The effect of yoga in stress reduction for dental students performing their first periodontal surgery: A randomized controlled study.
The dental students experience a lot of stress, which increase when they perform their first surgical procedure. Yoga as an anxiolytic tool in anxiety reduction has been practiced over centuries in India. To assess the efficacy of yoga in reducing the state trait anxiety of dental students before their first periodontal surgery performance. A randomized controlled study using a two-way split plot design (pre-post-test) was conducted in the department of periodontics, Pacific Dental College, Udaipur, India. One hundred clinical dental students who were ready to perform their first periodontal surgery were selected. Students were randomly assigned to two groups and were given a 60-min session on stress reduction. Group A, yogic intervention group, were instructed to do yoga and their performances were monitored for a period of one week and Group B, control group, were given a lecture on stress reduction without any yoga instructions. The investigator who was unaware of the groups had taken the state trait anxiety score of the students three times a) before assigning them to each group, b) prior to the surgical procedure and c) immediately after the performance of surgery. Analyses of variance (ANOVA) by SPSS V.16. The statistical results showed a significant reduction in the VAS and state trait anxiety of Group A compared to Group B (ANOVA; P<0.001). This study concludes that Yogic breathing has a significant effect on the reduction of state trait anxiety level of dental students.


¹H NMR Spectroscopy and MVA to Evaluate the Effects of Caulerpin-Based Diet on Diplodus sargus Lipid Profiles.
The biological invasion of the green algae Caulerpa cylindracea represents a serious scientific and public issue in the Mediterranean Sea, essentially due to strong modifications both to habitat structure and native benthic communities. Although alterations in health status and changes in flesh quality of some marine species (dietary exposed to C. cylindracea) have been observed, no studies on cause-effect relationships have been carried out. Here, for the first time, through a controlled feeding experiment followed by ¹H NMR Spectroscopy and multivariate analysis (PCA, OPLS-DA), we showed that caulerpin taken with diet is directly responsible of changes observed in metabolic profile of fish flesh, including alteration of lipid metabolism, in particular with a reduction of ω3 PUFA content. The potential of caulerpin to directly modulate lipid metabolism opens up new questions about causal mechanism triggered by algal metabolite also in view of a possible exploitation in the nutraceutical/medical field.


Contributing Factors of Unmet Needs Among Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia with Comorbidities.
Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. "Worry about earning money" (56%) and "Dealing with feeling tired" (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health.


COVID-19 and Adverse Social Determinants of Health.
This introduction to the Special Issue (SI) on COVID-19 and adverse social determinants of health (SDoH) provides theoretical and empirical context for featured articles. Existing disparities and inequities are highlighted and emerging research on disparities resulting from these and the COVID-19 pandemic are briefly reviewed. General disparities and inequities resulting from the COVID-19 pandemic are briefly conceptualized through the SDoH. Critical factors outlined by the SDoH framework parallel those discussed by the Centers for Disease Control and Prevention as well as those in a conceptual framework article also feature in this SI. Some of these consist of racism, exclusion, blocked opportunity, and socioeconomic status (SES), among others. Furthermore, we discuss broader social inequities, namely growing income and wealth inequality that undermine the health and wellbeing of the general population and ethnic minority groups in particular. Big Event theory is offered as an additional conceptual framework that can illuminate potential downstream negative impacts of the pandemic. Having provided summaries of featured articles in this SI, we make a call for researchers to engage in further theoretical and empirical work to identify the most critical SDOH to further the field of public health as well as related fields and inform policy.


Targeted disruption of CD43 gene enhances T lymphocyte adhesion.
CD43 is a major leukocyte surface glycoprotein thought to have important functions for T lymphocyte adhesion and activation. We investigated the function of CD43 by using gene targeting to eliminate CD43 expression in the human T lymphocyte line CEM and then testing their adhesive phenotype. Loss of CD43 expression by the CEM cells enhanced their homotypic adhesion and binding to two distinct ligands, fibronectin and HIV-1 gp120. The enhanced homotypic adhesion was blocked specifically by an anti-beta 1 integrin mAb, and the enhanced binding to fibronectin and gp120 was blocked specifically by anti-beta 1 integrin and anti-CD4 mAb, respectively. Partial reconstitution of CD43 expression in the CD43-negative cells resulted in a corresponding reversion to a less adhesive phenotype. These data suggest that CD43 interferes with T lymphocyte adhesion and that CD43 can regulate lymphocyte adhesion by providing a threshold that must be overcome for cell-cell and cell-ligand interactions to occur.


Risk Factors for Hyperglycaemia in Pregnancy in Tamil Nadu, India.
Hyperglycaemia in pregnancy (HIP), i.e. gestational diabetes mellitus (GDM) and diabetes in pregnancy (DIP), increases the risk of various short- and long-term adverse outcomes. However, much remains to be understood about the role of different risk factors in development of HIP. The aims of this observational study were to examine the role of potential risk factors for HIP, and to investigate whether any single or accumulated risk factor(s) could be used to predict HIP among women attending GDM screening at three centres in urban, semi-urban and rural Tamil Nadu, India. Pregnant women underwent a 75 g oral glucose tolerance test. Data on potential risk factors was collected and analysed using logistical regression analysis. Receiver operating characteristic (ROC) curves, sensitivity, specificity and predictive values were calculated for significant risk factors and a risk factor scoring variable was constructed. HIP was prevalent in 18.9% of the study population (16.3% GDM; 2.6% DIP). Increasing age and BMI as well as having a mother only or both parents with diabetes were significant independent risk factors for HIP. Among women attending the rural health centre a doubling of income corresponded to an 80% increased risk of HIP (OR 1.80, 95%CI 1.10-2.93; p = 0.019), whereas it was not significantly associated with HIP among women attending the other health centres. The performance of the individual risk factors and the constructed scoring variable differed substantially between the three health centres, but none of them were good enough to discriminate between those with and without HIP. The findings highlight the importance of socio-economic circumstances and intergenerational risk transmission in the occurrence of HIP as well as the need for universal screening.


Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication.
Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.


[The use of PCR for detecting pathogenic microorganisms in water].
This replication method, which was introduced in 1985, has been used to find and identify microorganisms in the environment, among others in samples of soil, sediments and waters. A gene or a DNA fragment specific to a microorganism is replicated in vitro by a chain reaction catalyzed by DNA polymerase (PCR: Polymerase Chain Reaction) and analyzed by electrophoretic procedures. At the moment in most legislations bacteriological criteria for drinking water depend on E. coli and other bacteria referring to fecal contamination (fecal coliforms and enterococci). Absence of these bacteria does not necessarily exclude contamination of water with protozoa or virus. Detection of the latter by common methods is difficult and time-consuming. Application of PCR to these purposes is interesting. During the last years several protocols have been developed such as methods for the detection of E. coli, bacteria referring to fecal contamination, pathogens like Legionella pneumophila as well as Salmonella and Shigella, enterovirus and protozoa i.e. Giardia. Compared to the traditional methods an obvious advantage of the new methods lies in their velocity, sensitivity and specificity. This review introduces to several different applications of PCR. Although this method is still restricted to specialized laboratories at the moment, it will gain importance as a complement to traditional methods for the detection of pathogenic microorganisms in water as soon as simple tests will be available.


MiR-96-5p promotes the proliferation, invasion and metastasis of papillary thyroid carcinoma through down-regulating CCDC67.
MicroRNAs (miRNAs) have been identified to play an important regulatory role in various biological behaviors of papillary thyroid carcinoma (PTC). However, the specific role and function of miR-96-5p in PTC remain unclear. Therefore, the aim of this study is to detect the expression of miR-96-5p in PTC, and to explore its exact function. The relative expression level of miR-96-5p in PTC tissues and cell lines was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). MiR-96-5p mimics or inhibitors were then constructed and transfected into cells to upregulate or downregulate miR-96-5p expression. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and colony formation assay were employed to evaluate the proliferation of PTC cells. Meanwhile, transwell assay was employed to detect the invasion and metastasis of PTC cells. In addition, the underlying mechanism of miR-96-5p was identified by Luciferase reporter gene assay and Western blot analysis. The expression of miR-96-5p in PTC tissues and PTC-derived cell lines was significantly higher than that of normal controls. The overexpression of miR-96-5p remarkably promoted the proliferation, invasion and migration of PTC cells. However, knockdown of miR-96-5p significantly decreased cell growth and metastasis. CCDC67 was verified as a target gene of miR-96-5p in PTC. Further experiments demonstrated that the restoration of CCDC67 could significantly reduce the carcinogenic function of miR-96-5p. MiR-96-5p was remarkably upregulated in PTC tumor tissues and cells. In addition, it promoted cell growth, invasion, and migration via repressing CCDC67 expression.


Accessibility of nitroxide side chains: absolute Heisenberg exchange rates from power saturation EPR.
In site-directed spin labeling, the relative solvent accessibility of spin-labeled side chains is taken to be proportional to the Heisenberg exchange rate (W(ex)) of the nitroxide with a paramagnetic reagent in solution. In turn, relative values of W(ex) are determined by continuous wave power saturation methods and expressed as a proportional and dimensionless parameter Pi. In the experiments presented here, NiEDDA is characterized as a paramagnetic reagent for solvent accessibility studies, and it is shown that absolute values of W(ex) can be determined from Pi, and that the proportionality constant relating them is independent of the paramagnetic reagent and mobility of the nitroxide. Based on absolute exchange rates, an accessibility factor is defined (0 < rho < 1) that serves as a quantitative measure of side-chain solvent accessibility. The accessibility factors for a nitroxide side chain at 14 different sites in T4 lysozyme are shown to correlate with a structure-based accessibility parameter derived from the crystal structure of the protein. These results provide a useful means for relating crystallographic and site-directed spin labeling data, and hence comparing crystal and solution structures.


The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC.
Matrix protein is known to have an important role in the process of virus assembly and virion release during measles virus replication. In the present in vitro study, a single mutation of E89K in the matrix protein was shown to affect cell death and virus replication efficiency in human PBMC. One strain with this mutation caused less cell death than the parental virus, and possessed high virus replication efficiency. Moreover, by Annexin V-FITC staining, polycaspase FLICA staining, and double labeling with poly-caspase FLICA and the Hoechst stain, the cell death seen was shown to be apoptosis.


Carbohydrates and colorectal cancer risk among Chinese in North America.
Previous studies have analyzed total carbohydrate as a dietary risk factor for colorectal cancer (CRC) but obtained conflicting results, perhaps attributable in part to the embedded potential confounder, fiber. The aim of this study was to analyze the nonfiber ("effective") carbohydrate component (eCarb) separately and to test the hypothesis that effective carbohydrate consumption is directly related to CRC risk. The data (473 cases and 1192 controls) were from a large, multicenter, case-control study of Chinese residing in North America. Multivariate logistic regression was used to perform a secondary analysis controlling for age; sex; consumption of fat, fiber, calcium, and total kilocalories; body mass (Quetelet's) index; family history; education; and years in North America. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate risk among subgroups by sex and cancer site. A statistically significant positive association was observed between eCarb consumption and risk of CRC in both men (OR, 1.7 comparing highest with lowest tertile of eCarb consumption; 95% CI, 1.1-2.7) and women (OR, 2.7; 95% CI, 1.5-4.8). As expected, the ORs for total carbohydrate were somewhat lower than those for effective carbohydrate, but the differences were not large. A sex difference in risk by colorectal subsite was observed, with risk concentrated in the right colon for women (OR, 6.5; 95% CI, 2.4-18.4) and in the rectum for men (OR, 2.4; 95% CI, 1.2-4.8). These data indicate that increased eCarb and total carbohydrate consumption are both associated with increased risk of CRC in both sexes, and that among women, relative risk appears greatest for the right colon, whereas among men, relative risk appears greatest for the rectum.


Selective endocytic uptake of targeted liposomes occurs within a narrow range of liposome diameter.
Cell surface receptors facilitate signaling and nutrient uptake. These processes are dynamic, requiring receptors to be actively recycled by endocytosis. Due to their differential expression in disease states, receptors are often the target of drug-carrier particles, which are adorned with ligands that bind specifically to receptors. These targeted particles are taken into the cell by multiple routes of internalization, where the best-characterized pathway is clathrin-mediated endocytosis. Most studies of particle uptake have utilized bulk assays, rather than observing individual endocytic events. As a result, the detailed mechanisms of particle uptake remain obscure. To address this gap, we have employed a live-cell imaging approach to study the uptake of individual liposomes as they interact with clathrin-coated structures. By tracking individual internalization events, we find that the size of liposomes, rather than the density of the ligands on their surfaces, primarily determines their probability of uptake. Interestingly, targeting has the greatest impact on endocytosis of liposomes of intermediate diameters, with the smallest and largest liposomes being internalized or excluded, respectively, regardless of whether they are targeted. These findings, which highlight a previously unexplored limitation of targeted delivery, can be used to design more effective drug carriers.


A rare complication of pica: Stone aspiration with severe respiratory distress.
Tracheobronchial foreign body aspiration (FBA), a common pediatric presentation to emergency departments, is still a public healthcare problem affecting children all over the world. There are several types of foreign bodies reported from different parts of the world, including both organic or nonorganic substances. Pica, another interesting clinical entity, is characterized by persistent eating of nonnutritive substances, which is inappropriate for the maturation stage of the individual. A 3-year-old pediatric patient was admitted to our emergency department with a 3-day history of coughing and new onset respiratory distress. A chest X-ray was performed and it showed a suspicious radiopaque foreign body in the localization of left bronchi. Urgent rigid bronchoscopy was performed. The foreign body in the left main bronchi was, surprisingly, a 0.5-1 cm diameter, irregularly shaped stone particle. The laboratory evaluations and patient history revealed the diagnosis of severe iron deficiency anemia and accompanying pica. Stone aspiration, as an FBA, is a rare but potentially life-threatening complication of pica. Iron deficiency anemia accompanied by pica should be diagnosed and treated in the early stage of the disease because of their complications. According to our knowledge and literature search, this is the first case of stone aspiration as a complication of severe iron deficiency anemia and pica.


Neuraxial and Perineural Bleeding after Neuraxial Techniques: An Overview of the Last Year.
Spinal hematoma following neuraxial or perineural techniques is a rare but severe complication that can potentially lead to catastrophic consequences. The aim of this review is to analyze all reported cases of neuraxial or perineural bleeding after performance of a locoregional technique since the last guidelines update in 2018. We included articles indexed by MEDLINE, Scopus, and Google Scholar. We analyzed the patient's age, surgical procedure, pre-operative anticoagulant and antiplatelet therapy, type of anesthetic procedure, vertebra level of the procedure, diameter and point type of the needle, hematoma type (spinal, subdural, epidural), signs and symptoms, time to imaging, and time to treatment and outcome. During our bibliographic research, we identified 5637 unique articles that were eligible according to our protocol criteria, identifying 18 separate cases of neuraxial bleeding. Although clinicians are usually aware of antiplatelet and anticoagulant perioperative management, a careful post-procedural observation and a detailed patient education are also imperative for the early detection of the symptoms of spinal cord ischemia.


Voltage-gated potassium channels in IB4-positive colonic sensory neurons mediate visceral hypersensitivity in the rat.
Irritable bowel syndrome (IBS) is associated with a state of chronic visceral hypersensitivity, but the underlying molecular mechanisms of visceral hyperalgesia remain elusive. This study was designed to examine changes in the excitability and alterations of voltage-gated K+ currents in subpopulations of colonic dorsal root ganglion (DRG) neurons in a rat model of IBS-like visceral hypersensitivity. The model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline from postnatal days 8 -21. Experiments were conducted when rats became adults. DRG neurons innervating the colon were identified by 1,1'-dioleoyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate (DiI) fluorescence labeling and were immunostained for isolectin B4 (IB4) binding to classify these colonic neurons. Patch-clamp recordings were made from acutely dissociated DiI-labeled DRG neurons, and the expression of K+ channel in L6-S2 DRG was examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. (1) Neonatal AA treatment induced long-lasting visceral hypersensitivity without significant inflammation but with mast cell hyperplasia. (2) Colonic DRG neurons contained IB4-positive and negative neurons with different electrophysiological properties. IB4-positive colonic neurons have longer action potentials (APs) and larger A-type K+ currents (I(A)) than the IB4-negative neurons, and IB4 phenotypic changes of colonic neurons were not involved in the chronic visceral hypersensitivity. (3) Neonatal AA treatment decreased I(A) density and changed the electrophysiological properties of I(A) and I(K) by shifting the steady-state inactivation toward a negative direction in IB4-positive colonic neurons. The excitability of these cells increased. (4) Kv4.3 was downregulated in neonatal AA-treated rats compared with control rats, which suggests a possible mechanism regarding the changes in electrical activity of DRG neurons in these rats. A new model for chronic visceral hypersensitivity following a diluted AA stimulus in the neonatal period is described. The hypersensitivity may be associated with mast cell hyperplasia in the colon and increased excitability of IB4-positive colonic neurons as a result of suppression of I(A) density and a shift in the inactivation curves of I(A) and I(K) in a hyperpolarizing direction in these cells. This study identifies for the first time a specific molecular mechanism in subpopulations of colonic DRG neurons that underlies chronic visceral hypersensitivity.


Effect of extrusion processing on the microstructure, mechanical properties, biocorrosion properties and antibacterial properties of Ti-Cu sintered alloys.
Ti-Cu sintered alloys, Ti-Cu(S) alloy, have exhibited good anticorrosion resistance and strong antibacterial properties, but low ductility in previous study. In this paper, Ti-Cu(S) alloys were subjected to extrusion processing in order to improve the comprehensive property. The phase constitute, microstructure, mechanical property, biocorrosion property and antibacterial activity of the extruded alloys, Ti-Cu(E), were investigated in comparison with Ti-Cu(S) by X-ray diffraction (XRD), optical microscopy (OM), scanning electronic microscopy (SEM) with energy disperse spectroscopy (EDS), mechanical testing, electrochemical testing and plate-count method in order to reveal the effect of the extrusion process. XRD, OM and SEM results showed that the extrusion process did not change the phase constitute but refined the grain size and Ti2Cu particle significantly. Ti-Cu(E) alloys exhibited higher hardness and compressive yield strength than Ti-Cu(S) alloys due to the fine grain and Ti2Cu particles. With the consideration of the total compressive strain, it was suggested that the extrusion process could improve the ductility of Ti-Cu alloy(S) alloys. Electrochemical results have indicated that the extrusion process improved the corrosion resistance of Ti-Cu(S) alloys. Plate-count method displayed that both Ti-Cu(S) and Ti-Cu(E) exhibited strong antibacterial activity (>99%) against S. aureus. All these results demonstrated that hot forming processing, such as the extrusion in this study, refined the microstructure and densified the alloy, in turn improved the ductility and strength as well as anticorrosion properties without reduction in antibacterial properties.


Streptozotocin-Induced Diabetic Models in Mice and Rats.
Streptozotocin (STZ) is an antibiotic that produces pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this unit are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition.


Treatment of Hodgkin lymphoma with adriamycin, bleomycin, vinblastine and dacarbazine without routine granulocyte-colony stimulating factor support does not increase the risk of febrile neutropenia: a prospective cohort study.
Although patients with Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy frequently develop neutropenia, febrile neutropenia is uncommon. Three retrospective trials reported that ABVD could be safely administered without dose delays or granulocyte-colony stimulating factor (G-CSF) support. We retrospectively reviewed the charts of 89 patients treated with ABVD and found that the incidence of febrile neutropenia was 0.5% (five of 927 treatments). This prompted a change to our institutional policy so that patients receiving ABVD no longer receive routine G-CSF for uncomplicated neutropenia. We then prospectively assessed the safety of this policy change. Thirty-three patients received a total of 327 ABVD treatments, 185 (57%) of which were administered with a neutrophil count <1.5 × 10(9)/L. Febrile neutropenia occurred in 2/33 patients (6%), complicating 0.6% of chemotherapy treatments (2/327). Eliminating routine G-CSF saved $10 241 per patient. Omission of G-CSF for uncomplicated neutropenic patients receiving ABVD for Hodgkin lymphoma is cost-saving and safe.


Macroarray Detection of Solanaceous Plant Pathogens in the Fusarium solani Species Complex.
Members of the Fusarium solani species complex (FSSC), which are morphologically similar but have more than 45 distinct lineages, were chosen as targets for the development of a macroarray detection system that would be broadly adaptable. Thirty-three oligonucleotides (17 to 27 mers) were designed from the internal transcribed spacer (ITS) of the ribosomal RNA genes of 17 FSSC isolates, which belong to 12 phylogenetically closely related species. Of the 33 oligonucleotides on the array, 21 were useful in discriminating all 12 species, some of which had only a single nucleotide difference among them. The high specificity of this method was achieved by optimizing the hybridization temperature and oligo probe length, which had a more substantial effect on the array performance than the melting temperature and the DNA G+C content (G/C%) of the probes. The array was validated by testing inoculated greenhouse samples and diseased field plant samples.


Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring.
The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.


Expression of the mRNA (N6-adenosine)-methyltransferase S-adenosyl-L-methionine binding subunit mRNA in cultured cells.
Ribonuclease protection assays (RPA) were used to detect and quantitate the amount of messenger RNA (mRNA) coding for the S-adenosyl-L-methionine binding subunit (MT-A70) of the mRNA (N6-adenosine)-methyltransferase from different types of cultured cells. HeLa cells cultured in suspension were analyzed at regular intervals along a normal growth curve. It was discovered that MT-A70 mRNA was transcribed constitutively across the time-course, irrespective of the rate of cellular proliferation. Further, 11 different cell lines representing non-tumorigenic, tumorigenic, and virally-transformed tumorigenic types from Homo sapiens, Mus musculus, and Rattus norvegicus were examined for MT-A70 mRNA expression. It was found that all the cell lines expressed a long and short splice-variant form of the gene. In general, the cell lines expressed a similar total amount of the MT-A70 mRNA while statistically significant differences existed between the quantity of the long and short forms among cell types. Tumorigenic cell lines synthesized as much as a 9-fold greater amount of long form versus short form MT-A70 mRNA. Comparatively, non-tumorigenic cell lines generally expressed only a 1.5-fold greater amount of long form versus short form MT-A70 mRNA.


Limited supermarket availability is not associated with obesity risk among participants in the Kansas WIC Program.
Socioecological theory and a growing body of research suggests that geographic, racial, ethnic, and socioeconomic disparities in the prevalence of obesity are linked to disparities in the availability of food retail outlets that provide healthy food options. We examined the availability of food stores for low-income women in Kansas and tested whether food store availability was associated with obesity using cross-sectional, geocoded data from women participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) (n = 21,166) in Kansas. The availability and density of food stores within a 1, 3, and 5 mile radius of residence was determined, and multivariate logistic regression was used to examine the association of food store availability with obesity. The availability of convenience, grocery stores, and supermarkets varied across the urban-rural continuum, but the majority of WIC recipients lived within a 1 mile radius of a small grocery store. WIC participants in micropolitan areas had the greatest availability of food stores within a 1 mile radius of residence. Availability and density of food stores was not associated with obesity in metropolitan and rural areas, but availability and density of any type of food store was associated with an increased risk of obesity among WIC recipients in micropolitan areas. These results suggest that limited spatial availability of grocery stores and supermarkets does not contribute to obesity risk among low-income WIC recipients in Kansas, and that urban influence moderates the contribution of food environments to obesity.


Huge dielectric response and molecular motions in paddle-wheel [Cu(II)2(adamantylcarboxylate)4(DMF)2]⋅(DMF)2.
The temperature-dependent dynamic properties of [Cu(II)(2)(ADCOO)(4)(DMF)(2)]⋅(DMF)(2) (1) and [Cu(II)(2)(ADCOO)(4)(AcOEt)(2)] (2) crystals were examined by X-ray crystallography, (1)H NMR spectroscopy, and measurements of the dielectric constants and magnetic susceptibilities (ADCOO = adamantane carboxylate, DMF = N,N-dimethylformamide, and AcOEt = ethyl acetate). In both crystals, four ADCOO groups bridged a binuclear Cu(II)-Cu(II) bond, forming a paddle-wheel [Cu(II)(2)(ADCOO)(4)] structure. The oxygen atoms of two DMF molecules in crystal 1 and two AcOEt molecules in crystal 2 were coordinated at axial positions of the [Cu(II)(2)(ADCOO)(4)] moiety, forming [Cu(II)(2)(ADCOO)(4)(DMF)(2)] and [Cu(II)(2)(ADCOO)(4)(AcOEt)(2)], respectively. Two additional DMF molecules were included in the unit cell of crystal 1, whereas AcOEt was not included in the unit cell of crystal 2. The structural analyses of crystal 1 at 300 K showed three-fold rotation of the adamantyl groups, whereas rotation of the adamantyl groups of crystal 2 at 300 K was not observed. Thermogravimetric measurements of crystal 1 indicated a gradual elimination of DMF upon increasing the temperature above 300 K. The dynamic behavior of the crystallized DMF yielded significant temperature-dependent dielectric responses in crystal 1, which showed a huge dielectric peak at 358 K in the heating process. In contrast, only small frequency-dependent dielectric responses were observed in crystal 2 because of the freezing of the molecular rotation of the adamantyl groups. The magnetic behavior was dominated by the strong antiferromagnetic coupling between the two S = 1/2 spins of the Cu(II)-Cu(II) site, with magnetic exchange energies (J) of -265 K (crystal 1) and -277 K (crystal 2).


HYBRIDdb: a database of hybrid genes in the human genome.
Hybrid genes are candidate risk factors for human tumors by inducing mutation, translocation, inversion, or rearrangement of genes. The occurrence of hybrid genes may also have given rise to new transcripts during hominid evolution. HYBRIDdb is a database of hybrid genes in humans. This system encompasses the bioinformatics analysis of mRNA, EST, cDNA, and genomic DNA sequences in the INDC databases, and can be used to identify hybrid genes. We searched for hybrid genes among the 28,171 genes listed in the NCBI database, and analyzed their structural patterns in the human genome. The 2,344 gene pairs were detected as hybrid forms of transcriptional products. We classified the hybrid genes into two groups: chromosomal-mediated translocation fusion transcripts and transcription-mediated fusion transcripts. The HYBRIDdb database will provide genome scientists with insight into potential roles for hybrid genes in human evolution and disease.


Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis.
Forty-six young women had unusual and presumably noninfectious disorders of unknown etiology involving tissues derived from the embryonic urogenital sinus (urogenital sinus syndromes). Ten women had interstitial cystitis, and 25 had focal vulvitis. Eleven women had both interstitial cystitis and focal vulvitis. The affected groups were similar in demographic and other characteristics. Most were white and in their mid-20s. Both unusual conditions occurred in the same woman more often than could be expected by chance. This observation suggests that some common, perhaps autoimmune mechanism may be involved in the etiology of these syndromes.


Human papillomavirus genotyping by oligonucleotide microarray and p16 expression in uterine cervical intraepithelial neoplasm and in invasive carcinoma in Korean women.
For evaluating the diagnostic significance of p16(INK4A) over-expression in the uterine cervical intraepithelial neoplasm and in invasive carcinoma, human papillomavirus (HPV) was detected and genotyped by oligonucleotide microarray in archival tissues of 117 cervical specimens, including 47 invasive squamous cell carcinomas (SCC), 30 cases of cervical intraepithelial neoplasia (CIN), 20 adenocarcinomas, and 20 cases of non-neoplastic cervix. The expression of p16(INK4A) protein was immunohistochemically studied in these cases and in five HPV-positive and one HPV-negative cervical cancer cell lines. HPV was detected in 50% of CIN, 61.7% of SCC, and 45.5% of adenocarcinomas. p16(INK4A) expression was seen in all 20 cases of adenocarcinoma, 78.7% (37/47) of SCC, and 96.7% (29/30) of CIN, but not in any cases of the non-neoplastic cervix. There was no difference in p16(INK4A) expression between the HPV-positive and HPV-negative cervical lesions. All HPV-positive and -negative cervical cancer cell lines expressed p16(INK4A) protein. In conclusion, the presence of p16(INK4A) expression in cervical squamous and glandular epithelium indicates the existence of dysplasia or malignancy in the uterine cervix, regardless of HPV infection.


Analysis of the complete human mtDNA genome: methodology and inferences for human evolution.
The analysis of mitochondrial DNA (mtDNA) sequences has been a potent tool in our understanding of human evolution. However, almost all studies of human evolution based on mtDNA sequencing have focused on the control region, which constitutes less than 7% of the mitochondrial genome. The rapid development of technology for automated DNA sequencing has made it possible to study the complete mtDNA genomes in large numbers of individuals, opening the field of mitochondrial population genomics. Here we describe a suitable methodology for determining the complete human mitochondrial sequence and the global mtDNA diversity in humans. Also, we discuss the implications of the results with respect to the different hypotheses for the evolution of modern humans.


Efficient transport of tropospheric aerosol into the stratosphere via the Asian summer monsoon anticyclone.
An enhanced aerosol layer near the tropopause over Asia during the June-September period of the Asian summer monsoon (ASM) was recently identified using satellite observations. Its sources and climate impact are presently not well-characterized. To improve understanding of this phenomenon, we made in situ aerosol measurements during summer 2015 from Kunming, China, then followed with a modeling study to assess the global significance. The in situ measurements revealed a robust enhancement in aerosol concentration that extended up to 2 km above the tropopause. A climate model simulation demonstrates that the abundant anthropogenic aerosol precursor emissions from Asia coupled with rapid vertical transport associated with monsoon convection leads to significant particle formation in the upper troposphere within the ASM anticyclone. These particles subsequently spread throughout the entire Northern Hemispheric (NH) lower stratosphere and contribute significantly (∼15%) to the NH stratospheric column aerosol surface area on an annual basis. This contribution is comparable to that from the sum of small volcanic eruptions in the period between 2000 and 2015. Although the ASM contribution is smaller than that from tropical upwelling (∼35%), we find that this region is about three times as efficient per unit area and time in populating the NH stratosphere with aerosol. With a substantial amount of organic and sulfur emissions in Asia, the ASM anticyclone serves as an efficient smokestack venting aerosols to the upper troposphere and lower stratosphere. As economic growth continues in Asia, the relative importance of Asian emissions to stratospheric aerosol is likely to increase.


Crevicular fluid-based diagnostic tests.
A diagnostic test seeks to establish the presence or absence of a disease. Many tests also seek to determine the severity, progression, or level of activity of a disease as well as the disease's likely further progression. Crevicular fluid-based diagnostic tests for various periodontal diseases are currently attracting much interest in clinical, academic, and industrial circles. This is because existing clinical diagnostic tests have many shortcomings. By the use of these techniques it is hoped that treatment will become more effective, and that overtreatment will be avoided, thus resulting in a more cost-effective outcome. Much basic work relevant to the development of such tests is underway, covering a wide range of potential analytes, and the contributions to the referred literature in all of these areas in the past year are reviewed.


Treatment of insomnia in Parkinson's disease: a controlled trial of eszopiclone and placebo.
Parkinson's disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Sleep disturbances, typically in sleep maintenance, are found in up to 88% of these individuals and are associated with a variety of poor outcomes. Despite being common and important, there are few data to guide clinical care. We conducted a 6-week, randomized, controlled trial of eszopiclone and placebo in 30 patients with PD and insomnia. Patients with other primary sleep disorders (PSG defined) were excluded. The primary outcome was total sleep time (TST), and secondary measures included wake after sleep onset (WASO), number of awakenings, and quality of sleep, among others. The groups did not significantly differ on TST, but significant differences, favoring eszopiclone, did emerge in number of awakenings (P = 0.035), quality of sleep (P = 0.018), and in physician-rated CGI improvement (P = 0.035). There was also a trend toward significance in WASO (P = 0.071). There were no significant differences between groups in measures of daytime functioning. The drug was well tolerated, with 33% of patients on eszopiclone and 27% of patients on placebo reporting adverse events. Although modest in size, this is the first controlled study of the treatment of insomnia in patients with PD. Eszopiclone did not increase TST significantly but was superior to placebo in improving quality of sleep and some measures of sleep maintenance, which is the most common sleep difficulty experienced by patients with PD. Definitive trials of the treatment of sleep disorders in this population are warranted.


The role of the Snf1 kinase in the adaptive response of Saccharomyces cerevisiae to alkaline pH stress.
Alkaline pH stress invokes a potent and fast transcriptional response in Saccharomyces cerevisiae that includes many genes repressed by glucose. Certain mutants in the glucose-sensing and -response pathways, such as those lacking the Snf1 kinase, are sensitive to alkalinization. In the present study we show that the addition of glucose to the medium improves the growth of wild-type cells at high pH, fully abolishes the snf1 alkali-sensitive phenotype and attenuates high pH-induced Snf1 phosphorylation at Thr(210). Lack of Elm1, one of the three upstream Snf1 kinases (Tos3, Elm1 and Sak1), markedly increases alkali sensitivity, whereas the phenotype of the triple mutant tos3 elm1 sak1 is even more pronounced than that of snf1 cells and is poorly rescued by glucose supplementation. DNA microarray analysis reveals that about 75% of the genes induced in the short term by high pH are also induced by glucose scarcity. Snf1 mediates, in full or in part, the activation of a significant subset (38%) of short-term alkali-induced genes, including those encoding high-affinity hexose transporters and phosphorylating enzymes. The induction of genes encoding enzymes involved in glycogen, but not trehalose, metabolism is largely dependent of the presence of Snf1. Therefore the function of Snf1 in adaptation to glucose scarcity appears crucial for alkaline pH tolerance. Incorporation of micromolar amounts of iron and copper to a glucose-supplemented medium resulted in an additive effect and allows near-normal growth at high pH, thus indicating that these three nutrients are key limiting factors for growth in an alkaline environment.


Streamflow Prediction in Highly Regulated, Transboundary Watersheds Using Multi-Basin Modeling and Remote Sensing Imagery.
Despite the potential of remote sensing for monitoring reservoir operation, few studies have investigated the extent to which reservoir releases can be inferred across different spatial and temporal scales. Through evaluating 21 reservoirs in the highly regulated Greater Mekong region, remote sensing imagery was found to be useful in estimating daily storage volumes for within-year and over-year reservoirs (correlation coefficients [CC] ≥ 0.9, normalized root mean squared error [NRMSE] ≤ 31%), but not for run-of-river reservoirs (CC < 0.4, 40% ≤ NRMSE ≤ 270%). Given a large gap in the number of reservoirs between global and local databases, the proposed framework can improve representation of existing reservoirs in the global reservoir database and thus human impacts in hydrological models. Adopting an Integrated Reservoir Operation Scheme within a multi-basin model was found to overcome the limitations of remote sensing and improve streamflow prediction at ungauged cascade reservoir systems where previous modeling approaches were unsuccessful. As a result, daily regulated streamflow was predicted competently across all types of reservoirs (median values of CC = 0.65, NRMSE = 8%, and Kling-Gupta efficiency [KGE] = 0.55) and downstream hydrological stations (median values of CC = 0.94, NRMSE = 8%, and KGE = 0.81). The findings are valuable for helping to understand the impacts of reservoirs and dams on streamflow and for developing more useful adaptation measures to extreme events in data sparse river basins.


Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis.
In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.


Cpkk1, MAPKK of Cryphonectria parasitica, is necessary for virulence on chestnut.
ABSTRACT The role of Cpkk1, a mitogen-activated protein kinase from Cryphonectria parasitica, was investigated by generating a number of mutant strains that overexpress, under the control of the cryparin promoter, both the wild-type protein and its allele with an extensive deletion in the catalytic domain. Furthermore, a hairpin construct was built and expressed to cause specific silencing of Cpkk1 mRNA transcripts. Specific mRNA silencing or overexpression was confirmed on both Northern and Western blot analysis. Selected C. parasitica strains with Cpkk1 either silenced or overexpressed were evaluated for their biological characteristics, including virulence on European chestnut, growth on different substrates, conidial sporulation, and resistance to cell-wall-degrading enzymes. Silencing of Cpkk1 and the overexpression of a defective Cpkk1 correlated with a marked reduction in virulence on 3-year-old chestnut trees, with no statistically significant effect on fungal growth in the various conditions tested.


Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency.
The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency. A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were randomly assigned to four groups. Patients received open-label treatment with a conventional dosage of benazepril (10 mg/d), individual uptitration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual uptitration of losartan (median 100 mg/d; range 50 to 200). Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. The primary end point was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease. Compared with the conventional dosages, optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53% reduction in the risk for the primary end point (P = 0.028 and 0.022, respectively). Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages. There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms. It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency.


Low serum HDL-cholesterol is associated with raised tumor necrosis factor-alpha during ENL reactions.
The concentrations of serum lipids and tumor necrosis factor (TNF) were measured in leprosy patients across the spectrum of the disease and in erythema nodosum leprosum (ENL) patients at the onset of the reaction and after the reaction had clinically subsided. Lepromatous/borderline lepromatous (LL/BL) patients had significantly higher serum triglyceride and lower HDL-cholesterol levels; there was no such change in the tuberculoid/borderline tuberculoid (TT/BT) patients. The household contacts (HC) of the LL/BL patients also had significantly lower serum HDL levels. ENL patients during the acute phase of the reaction had significantly lower total, LDL-, HDL-cholesterol levels compared to the stable LL/BL patients, and these changes were reversible to pre-ENL levels after the reaction had subsided. Serum TNF levels were significantly higher in household contacts and in LL/BL patients but were not statistically different in TT/BT patients. Serum TNF levels were also significantly higher during the acute phase of ENL, and declined after the clinical remission of the reaction to levels comparable with those of LL/BL patients. There was a significant negative correlation between serum TNF and HDL-cholesterol levels during and after ENL reaction. However, there was no such correlation between TNF and total or LDL-cholesterol levels in ENL patients. Our results suggest that the changes in HDL-cholesterol metabolism are a specific part of the host response to lepromatous leprosy and to the ENL reaction and may be mediated by increased TNF production.


The role of transition metal transporters for iron, zinc, manganese, and copper in the pathogenesis of Yersinia pestis.
Yersinia pestis, the causative agent of bubonic, septicemic and pneumonic plague, encodes a multitude of Fe transport systems. Some of these are defective due to frameshift or IS element insertions, while others are functional in vitro but have no established role in causing infections. Indeed only 3 Fe transporters (Ybt, Yfe and Feo) have been shown to be important in at least one form of plague. The yersiniabactin (Ybt) system is essential in the early dermal/lymphatic stages of bubonic plague, irrelevant in the septicemic stage, and critical in pneumonic plague. Two Mn transporters have been characterized (Yfe and MntH). These two systems play a role in bubonic plague but the double yfe mntH mutant is fully virulent in a mouse model of pneumonic plague. The same in vivo phenotype occurs with a mutant lacking two (Yfe and Feo) of four ferrous transporters. A role for the Ybt siderophore in Zn acquisition has been revealed. Ybt-dependent Zn acquisition uses a transport system completely independent of the Fe-Ybt uptake system. Together Ybt components and ZnuABC play a critical role in Zn acquisition in vivo. Single mutants in either system retain high virulence in a mouse model of septicemic plague while the double mutant is completely avirulent.


Longitudinal Associations Between Parental Monitoring Discrepancy and Delinquency: An Application of the Latent Congruency Model.
Studies have shown that discrepancies (relative concordance or discordance) between parent and adolescent ratings are predictive of problem behaviors; monitoring, in particular, has been consistently linked to them. The current study tested whether discrepancies in perceptions of maternal monitoring, rated by mothers and youth at age 12, foretold delinquency (rule breaking) at age 15, and whether parental closeness and conflict predicted higher discrepancies, and indirectly, higher delinquency. The final study sample used the NICHD longitudinal dataset with N = 966 youth (50.1 % female) and their mothers (80.1 % European American, 12.9 % African American, 7 % other ethnicity). The analytic approach consisted of an extension and application of the Latent Congruency Model (LCM) to estimate monitoring discrepancies as well as age 15 delinquency scores. Findings showed that age 12 monitoring discrepancy was predictive of age 15 delinquency for both boys and girls based on youth reports, but not for maternal reports. Age 11 closeness predicted age 12 monitoring discrepancy, which served as a mediator for its effect on age 15 adolescent-reported delinquency. Thus, based on the rigorous LCM analytic approach which seeks to minimize the effects by competing explanations and to maximize precision in providing robust estimates, rates of perceived discordance in parenting behaviors during early adolescence matter in understanding variability in adolescent delinquency during middle adolescence.


Life history trade-offs in tropical trees and lianas.
It has been hypothesized that tropical trees partition forest light environments through a life history trade-off between juvenile growth and survival; however, the generality of this trade-off across life stages and functional groups has been questioned. We quantified trade-offs between growth and survival for trees and lianas on Barro Colorado Island (BCI), Panama using first-year seedlings of 22 liana and 31 tree species and saplings (10 mm < dbh < 39 mm) of 30 tree species. Lianas showed trade-offs similar to those of trees, with both groups exhibiting broadly overlapping ranges in survival and relative growth rates as seedlings. Life history strategies at the seedling stage were highly correlated with those at the sapling stage among tree species, with all species showing an increase in survival with size. Only one of 30 tree species demonstrated a statistically significant ontogenetic shift, having a relatively lower survival rate at the sapling stage than expected. Our results indicate that similar life history trade-offs apply across two functional groups (lianas and trees), and that life history strategies are largely conserved across seedling and sapling life-stages for most tropical tree species.


Effects of long-term anticoagulant therapy in subgroups after acute myocardial infarction.
This post hoc analysis of the Warfarin Re-Infarction Study evaluates the effect of long-term anticoagulant therapy in different subgroups after acute myocardial infarction (MI). The study population comprised 1214 patients. The mean duration of treatment was 37 months. The overall significance of prespecified prognostic factors was assessed by univariate survival analyses. Those risk factors that yielded a statistically significant result were evaluated with regard to response to treatment in a stratified manner. After stratification, heterogeneity across the strata was found to pertain to the effect of treatment with warfarin in subjects with prior MI and diabetes mellitus. Hence, mortality was not found to be influenced favorably by warfarin therapy in patients with previous MI. Likewise, recurrent MI was not significantly reduced by warfarin therapy in patients with prior MI or diabetes mellitus. Although not statistically significant, increasing age was associated with less benefit from therapy. The findings persisted also after controlling for possible confounders in a Cox regression model. Thus, our data suggest a lack of a beneficial effect by warfarin therapy in subjects with prior MI or diabetes mellitus, when the therapy is given for the sole purpose of secondary prophylaxis of MI. Furthermore, a trend toward an attenuated effect of therapy was found among the oldest patients.


Differential hyperemic responses following femoral arterial and thigh cuff occlusion in the canine hindlimb.
The hyperemic response following arterial reconstruction is variable. To further evaluate this response, arterial blood flows in the canine hindlimb were compared following isolated femoral arterial occlusion and after thigh cuff tourniquet occlusion, which also obstructs collateral circulation. Arterial occlusion and tourniquet occlusion produced significant (P less than 0.05) increases in femoral arterial flow after all intervals of occlusion, except following 30 minutes of isolated arterial occlusion. Isolated arterial occlusion and tourniquet occlusion produced comparable hyperemic responses through five minutes of occlusion. However, tourniquet occlusion produced a significantly greater increase (P less than 0.05) in femoral flow when occlusions exceeded five minutes. These data suggest that the extent of collateralization may moderate the postobstructive hyperemic response following aortic and femoropopliteal reconstruction. The collateral recruitment during isolated arterial occlusion may be responsible for a diminished hyperemic response with time, while obstruction of the collateral circulation during tourniquet occlusion may result in a greater hyperemic response.


Neuroendocrine and Metabolic Disorders in Bulimia Nervosa.
Bulimia nervosa, is an eating disorder characterized by excessive influence of weight and body shape on the levels of self-esteem, with pervasive feelings of failure and inadequacy. The eating is characterized by the presence of episodes of uncontrolled eating (Binge), during which the person ingests mass wide variety of foods and the feeling of not being able to stop eating. This review focuses on the metabolic and hormonal alterations in the in bulimia nervosa. A literature search was conducted using the electronic database Medline and PubMed and with additional hand searches through the reference list obtained from the articles found. Journal were searched up to 2015. Inclusion criteria were: 1) full text available in English; 2) published in a peerreviewed journal and using the following keywords: neurotransmitters (AgRP, BDNF, αMSH, NP Y, endocannabinoids, adiponectin, CCK, ghrelin, GLP-1, insulin, leptin, PP, PYY), hormones (FSH, LH, estrogen, progesterone, testosterone) and bulimia nervosa, eating disorders. All data reported in the present review indicated that changes in the central and peripheral neuroendocrine equilibria may favor the onset and influence the course and prognosis of a DA. However, it is still questionable whether the alterations of the peptides and hormones regulating the mechanisms of eating behavior are the cause or consequence of a compromised diet. The results of the present review indicate that the altered balance of the various peptides or hormones can be relevant not only for the genesis and / or maintenance of altered dietary behaviors, but also for the development of specific psychopathological aspects in eating disorders.


Stabilisation of Recombinant Human Basic Fibroblast Growth Factor (FGF-2) against Stressors Encountered in Medicinal Product Processing and Evaluation.
Basic fibroblast growth factor (FGF-2) is a highly labile protein with strong potential for tissue engineering. The aim of this study was to develop FGF-2 formulations that are stable against physical stressors encountered in pharmaceutical processing and evaluation. Pharmaceutical excipients, alone or in combination, were added to aqueous FGF-2 (770 ng/mL) solution and the stability of the resulting solutions on storage at 4-37 °C was evaluated. Stability of the solutions to repeated freeze-thaw cycles and lyophilisation was also evaluated, as well as the stability of the lyophilised stabilised protein to storage at -4, 4 and 18 °C for up to 12 months. In all of these experiments FGF-2 was quantified by ELISA assay. The as-received FGF-2, when dissolved in water, was highly unstable, retaining only 50% of baseline protein content after 30 min at 37 °C or 1 h at 25 °C. By contrast, FGF-2 solutions prepared with 0.5% w/v methylcellulose (MC) and 20 mM alanine (formulation F5) or with 0.5% w/v MC and 1 mg/mL human serum albumin (HSA) (formulation F6) were highly stable, having residual FGF-2 content comparable to baseline levels even after 2 h at 37 °C and 5 h at 25 °C. F5 and F6 were also highly stable to repeated freeze-thaw cycles, with >99% of FGF-2 load remaining after the third cycle. In addition, F5 and F6 were stable to lyophilisation, and the lyophilised products could be stored at -4, 4 or 18 °C for at least 12 months, with less than 1% loss in mean FGF-2 content. Thus, FGF-2 solution is effectively stabilised against both thermal and processing stressors in the presence of MC and alanine (F5), or MC and HSA (F6). The resultant FGF-2 solutions may be applied as medicinal products or further processed into more advanced medicinal products, e.g., scaffolds, for wound healing and tissue regeneration.


High-resolution whole-brain staining for electron microscopic circuit reconstruction.
Currently only electron microscopy provides the resolution necessary to reconstruct neuronal circuits completely and with single-synapse resolution. Because almost all behaviors rely on neural computations widely distributed throughout the brain, a reconstruction of brain-wide circuits-and, ultimately, the entire brain-is highly desirable. However, these reconstructions require the undivided brain to be prepared for electron microscopic observation. Here we describe a preparation, BROPA (brain-wide reduced-osmium staining with pyrogallol-mediated amplification), that results in the preservation and staining of ultrastructural details throughout the brain at a resolution necessary for tracing neuronal processes and identifying synaptic contacts between them. Using serial block-face electron microscopy (SBEM), we tested human annotator ability to follow neural 'wires' reliably and over long distances as well as the ability to detect synaptic contacts. Our results suggest that the BROPA method can produce a preparation suitable for the reconstruction of neural circuits spanning an entire mouse brain.


Measuring viability selection from prospective cohort mortality studies: A case study in maritime pine.
By changing the genetic background available for selection at subsequent life stages, stage-specific selection can define adaptive potential across the life cycle. We propose and evaluate here a neutrality test and a Bayesian method to infer stage-specific viability selection coefficients using sequential random genotypic samples drawn from a longitudinal cohort mortality study, within a generation. The approach is suitable for investigating selective mortality in large natural or experimental cohorts of any organism in which individual tagging and tracking are unfeasible. Numerical simulation results indicate that the method can discriminate loci under strong viability selection, and provided samples are large, yield accurate estimates of the corresponding selection coefficients. Genotypic frequency changes are largely driven by sampling noise under weak selection, however, compromising inference in that case. We apply the proposed methods to analyze viability selection operating at early recruitment stages in a natural maritime pine (Pinus pinaster Ait.) population. We measured temporal genotypic frequency changes at 384 candidate-gene SNP loci among seedlings sampled from the time of emergence in autumn until the summer of the following year, a period with high elimination rates. We detected five loci undergoing allele frequency changes larger than expected from stochastic mortality and sampling, with putative functions that could influence survival at early seedling stages. Our results illustrate how new statistical and sampling schemes can be used to conduct genomic scans of contemporary selection on specific life stages.


Effects of resolvin D1 on cell survival and cytokine expression of human gingival fibroblasts.
Tissue breakdown in periodontitis is initiated by bacteria, such as Porphyromonas gingivalis, and is caused largely by host responses. Resolvins protect the host against acute inflammation by blocking the migration of polymorphonuclear neutrophils to initiate resolution. The effects of resolvins on human gingival fibroblasts (HGFs) are unknown. This study examines the effects of resolvin D1 on HGF survival and cytokine expression when treated with or without P. gingivalis supernatant. Cytotoxicity of resolvin D1 on HGFs with or without a toxic level of P. gingivalis supernatant was measured with lactate dehydrogenase assays. Cytokine arrays were performed on HGF-conditioned media treated with or without resolvin D1 and with or without P. gingivalis supernatant. Resolvin D1 had no cytotoxic effects on HGFs at concentrations between 1 and 1,000 nM (all P > 0.05). Resolvin D1 (1,000 nM) significantly inhibited the toxic effects of 13.5% (v/v) P. gingivalis supernatant on HGFs (P = 0.002). Resolvin D1 significantly reduced the expression of interleukin (IL)-6 (P = 0.010) and monocyte chemoattractant protein (MCP)-1 (P = 0.04) in untreated fibroblasts. P. gingivalis (10%) supernatant significantly increased the expression levels of granulocyte-macrophage colony-stimulating factor (CSF), granulocyte CSF, growth-regulated oncogene (GRO), IL-5, IL-6, IL-7, IL-8, IL-10, MCP-1, MCP-2, MCP-3, and monokine induced by γ-interferon. Resolvin D1 significantly reduced the expression of GRO (P = 0.04), marginally reduced the levels of MCP-1 (P = 0.10), and marginally increased the levels of transforming growth factor (TGF)-β1 (P = 0.07) from HGFs treated with P. gingivalis supernatant. Resolvin D1 altered the cytotoxicity of P. gingivalis supernatant on HGFs. Resolvin D1 significantly reduced GRO, marginally reduced MCP-1, and marginally increased TGF-β1 from P. gingivalis-treated HGFs, which could alter the ability of P. gingivalis to induce inflammation.


The cortical projections of foveal striate cortex in the rhesus monkey.
1. The cortical projections of the foveal and extrafoveal parts of the striate cortex have been compared, using conventional degeneration techniques, as well as combinations of anatomical methods. While both foveal and extrafoveal striate cortex share a common pattern of projections (to areas V2, V3 and the visual area in the medial part of the posterior bank of the superior temporal sulcus), foveal striate cortex was found to have an additional projection (to part of the cortex of the fourth visual areas, V4). The latter projection includes the posterior lip of the inferior occipital sulcus which, on anatomical grounds, is regarded as the ventral extension of V4. 2. Anatomical studies using double tracers were employed to clarify the nature of the projections from the striate cortex and from V2 to V4. In one such experiment, tritiated proline was injected into extra-foveal striate cortex and a small lesion was made in that part of V2 receiving a direct projection from the region of the striate cortex into which the radioactive tracer was injected. Only degenerating fibres (due to the lesion), and no radioactive label, was found in V4. Such an experiment showed that, unlike foveal striate cortex, the projections from extrafoveal striate cortex to V4 are not direct, but through V2. 3. In another type of anatomical experiment using double tracers, the corpus callosum was sectioned and tritiated proline was injected into foveal striate cortex. Such an experiment allowed a more accurate determination of the extent of V4, as judged from its callosal connexions, to which foveal striate cortex projects. 4. Considering the projections of V1 to areas V2, V3 and the visual area in the medial part of the posterior bank of the superior temporal sulcus, and considering the differences in the projections of foveal and extrafoveal striate cortex, it is suggested that, among other functions, the striate cortex acts as a distribution centre for the information coming over the retino-geniculo-cortical pathways, parcelling this information out to different visual areas of the prestriate cortex for further analysis.


Characteristics of disrupted topological organization in white matter functional connectome in schizophrenia.
Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function. Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (β) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks. At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and β only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions. These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.


Nonfluid therapy and selected chemoprophylaxis of acute diarrhea.
Various available forms of therapy can decrease morbidity and mortality associated with acute diarrhea. Oral fluids represent the cornerstone of therapy of all cases. A variety of agents acting nonspecifically can decrease diarrhea and improve other worrisome symptoms associated with enteric infection. Kaopectate makes the stool more formed but has little additional effects. Bismuth subsalicylate, an antisecretory agent, reduces the number of stools passed by about 50 percent and improves other associated symptomatology. The drugs that affect motility such as loperamide and diphenoxylate are the most active of the nonspecifically acting drugs. They must be avoided in patients with significant fever and dysentery. Trimethoprim/sulfamethoxazole is now considered the drug of choice for shigellosis due to the presence of ampicillin-resistant Shigella strains in most regions of the world. Trimethoprim/sulfamethoxazole is also an effective form of therapy for enterotoxigenic Escherichia coli infection and for traveler's diarrhea without definable cause. Erythromycin, although not proved to be effective against Campylobacter, probably shortens the disease. Furazolidone, although not dramatically effective, has a spectrum of activity that includes Shigella, enterotoxigenic E. coli, Campylobacter, and Giardia lamblia. It may not be effective in severely ill (hospitalized) patients with diarrhea. The various forms of available therapy can be administered empirically, depending on symptomatology. Mildly ill patients (one to three unformed stools in 24 hours with minimal additional symptoms) probably are best treated with fluids only. Mild to moderately ill persons (three to six unformed stools in 24 hours) can be treated with a drug that acts nonspecifically, such as bismuth subsalicylate or loperamide. Those with severe diseases (six or more unformed stools with moderate to severe associated symptoms), particularly when associated with fever and the passage of bloody mucoid stools, may be given an antimicrobial agent. The antimicrobial drug given will be determined by ancillary laboratory tests (dark-field examination or examination of a wet-mount preparation for motile Campylobacter or stool culture for Shigella, Campylobacter, or Salmonella) or may be administered on an empiric basis. Traveler's diarrhea can be eliminated in selected persons by the administration of a pharmacologic agent. Liquid bismuth subsalicylate is effective in large doses, which may be impractical. Studies with the tablet formulation suggest that it is partially effective in preventing the illness. Doxycycline and trimethoprim/sulfamethoxazole are more effective, particularly when admini


Wound healing in plants: Cooperation of copper amine oxidase and flavin-containing polyamine oxidase.
Copper amine oxidases (CuAO) and flavin-containing amine oxidases (PAO) are hydrogen peroxide (H(2)O(2))-producing enzymes responsible for the oxidative de-amination of polyamines. Currently, a key role has been ascribed to apoplastic amine oxidases in plants, i.e., to behave as H(2)O(2)-delivering systems in the cell wall during cell growth and differentiation as well as in the context of host-pathogen interactions. Indeed, H(2)O(2) is the co-substrate for the peroxidase-driven reactions during cell-wall maturation and a key signalling molecule in defence mechanisms. We recently demonstrated the involvement of an apoplastic PAO in the wound-healing process of the Zea mays mesocotyl. Experimental evidence indicated a similar role for an apoplastic PAO in Nicotiana tabacum. In this addendum we suggest that a CuAO activity is also involved in this healing event.


Bacteraemia prediction in emergency medical admissions: role of C reactive protein.
To define the contribution made by C reactive protein (CRP) measurement to bacteraemia prediction in adults with medical emergencies in the UK. This two year cohort study involved 6234 patients admitted as emergency cases to the acute medical or infectious diseases services of the Oxford Radcliffe Hospitals, in whom blood cultures were taken on arrival. The main outcome measures were bacteraemia risk associated with admission CRP concentrations, lymphocyte counts, and neutrophil counts. The quantitative associations between CRP concentration, admission lymphocyte count, and neutrophil count were defined. Risk of bacteraemia rose continuously as the CRP increased: no "cutoff" value was evident. Models examining combinations of CRP, neutrophil count, and lymphocyte count were developed and validated using a split sample technique. CRP contributed to a model including lymphocyte and neutrophil counts, but its effect was small. CRP alone performed no better than either a model combining lymphopenia and neutrophilia, or than lymphopenia alone. In patients with acute medical emergencies who are suspected of bacteraemia clinically, CRP concentrations, although associated with bacteraemia, have a limited role in bacteraemia prediction.


Ultrastructure of the hyaloid vasculature in primates.
The histology and ultrastructure of the hyaloid vascular system was studied in 16 monkeys, ages 85 days in utero to 3 years old. The well-developed hyaloid artery is identifiable ultrastructurally as an arteriole consisting of a nonfenestrated intima, a multilayered smooth muscular media, a connective tissue adventitia, and a perivascular sheath. By the fourth week after birth, the vessel walls appear hyalinized and acellular; the lumen is occluded by a thrombus. The time of the complete disappearance of the hyaloid artery varied considerably in individual monkeys; remnants of the hyaloid artery were often present on the disc (Bergmeister's papilla) in adult life. The vasa hyaloidea propria and tunica vasculosa lentis are small branches of the hyaloid artery which fill the primary vitreous. Ultrastructurally, they are Type A-1-alpha capillaries having a nonfenestrated endothelium, incomplete pericyte layer, and basement membranes surrounding each. Fluorescein angiography of several newborn monkeys revealed nonleakage of dye from the hyaloid artery and its branches, thus correlating with the presence of endothelial tight functions.


Rekindling Action Language: A Neuromodulatory Study on Parkinson's Disease Patients.
Impairments of action semantics (a cognitive domain that critically engages motor brain networks) are pervasive in early Parkinson's disease (PD). However, no study has examined whether action semantic skills in persons with this disease can be influenced by non-invasive neuromodulation. Here, we recruited 22 PD patients and performed a five-day randomized, blinded, sham-controlled study to assess whether anodal transcranial direct current stimulation (atDCS) over the primary motor cortex, combined with cognitive training, can boost action-concept processing. On day 1, participants completed a picture-word association (PWA) task involving action-verb and object-noun conditions. They were then randomly assigned to either an atDCS (n = 11, 2 mA for 20 m) or a sham tDCS (n = 11, 2 mA for 30 s) group and performed an online PWA practice over three days. On day 5, they repeated the initial protocol. Relative to sham tDCS, the atDCS group exhibited faster reaction times for action (as opposed to object) concepts in the post-stimulation test. This result was exclusive to the atDCS group and held irrespective of the subjects' cognitive, executive, and motor skills, further attesting to its specificity. Our findings suggest that action-concept deficits in PD are distinctively grounded in motor networks and might be countered by direct neuromodulation of such circuits. Moreover, they provide new evidence for neurosemantic models and inform a thriving agenda in the embodied cognition framework.


Slow, slow, quick, quick, slow: five altmetric sources observed over a decade show evolving trends, by research age, attention source maturity and open access status.
The study of temporal trends in altmetrics is under-developed, and this multi-year observation study addresses some of the deficits in our understanding of altmetric behaviour over time. The attention surrounding research outputs, as partially captured by altmetrics, or alternative metrics, constitutes many varied forms of data. Over the years 2008-2013, a set of 7739 papers were sampled on six occasions. Five altmetric data sources were recorded (Twitter, Mendeley, News, Blogs and Policy) and analysed for temporal trends, with particular attention being paid to their Open Access status and discipline. Twitter attention both starts and ends quickly. Mendeley readers accumulate quickly, and continue to grow over the following years. News and blog attention is quick to start, although news attention persists over a longer timeframe. Citations in policy documents are slow to start, and are observed to be growing over a decade after publication. Over time, growth in Twitter activity is confirmed, alongside an apparent decline in blogging attention. Mendeley usage is observed to grow, but shows signs of recent decline. Policy attention is identified as the slowest form of impact studied by altmetrics, and one that strongly favours the Humanities and Social Sciences. The Open Access Altmetrics Advantage is seen to emerge and evolve over time, with each attention source showing different trends. The existence of late-emergent attention in all attention sources is confirmed.


Spatial confinement downsizes the inflammatory response of macrophages.
Macrophages respond to chemical/metabolic and physical stimuli, but their effects cannot be readily decoupled in vivo during pro-inflammatory activation. Here, we show that preventing macrophage spreading by spatial confinement, as imposed by micropatterning, microporous substrates or cell crowding, suppresses late lipopolysaccharide (LPS)-activated transcriptional programs (biomarkers IL-6, CXCL9, IL-1β, and iNOS) by mechanomodulating chromatin compaction and epigenetic alterations (HDAC3 levels and H3K36-dimethylation). Mechanistically, confinement reduces actin polymerization, thereby lowers the LPS-stimulated nuclear translocation of MRTF-A. This lowers the activity of the MRTF-A-SRF complex and subsequently downregulates the inflammatory response, as confirmed by chromatin immunoprecipitation coupled with quantitative PCR and RNA sequencing analysis. Confinement thus downregulates pro-inflammatory cytokine secretion and, well before any activation processes, the phagocytic potential of macrophages. Contrarily, early events, including activation of the LPS receptor TLR4, and downstream NF-κB and IRF3 signalling and hence the expression of early LPS-responsive genes were marginally affected by confinement. These findings have broad implications in the context of mechanobiology, inflammation and immunology, as well as in tissue engineering and regenerative medicine.


N-Glycosylation in isolated rat nerve terminals.
N-linked glycosylation is a ubiquitous protein modification that is capable of modulating protein structure, function and interactions. Many proteins in the brain associated with the synapse and important for synaptic transmission are highly glycosylated and their glycosylation could be important for learning and memory related molecular processes and synaptic plasticity. In the present study, we extend the knowledge of the synaptic glycome and glycoproteome by performing glycan- and intact glycopeptide-focused analyses of isolated rat nerve terminals (synaptosomes) by LC-MS/MS. Overall, glycomics identified a total of 41 N-glycans in isolated synaptosomes. Sialylated N-glycans represented only 7% of the total abundance of the rat synaptosome N-glycome with oligomannose, neutral hybrid and complex type N-glycans being the most abundant structures. Using detergent extraction of the active zone proteins from the synaptosomes revealed a change in the active zone glycan abundance in comparison with the rest of the synaptosome glycan content. Characterization of intact sialylated N-linked glycopeptides enriched by titanium dioxide chromatography revealed more than 85% selectivity of sialylated species and the presence of NeuGc on active zone proteins. In addition, both disialic and trisialic acid modified glycans were present on synaptic glycoproteins, although oxonium ion profiling revealed that trisialic units were only present on glycoproteins in the detergent soluble fraction. However, correct identification of intact sialylated N-linked glycopeptides using the Byonic program failed, most likely due to the lack of peptide backbone fragmentation during tandem mass spectrometry.


The placebo response in clinical trials: more questions than answers.
Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.


Influence of playing position on the site, nature, and cause of rugby league injuries.
This study investigated the influence of playing position on the site, nature, and cause of injuries in rugby league. The incidence, site, nature, and cause of playing injuries was prospectively studied in 156 rugby league players over 2 seasons. An injury was defined as any pain or disability suffered by a player during a match that resulted in the player missing a subsequent match. The hooker (101 per 1,000 playing hours) and prop (92 per 1,000 playing hours) positions had the highest incidence of injury. Injuries sustained by the fullback (32 per 1,000 playing hours) and halfback (44 per 1,000 playing hours) positions were less common. Compared with other individual playing positions, props had a significantly higher incidence of overexertion injuries (22 per 1,000 playing hours), thigh and calf injuries (47 per 1,000 playing hours), and hematomas (19 per 1,000 playing hours), whereas the five-eighth position (31 per 1,000 playing hours) and the hookers and halves positional group (17 per 1,000 playing hours) had a significantly higher incidence of falling and stumbling injuries. These results demonstrate that the hooker and prop positions have higher injury rates than other rugby league positions. Furthermore, the site, type, and cause of injuries are different among individual playing positions and playing groups. These findings suggest that individual position training for injury prevention is warranted in rugby league.


Evidence for involvement of phospholipase C-gamma 2 in signal transduction of platelet-derived growth factor in vascular smooth-muscle cells.
In order to examine the mechanisms underlying smooth-muscle cell proliferation, we investigated effect of platelet-derived growth factor (PDGF) dimers on proliferation of rabbit vascular smooth-muscle cells (VSMCs) and also involvement of phospholipase C (PLC) isoforms in the signal transduction. PDGF-BB and -AB, but not -AA, stimulated cell proliferation and intracellular production of inositol trisphosphate. Northern and Western analyses demonstrated that VSMCs mainly expressed PLC-gamma 2 and PLC-delta 1 among four PLC isoforms tested. A number of cellular proteins, including PLC-gamma 2, but not PLC-delta 1, were phosphorylated on a tyrosine residue by the stimulation of either PDGF-BB or -AB. These results suggest a functional association of PDGF receptor and PLC-gamma 2 that might be responsible for PDGF-dependent VSMC growth. In addition, the expression of PLC-gamma 2 was extremely low in the primary VSMC cultures and was induced during further cultivation of the primary cultures, indicating that an acquisition of PDGF-signal-transducing components, including PLC-gamma 2, may be an important step for proliferation of smooth-muscle cells.


Volume regulation following Na+ pump inhibition in CCT principal cells: apical K+ loss.
Ouabain caused rabbit cortical collecting tubule (CCT) principal cells to swell 67%. Swollen cells downregulated their volume at a rate of 4%/min to a new volume 16% below control. A qualitatively similar pattern of swelling and volume regulation was observed with peritubular addition of 2.0 microM prostaglandin E2 (PGE2), a putative endogenous Na+ pump inhibitor. Regulatory volume decrease (RVD) in ouabain-swollen cells was inhibited 50-70% by bilateral addition of 2.0 mM Ba2+ or 5.0 mM TEA+. Peritubular TEA+ had no effect on RVD. Luminal addition of 5.0 mM TEA+ or 0.2 mM quinidine inhibited RVD 50-60%, suggesting involvement of an apical K+ channel. This channel appeared to be distinct from the resting apical K+ conductance. Replacement of cellular K+ with Rb+, which is commonly used as a tracer of K+ secretion in the CCT, had little effect on the rate and magnitude of ouabain swelling but inhibited RVD 50-60%. A 10-fold elevation of luminal K+ before ouabain or after completion of RVD caused principal cells to swell 10% and 31%, respectively. In control cells, this K(+)-induced swelling was unaffected by the presence of 1.0 mM quinidine in the perfusate and could be mimicked by elevation of Rb+ instead of K+ concentration. The magnitude of swelling in volume-regulated principal cells, however, was reduced 50-60% by the presence of luminal quinidine or by luminal addition of Rb+ instead of K+. The putative apical RVD K+ channel may be similar to high-conductance K+ channels described in principal cell patch-clamp studies from other laboratories.


Effect of primary percutaneous coronary intervention versus thrombolysis on ventricular arrhythmias and heart rate variability in acute myocardial infarction.
Several studies showed that thrombolysis reduces ventricular arrhythmias and improves heart rate variability (HRV) in patients with acute myocardial infarction (AMI). Primary percutaneous coronary intervention (PCI) has recently become the treatment of choice for AMI, but it is still unknown whether it has favorable effects on these prognostic variables. We studied a group of 44 consecutive AMI patients (39 males, 5 females, mean age 59 +/- 9 years) submitted to primary PCI and 93 consecutive AMI patients (80 males, 13 females, mean age 61.0 +/- 11 years) treated with thrombolytic therapy within 6 hours of symptom onset. All patients underwent 24-hour Holter recording before discharge. The number of premature ventricular beats and the prevalence of non-sustained ventricular tachycardia in the 24 hours were lower in the PCI group (162 +/- 474 and 9%, respectively) than in the thrombolysed group (334 +/- 1730 and 14%, respectively), but the difference did not achieve statistical significance (p = 0.62 and p = 0.58, respectively). There were also no significant differences in HRV variables between the two groups, although a lower proportion of PCI patients tended to have bottom quartile values of HRV variables. The favorable trend for arrhythmias and HRV in PCI patients, however, seemed to be related to a worse basal clinical profile of thrombolysed patients, including a higher prevalence of previous AMI (14 vs 2%, p = 0.065), diabetes (27 vs 18%, p = 0.14) and, in particular, a lower use of beta-blockers (35 vs 93%, p < 0.001). In this study, we failed to show any significant benefit of primary PCI compared to thrombolysis on ventricular arrhythmias and HRV in patients with ST-segment elevation AMI. The clinical implications of these findings deserve investigation in future studies.


Simulating the Coupled Structural-Electronic Dynamics of Photoexcited Lead Iodide Perovskites.
Motivated by the optoelectronic applications of lead halide perovskites (LHPs), researchers have paid considerable attention to their photoexcited-state dynamics, where the coupling between the electronic and nuclear dynamics is pronounced. Here, we present simulations of the photoexcited-state dynamics of representative lead iodide perovskites, CsPbI3 and MAPbI3 (MA = CH3NH3), by adopting nonadiabatic molecular dynamics combined with the linear-response time-dependent density-functional tight-binding (LR-TD-DFTB) method, an efficient excited-state calculation framework. In the calculations, the electronic wave function and the nuclear coordinates were propagated in a mutually dependent manner. The results suggest that the excited LHPs undergo exciton dissociation, hot carrier cooling, and polaron formation on similar time scales. In particular, the decay of the carrier energy is attributed to not only the relaxation toward the band edge but also the change in orbital energy originating from the structural deformation, highlighting the importance of coupling between the electronic and nuclear degrees of freedom.


Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes.
During percutaneous coronary intervention (PCI), and in non-ST segment elevation acute coronary syndromes (NSTEACS), the risk of acute vessel occlusion by thrombosis is high. Glycoprotein IIb/IIIa blockers strongly inhibit platelet aggregation and may prevent mortality and myocardial infarction. This is an update of a Cochrane review first published in 2001, and previously updated in 2007 and 2010. To assess the efficacy and safety effects of glycoprotein IIb/IIIa blockers when administered during PCI, and as initial medical treatment in patients with NSTEACS. We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 12, 2012), MEDLINE (OVID, 1946 to January Week 1 2013) and EMBASE (OVID, 1947 to Week 1 2013) on 11 January 2013. Randomised controlled trials comparing intravenous IIb/IIIa blockers with placebo or usual care. Two authors independently selected studies for inclusion, assessed trial quality and extracted data. We collected major bleeding as adverse effect information from the trials. We used odds ratios (OR) and 95% confidence intervals (CI) for effect measures. Sixty trials involving 66,689 patients were included. During PCI (48 trials with 33,513 participants) glycoprotein IIb/IIIa blockers decreased all-cause mortality at 30 days (OR 0.79, 95% CI 0.64 to 0.97) but not at six months (OR 0.90, 95% CI 0.77 to 1.05). All-cause death or myocardial infarction was decreased both at 30 days (OR 0.66, 95% CI 0.60 to 0.72) and at six months (OR 0.75, 95% CI 0.64 to 0.86), although severe bleeding was increased (OR 1.39, 95% CI 1.21 to 1.61; absolute risk increase (ARI) 8.0 per 1000). The efficacy results were homogeneous for every endpoint according to the clinical condition of the patients, but were less marked for patients pre-treated with clopidogrel, especially in patients without acute coronary syndromes.As initial medical treatment of NSTEACS (12 trials with 33,176 participants), IIb/IIIa blockers did not decrease mortality at 30 days (OR 0.90, 95% CI 0.79 to 1.02) or at six months (OR 1.00, 95% CI 0.87 to 1.15), but slightly decreased death or myocardial infarction at 30 days (OR 0.91, 95% CI 0.85 to 0.98) and at six months (OR 0.88, 95% CI 0.81 to 0.96), although severe bleeding was increased (OR 1.29, 95% CI 1.14 to 1.45; ARI 1.4 per 1000). When administered during PCI, intravenous glycoprotein IIb/IIIa blockers reduce the risk of all-cause death at 30 days but not at six months, and reduce the risk of death or myocardial infarction at 30 days and at six months, at a price of an increase in the risk of severe bleeding. The efficacy effects are homogeneous but are less marked in patients pre-treated with clopidogrel where they seem to be effective only in patients with acute coronary syndromes. When administered as initial medical treatment in patients with NSTEACS, these agents do not reduce mortality although they slightly reduce the risk of death or myocardial infarction.