitive-behaviour therapy for patients with Abridged Somatization Disorder (SSI 4,6) in primary care: a randomized, controlled study.
Somatoform disorders are characterized by the presence of multiple somatic symptoms without an organic cause that completely explains their symptoms. These patients generate a high cost in health services. We aim to evaluate the effectiveness and feasibility of a cognitive-behaviour therapy (CBT) programme, administered in group and individual formats in primary care for patients who are diagnosed with abridged somatization disorder. Multicentre, randomized, controlled trial involving 3 groups, one of which is the control group consisting of standardized recommended treatment for somatization disorder in primary care (Smith's norms) and the 2 others, the intervention groups, consisting of cognitive-behavioural therapy (10 sessions) administered in individual format (intervention group 1) or in group format (intervention group 2). 29 primary care health centres in the province of Zaragoza and 3 primary care health centres in the province of Mallorca, Spain. N = 204 patients, (68 in each of the three groups), aged 18-65 years, able to understand and read Spanish, who fulfil Escobar's criteria of Abridgged Somatization Disorder (SSI 4,6), stable with pharmacotherapy over the previous month, and who will remain stable for the next 3 months in the doctor's opinion, having signed informed consent. Standardized recommended treatment for somatization disorder in primary care (Smith's norms). INTERVENTION group: 10 weekly sessions of CBT, following a protocol designed by Prof. Escobar's group at UMDNJ, USA. There are 2 different treatment conditions: individual and group format. Survey on the use of health services, number and severity of somatic symptoms, anxiety, depression, quality of life and clinical global impression. The interviewers will not know which group the patient belongs to (blind). The assessments will be carried out at baseline, post-treatment, 6 months and 12 post-treatment. Utilization of health services, number and severity of somatic symptoms. The analysis will be per intent to treat. We will use the general linear models of the SPSS v.15 statistical package, to analyse the effect of treatment on the result variable (utilization of health services, number and severity of somatic symptoms). It is necessary to develop more effective psychological treatments for somatoform disorders. This randomised clinical trial will determine whether cognitive behaviour therapy, both in group or in individual format, is effective for the treatment of these patients. Current controlled trials ISRCTN69944771.


The early years of on-line HDF: how did it all start? How did we get here?
In the mid-1980s, limits and side effects of contemporary hemodialysis were basically due to short treatment time, use of low-flux membranes and employment of acetate-buffered dialysate. These were already associated with a relatively high morbidity and cardiovascular mortality as part of diaysis-related pathology. Based on these considerations, the concept of on-line hemodiafiltration (HDF) was proposed as an innovative solution. By combining diffusive and convective clearances, HDF offered the most efficient modality to clear small and middle-sized uremic toxins. Furthermore, by using ultrapure dialysis fluid and high-flux synthetic membranes, HDF also offered the most biocompatible dialysis system, thereby going a long way towards preventing inflammation. Through provision of virtually unlimited amounts of sterile dialysis fluid by cold sterilization of fresh dialysate, on-line HDF offered an economical and viable method of conducting high-efficiency HDF (high volume exchange) therapy. By keeping the hemodialysis machine with all built-in technical options (e.g. adjustable blood pump, fluid-balancing system, conductivity meter, flow and pressure monitoring, bicarbonate-buffered dialysate), HDF benefited from being associated with the use of dialysis machines with excellent technology as well as highest safety standards. Use of ultrapure water made it then possible to produce dialysis fluid of intravenous grade quality with these machines. The first on-line HDF clinical trial was performed with a modified A2008C dialysis machine in 1984-85. This confirmed the feasibility and potential of the on-line HDF method. Some 25 years later, on-line HDF has proven to be safe, efficacious and with clinical benefits that justify it becoming a new standard for high-quality care of chronic kidney patients.


Morphology, morphogenesis, and molecular phylogeny of Paraparentocirrus sibillinensis n. gen., n. sp., a "Stylonychine Oxytrichidae" (Ciliophora, Hypotrichida) without transverse cirri.
A terrestrial oxytrichid ciliate Paraparentocirrus sibillinensis n. gen., n. sp., which was found in soil samples of a beech forest stand within the National Park of Sibillini Mountains, Italy, was investigated using live observation and protargol impregnation. The morphology of interphase, morphogenesis, and molecular phylogeny inferred from SSU rDNA sequences of this ciliate were studied. Paraparentocirrus n. gen., is mainly characterized by a semirigid body, an undulating membrane in the Oxytricha pattern, six fronto-ventral (FV) rows, the absence of transverse cirri, one right and one left row of marginal cirri, four dorsal kineties, two dorsomarginal rows, and caudal cirri at the end of dorsal kinety 4. During morphogenesis, oral primordia develop through the proliferation of basal bodies from some cirri of FV rows 4 and 5, and FV row 6 takes part in the anlagen formation of the proter. The dorsal morphogenesis was typical of oxytrichids, with simple fragmentation of dorsal kinety 3, and the dorsomarginal rows developed from the right marginal row. Phylogenetic analyses based on the SSU rDNA sequences support the classification of this new genus in the stylonychines.


Differences in clinical profile of individuals with severe and markedly elevated coronary artery calcification detected by electron beam computed tomography.
Although several studies have demonstrated the association between coronary artery calcification (CAC) and coronary artery disease events, the underlying mechanism has not been fully elucidated. Furthermore, extensive CAC still remains a poorly understood phenomenon. The objective of this study is to determine the clinical characteristics and differences between 831 asymptomatic individuals with very high CAC scores (CACS ≥ 1000) and 497 asymptomatic individuals with CAC scores of 400 to 999. Individuals with CACS ≥ 1000 were more likely to have hypertension ([HTN]; P = .0004), hypercholesterolemia (P = .0001), diabetes mellitus ([DM] P = .005), and high body mass index ([BMI]; P = .03) compared with individuals with CACS = 400-999. On multivariable analysis, age (P < .0001) and BMI (P = .01) were found to be significant risk factors for the presence of very high CAC. While for males, age (P < .0001), hypercholesterolemia (P = .001), DM (P = .002), and obesity (P = .003) were independent risk factors; in females only HTN (P = .04) was independent risk factor.


Transcriptional and functional analysis of galactooligosaccharide uptake by lacS in Lactobacillus acidophilus.
Probiotic microbes rely on their ability to survive in the gastrointestinal tract, adhere to mucosal surfaces, and metabolize available energy sources from dietary compounds, including prebiotics. Genome sequencing projects have proposed models for understanding prebiotic catabolism, but mechanisms remain to be elucidated for many prebiotic substrates. Although β-galactooligosaccharides (GOS) are documented prebiotic compounds, little is known about their utilization by lactobacilli. This study aimed to identify genetic loci in Lactobacillus acidophilus NCFM responsible for the transport and catabolism of GOS. Whole-genome oligonucleotide microarrays were used to survey the differential global transcriptome during logarithmic growth of L. acidophilus NCFM using GOS or glucose as a sole source of carbohydrate. Within the 16.6-kbp gal-lac gene cluster, lacS, a galactoside-pentose-hexuronide permease-encoding gene, was up-regulated 5.1-fold in the presence of GOS. In addition, two β-galactosidases, LacA and LacLM, and enzymes in the Leloir pathway were also encoded by genes within this locus and up-regulated by GOS stimulation. Generation of a lacS-deficient mutant enabled phenotypic confirmation of the functional LacS permease not only for the utilization of lactose and GOS but also lactitol, suggesting a prominent role of LacS in the metabolism of a broad range of prebiotic β-galactosides, known to selectively modulate the beneficial gut microbiota.


Visualizing the kinetics of tumor-cell clearance in living animals.
Evaluation of potential antineoplastic therapies would be enhanced by noninvasive detection of tumor cells in living animals. Because light is transmitted through mammalian tissues, it was possible to use bioluminescence to monitor (both externally and quantitatively) growth and regression of labeled human cervical carcinoma (HeLa) cells engrafted into immunodeficient mice. The efficacy of both chemotherapy and immunotherapeutic treatment with ex vivo expanded human T cell-derived effector cells was evaluated. In the absence of therapy, animals showed progressive increases in signal intensity over time. Animals treated with cisplatin had marked reductions in tumor signal; 5'-fluorouracil was less effective, and cyclophosphamide was ineffective. Immunotherapy dramatically reduced signals at high effector-to-target cell ratios, and significant decreases were observed with lower ratios. This model system allowed sensitive, quantitative, real-time spatiotemporal analyses of the dynamics of neoplastic cell growth and facilitated rapid optimization of effective treatment regimens.


Operated and unoperated cataract in Australia.
To quantify the prevalence of cataract, the outcomes of cataract surgery and the factors related to unoperated cataract in Australia. Participants were recruited from the Visual Impairment Project: a cluster, stratified sample of more than 5,000 Victorians aged 40 years and over. At examination sites interviews, clinical examinations and lens photography were performed. Cataract was defined in participants who had: had previous cataract surgery, cortical cataract greater than 4/16, nuclear greater than Wilmer standard 2, or posterior subcapsular greater than 1 mm2. The participant group comprised 3,271 Melbourne residents, 403 Melbourne nursing home residents and 1,473 rural residents. The weighted rate of any cataract in Victoria was 21.5%. The overall weighted rate of prior cataract surgery was 3.79%. Two hundred and forty-nine eyes had had prior cataract surgery. Of these 249 procedures, 49 (20%) were aphakic, 6 (2.4%) had anterior chamber intraocular lenses and 194 (78%) had posterior chamber intraocular lenses. Two hundred and eleven of these operated eyes (85%) had best-corrected visual acuity of 6/12 or better, the legal requirement for a driver's license. Twenty-seven (11%) had visual acuity of less than 6/18 (moderate vision impairment). Complications of cataract surgery caused reduced vision in four of the 27 eyes (15%), or 1.9% of operated eyes. Three of these four eyes had undergone intracapsular cataract extraction and the fourth eye had an opaque posterior capsule. No one had bilateral vision impairment as a result of cataract surgery. Surprisingly, no particular demographic factors (such as age, gender, rural residence, occupation, employment status, health insurance status, ethnicity) were related to the presence of unoperated cataract. Although the overall prevalence of cataract is quite high, no particular subgroup is systematically underserviced in terms of cataract surgery. Overall, the results of cataract surgery are very good, with the majority of eyes achieving driving vision following cataract extraction.


Influence of root fragility and irrigation on external root temperature variation during preparation for fiberglass posts.
This paper analyses the effects of root canal fragility and irrigation on external temperature change (ΔT) of different sections of roots during post-space preparation. Forty endodontic treated human premolars were evaluated. Roots were divided into four groups based on their root wall thickness (fragile or non-fragile), and whether they received irrigation (yes or no) during post-space preparation. Initial root canal temperature was kept at 37°C. ∆T was evaluated with thermistors attached to the cervical and apical thirds of the roots during two preparation steps: 1) removal of gutta-percha with Largo drills, and 2) using the specific drill for post-space preparation for cementation of fiber-reinforced posts. In the irrigated groups, we used a 2% chlorhexidine solution during the exchange of drills. ∆T data was analyzed using four-way ANOVA with repeated measures and Tukey's test (α = 0.05). Significant differences in ∆T based on root fragility (p = 0.017), root canal third (p = 0.013), and preparation step (p = 0.006). We found that non-fragile roots tended to have higher ∆T than fragile roots, particularly in the apical third, during the use of the second drill. Irrigation did not have a significant effect on temperature variation, regardless of root wall thickness or the third evaluated (p> 0.05). Findings suggest that root wall thickness and the third evaluated influence temperature changes during post-space preparation for cementation of posts. Non-fragile roots showed greater temperature variation than fragile roots, while irrigation did not significantly impact temperature changes. Key words:Temperature, post and core technique, tooth preparation.


Single-site mutations in a hyperthermophilic variant of the B1 domain of protein G result in self-assembled oligomers.
We have characterized two homologous, single-point core mutants of a 57-residue, hyperthermophilic variant of the B1 domain of protein G (HTB1). These single-point mutations in HTB1 replace a Phe residue in the hydrophobic core with either a Glu or Asp residue. Both of these homologous core-variant mutants undergo significant structural rearrangement from the native, monomeric fold and exist as stable soluble oligomeric species of 5 and 30 nm in diameter. Gel-filtration, dynamic light scattering, circular dichroism spectroscopy, fluorescence spectroscopy, along with Congo Red and Thioflavin T binding clearly demonstrated that these core-variants undergo significant structural rearrangement from the native, monomeric ubiquitin fold. The two oligomeric species did not equilibrate over extended periods of time and displayed distinct secondary structures. The larger of the two species was found to possess structural features that are reminiscent of an emerging class of protein assemblies prone to beta-sheet-mediated aggregation. These results are significant as there are very few examples of extensive conformational or oligomerization switching brought about by single-point mutations in a stable protein-fold.


Atorvastatin treatment modulates the interaction between leptin and adiponectin, and the clinical parameters in patients with type II diabetes.
The aim of this study was to examine the effect of atorvastatin treatment on levels of leptin, adiponectin and insulin resistance, and their correlation with clinical parameters, in patients with type II diabetes. Patients with diabetes (n=394) were divided into two groups, comprising 161 patients who received 20 mg/day atorvastatin (statin group), and 233 patients who did not receive statins (statin-free group). The results showed that atorvastatin treatment of patients with diabetes was not associated with changes in leptin, adiponectin, the leptin/adiponectin (L/A) ratio or homeostasis model assessment-insulin resistance (HOMA-IR). However, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and total cholesterol (Tchol) were positively correlated with leptin and L/A ratio in the statin group only (P<0.05). By contrast, high-density lipoprotein cholesterol (HDL-C) showed a significant positive correlation with adiponectin in the statin and statin-free groups (P<0.05). Additionally, a positive correlation was found between HOMA-IR and glycated hemoglobin (HbA1c), and TG, in both groups, whereas Tchol was positively correlated with HOMA-IR in the statin group only (P<0.05). When multivariate analysis was performed with HOMA-IR as the dependent variable, and with adjustment for age, body mass index (BMI) and waist circumference, HbA1c was found to be a significant predictor of HOMA-IR or insulin resistance. In conclusion, atorvastatin treatment may have several effects on the interaction between leptin and adiponectin, and on clinical parameters in patients with type II diabetes.


Evaluating interventions in health: a reconciliatory approach.
Health-related Quality of Life measures have recently been attacked from two directions, both of which criticize the preference-based method of evaluating health states they typically incorporate. One attack, based on work by Daniel Kahneman and others, argues that 'experience' is a better basis for evaluation. The other, inspired by Amartya Sen, argues that 'capability' should be the guiding concept. In addition, opinion differs as to whether health evaluation measures are best derived from consultations with the general public, with patients, or with health professionals. And there is disagreement about whether these opinions should be solicited individually and aggregated, or derived instead from a process of collective deliberation. These distinctions yield a wide variety of possible approaches, with potentially differing policy implications. We consider some areas of disagreement between some of these approaches. We show that many of the perspectives seem to capture something important, such that it may be a mistake to reject any of them. Instead we suggest that some of the existing 'instruments' designed to measure HR QoLs may in fact successfully already combine these attributes, and with further refinement such instruments may be able to provide a reasonable reconciliation between the perspectives.


Bacteriophage Treatment of Infected Diabetic Foot Ulcers.
Diabetic foot ulcers occur as a common complication of diabetes. The concomitant infection significantly delays the healing of the ulcers. Antibiotic treatment of infected ulcers is complicated by the formation of microbial biofilms, which are often heterogeneous and resistant to antibiotics. Bacteriophage therapy is considered an additional approach to the treatment of infected wounds. Here, we describe the basic method of application of bacteriophages for the treatment of infected diabetic foot ulcers, including very large ones.


Knowledge, attitudes, and behaviors related to child safety restraint in citizens of Shenzhen Municipality, China, and the associations between these factors.
A child safety restraint (CSR) is an effective measure to reduce the risk of child injury from traffic collisions. This study aims to explore knowledge, attitudes, and behaviors regarding CSRs in a Chinese population. A cross-sectional survey regarding CSR use was conducted from April to May 2014 in Shenzhen municipality. Respondents were parents who had at least one child 0 to 6 years of age and owned a car. These parents provided a self-report of demographic characteristics as well as information about their knowledge, attitudes, and behaviors toward CSR use. Most respondents had a fair level of knowledge about CSRs, with higher mean knowledge scores demonstrated among the respondents who were male, had an advanced degree, had a higher income, owned an expensive car, had an older child, drove frequently with children, and routinely drove greater distances with children. In addition, most respondents had a more positive attitude toward CSR use, with a higher mean attitude score among those who had an advanced degree, owned an expensive car, drove frequently with children, and routinely drove greater distances with children. However, some myths regarding CSR use also existed (e.g., parents can effectively protect their children in a car collision by holding them, they are not required to purchase the CSR for child safety if there is no mandatory provision by law, among others). Among 3,768 respondents who had at least one child and a car, 27.8% (1,047) had a CSR and 22.9% (864) used the CSR. A logistic regression model showed the likelihood of CSR ownership to be higher if respondents drove frequently or greater distances and was dependent on both the education level of the respondents and the age of the children. The frequency of CSR use increased as the age of children decreased (P = .0274). Respondents who owned a CSR and those who frequently used CSRs had higher mean knowledge and mean attitude scores. This observational study found that although the majority of respondents had fair levels of knowledge and positive attitudes, they had lower rates of CSR ownership and use. Therefore, efforts at developing opportunities to expand public awareness of CSR use should be made to improve child passenger safety practices and eliminate child injury caused by traffic collisions.


Role of salt-inducible kinase 1 in the activation of MEF2-dependent transcription by BDNF.
Substantial evidence supports a role for myocyte enhancer factor 2 (MEF2)-mediated transcription in neuronal survival, differentiation and synaptic function. In developing neurons, it has been shown that MEF2-dependent transcription is regulated by neurotrophins. Despite these observations, little is known about the cellular mechanisms by which neurotrophins activate MEF2 transcriptional activity. In this study, we examined the role of salt-inducible kinase 1 (SIK1), a member of the AMP-activated protein kinase (AMPK) family, in the regulation of MEF2-mediated transcription by the neurotrophin brain-derived neurotrophic factor (BDNF). We show that BDNF increases the expression of SIK1 in primary cultures of rat cortical neurons through the extracellular signal-regulated kinase 1/2 (ERK1/2)-signaling pathway. In addition to inducing SIK1 expression, BDNF triggers the phosphorylation of SIK1 at Thr182 and its translocation from the cytoplasm to the nucleus of cortical neurons. The effects of BDNF on the expression, phosphorylation and, translocation of SIK1 are followed by the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5). Blockade of SIK activity with a low concentration of staurosporine abolished BDNF-induced phosphorylation and nuclear export of HDAC5 in cortical neurons. Importantly, stimulation of HDAC5 phosphorylation and nuclear export by BDNF is accompanied by the activation of MEF2-mediated transcription, an effect that is suppressed by staurosporine. Consistent with these data, BDNF induces the expression of the MEF2 target genes Arc and Nur77, in a staurosporine-sensitive manner. In further support of the role of SIK1 in the regulation of MEF2-dependent transcription by BDNF, we found that expression of wild-type SIK1 or S577A SIK1, a mutated form of SIK1 which is retained in the nucleus of transfected cells, is sufficient to enhance MEF2 transcriptional activity in cortical neurons. Together, these data identify a previously unrecognized mechanism by which SIK1 mediates the activation of MEF2-dependent transcription by BDNF.


Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential.
The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide.


Influence of heavy metals on synaptic transmission: a review.
The acute effects of Pb++, Cd++ and Hg++ have been studied on the amphibian neuromuscular junction. These heavy metal ions primarily affect those presynaptic mechanisms which underlie neurotransmitter release; no significant postsynaptic effects were observed. All experiments were performed on the isolated sciatic nerve/sartorius muscle preparation. Conventional electrophysiological techniques using intracellular recordings were used to monitor acetylcholine (ACh) release. Ringer solutions usually contained high Mg++ and low Ca++ concentrations so that endplate potentials (EPPs) could be recorded under contraction-free conditions. Pb++, Cd++ and Hg++ were added to the Ringer solutions as chloride salts. Of the two forms of transmitter release, Pb++ blocked one (evoked release or EPP amplitude) and stimulated the other (the rate of spontaneous release or MEPP frequency). When a preparation was first exposed to a moderate dose of Pb++, the EPP amplitude decreased within about 1-2 min; however, at that time, the MEPP frequency was just beginning to increase. Low concentrations of Pb++ often reduced the EPP greatly without altering the MEPP frequency. Evidence is provided for a competitive interaction between Pb++ and Ca++ ions in evoked release which is believed to occur on the extracellular side of the nerve terminal. The dissociation constant between Pb++ and the presynaptic Ca++ receptor is about 1 microM. The increase in MEPP frequency is assumed to be due to an intracellular action of Pb++ which may reduce the ability of nerve terminal organelles to sequester Ca++ and thereby increase the intracellular concentration of ionized Ca++. Cd++ also blocks evoked ACh release by a competitive inhibitory mechanism similar to that for Pb++. Cd++ is slightly less potent than Pb++, the dissociation constant for Cd++ being around 2.8 microM. In contrast to Pb++, Cd++ does not increase resting MEPP frequency. Hg++ is unique in that it first causes an increase in evoked ACh release and then a sudden and complete blockade; the MEPP frequency follows a similar time course. The mechanism underlying these effects of Hg++ is uncertain.


[The strategic management: the methodology applied by the "Centre Hospitalier Regional Universitaire"]
This work is a general presentation of the "Démarche Stratégique", a strategic process applied by the "Centre Hospitalier Régional Universitaire" (CHRU) at Lille, France. The hospital management methodology relies on the strategic analysis of the best alternatives for rationalizing the hospital mission. It takes into account a competitive environment, in which it is necessary to structure health care networks based on the negotiation of inpatient care goals. The author presents the phases and main methodological tools of the approach, as well as a preliminary evaluation of its potentials.


Genetic justice must track genetic complexity.
Many different factors influence our health prospects. The food we consume, the lifestyle we live (e.g., sedentary or active), our economic prospects, our love prospects, our gender, our age, and our education all influence our expected lifetime acquisition of what John Rawls calls the "natural primary goods" (e.g., health, vigor, imagination, and intelligence). Our well-being is also influenced by the natural endowments we inherit from our parents. All people have two copies of most genes, one from their mother and one from their father. Genes are the fundamental physical and functional unit of heredity; they "specify the proteins that form the units of which homoeostatic devices are composed."Earlier versions of this paper were presented to the Department of Philosophy at the University of Waterloo, the James Martin Advanced Research Seminar at Oxford University, and the Department of Politics at Manchester University. I am grateful for the helpful feedback that I received on those occasions.


Chocolate and chocolate constituents influence bone health and osteoporosis risk.
Bone loss resulting in increased risk for osteoporosis is a major health issue worldwide. Chocolate is a rich source of antioxidant and antiinflammatory flavonoids and dietary minerals with the potential to benefit bone health. However, other chocolate constituents such as cocoa butter, sugar, and methylxanthines may be detrimental to bone. Human studies investigating the role of chocolate consumption on serum bone markers and bone mineral density (BMD) have been inconsistent. A contributing factor is likely the different composition and thereby the nutrient and bioactive content among chocolate types. White and milk chocolate are high in sugar and low in flavonoids and most minerals. Dark chocolate (45-85% cocoa solids) is high in flavonoids, most minerals, and low in sugar with ≥70% cocoa solids resulting in higher fat and methylxanthine content. The aim of this review was to examine the relationship between chocolate consumption and its constiuents, including flavonoid content, on bone health and osteoporosis risk. Studies showed postmenopausal women had no bone effects at moderate chocolate intakes, whereas adolescents consuming chocolate had greater longitudinal bone growth. Based on flavonoid and mineral content, unsweetened cocoa powder appeared to be the best option followed by dark chocolate with higher cocoa content in terms of supporting and preserving bone health. Determining dietary recommendations for chocolate consumption relative to bone health is important because of the growing popularity of chocolate, particularly dark chocolate, and an expected increase in consumption owing to suggestions of health benefits against various degenerative diseases.