Exploiting Genetic Interference for Antiviral Therapy.
Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus's inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles-the evolution of drug resistance and targeting therapy to high-risk populations-both of which impede treatment in resource-poor settings.


Differential vascular response to laser photothermolysis.
Individual blood vessels in the chick choriallantoic membrane were selectively coagulated through photothermolysis, using pulsed laser irradiation at 585 nm. Pulse durations were chosen to be 0.45 ms and 10 ms, which correspond to the thermal relaxation times in blood vessels of 30 microns and 150 microns diameter, respectively. The short pulses, at a light fluence F = 3 Jcm-2, caused permanent occlusion of vessels of 40 microns diameter or less, whereas larger caliber vessels (60-120 microns) required F = 4-5 Jcm-2. The long-duration pulses, at F = 7 Jcm-2, caused coagulation of the larger diameter vessels; the small-caliber vessels and capillaries showed resistance to photothermolysis and required multiple exposures to achieve coagulation. The fluence versus diameter (F versus d) relationship for coagulation was calculated for the two pulse durations. The energy deposited in a cylindrical absorber of diameter d by an optical field, incident perpendicular to the vessel, was expressed analytically and compared with the energy required to coagulate a blood vessel of the same lumen dimeter. When thermal diffusion is incorporated into the model, our findings can be accounted for quantitatively. This information will be of use for improving the laser treatment of port wine stains and other vasculopathies. A surprising observation was that arterioles were damaged at lower incident energy densities than venules having the same lumen diameter, despite the fact that absorbance in oxygen-rich and oxygen-poor blood is the same at 585 nm.


[High volume exercise can be unhealthy].
There are positive health effects of exercise performed at regular intervals also in high volume exercisers. However, at present there is no exact definition of the optimal dose or the maximal safe dose of exercise, nor can the level of exercise to induce increased risk of harmful effects be defined. People who often exercise with a high volume and intensity should therefore individually consider the health-related effects and possible risks of their training as well as the physical or psychological warning signals.


Context-Dependent Accuracy of the BG-Counter Remote Mosquito Surveillance Device in North Carolina.
There is a clear need for improved vector surveillance approaches that are affordable, labor efficient, and safer than traditional methods. The BG-Counter (Biogents USA, Moorefield, WV) is a device for remotely monitoring mosquito activity in combination with the BG-Sentinel (Biogents USA), a widely used trap for the collection of host-seeking mosquitoes. The BG-Counter uses a wireless connection to provide real-time counts of mosquitoes captured by the BG-Sentinel, allowing users to remotely monitor mosquito populations. This study tested the effectiveness of the BG-Counter in 5 North Carolina counties. A total of 96 trap-days resulted in the collection of >45,000 individual mosquitoes representing 35 species. Aedes albopictus was the most common species collected in all counties, except for New Hanover County where Culex nigripalpus was the most common. The mean daily accuracy ranged from 80.1% (New Hanover County) to 9.4% (Jackson County). There was a significant linear relationship between the actual number of mosquitoes collected and the device counts at all sites except Jackson County, the site with the lowest relative mosquito abundance compared with nontarget organisms. A linear regression of daily BG-Counter accuracy and the daily proportion of mosquitoes to the total number of arthropods collected revealed a significant positive linear relationship, supporting the premise that the BG-Counter is less effective when the relative abundance of mosquitoes is low. Mosquito surveillance programs using the BG-Counter should recognize its context-dependent accuracy and routinely evaluate the accuracy of the device based on local conditions.


Early Prediction of Intensive Care Unit-Acquired Weakness: A Multicenter External Validation Study.
An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention.


The kinetics of gene expression and maturation of IL-1 alpha after induction with the surface coat of Trypanosoma brucei rhodesiense or lipopolysaccharide.
The purpose of this study was threefold: to determine if the variant surface coat glycoprotein (VSG) of Trypanosoma brucei rhodesiense induces IL-1 alpha; to study the kinetics of IL-1 alpha transcription, maturation and secretion; and to compare VSG to LPS in its ability to induce IL-1 alpha. VSG was added to cultures of the P388D1 murine macrophage cell line. RNA was dotted onto nitrocellulose and hybridized with a murine IL-1 alpha cDNA probe. Maximal production of IL-1 alpha mRNA occurred in a dose- and time-dependent manner, peaking at 25 micrograms/ml VSG, within 2 h. Induction of IL-1 alpha was not due to contaminants because 1) absorption of VSG with a mAb abrogated IL-1 alpha mRNA synthesis, 2) the addition of polymyxin B did not affect mRNA levels, and 3) cellular IL-1 alpha was detectable in VSG-treated splenocytes from endotoxin nonresponder C3H/HeJ mice. Murine splenic macrophages also had enhanced levels of IL-1 alpha mRNA after administration of VSG in vivo or during an acute infection. Antiserum generated against the synthetic peptide SGDDSKYPV (amino acids 177-185 from the murine IL-1 alpha sequence) was used to measure the levels of the 33-, 22-, and 14-kDa proteins in cell lysates and medium of VSG-stimulated P388D1 cells. The 22-kDa protein was the predominant cellular form until secretion started. Secretion of the 14-kDa form began abruptly 6 to 8 h after the addition of VSG. By 12 h, the 33-kDa precursor was the major cytoplasmic form. In comparative analyses, LPS-stimulated P388D1 cells produced more transcript, generated peak levels of 22-kDa protein 3 h earlier, and began to secrete the 14-kDa molecule 5 h earlier. The rate of IL-1 alpha accumulation in the medium was linear between 6 and 24 h after LPS treatment, but began to drop by 8 h in VSG-treated cells. Functional (comitogenic) IL-1 activity was also detected in media from VSG-treated splenic macrophages and P388D1 cells. Activity peaked at 50 micrograms/ml and was lost if 0.2% IL-1 antisera were added to the cultures.


Bone mineral density is not sensitive enough to assess the risk of vertebral fractures in type 2 diabetic women.
Although the association between diabetes and osteoporosis has been studied, it remains unclear if the pathogenesis of vertebral fractures in patients with type 2 diabetes would be similar to those without diabetes. One hundred and fifty female diabetic patients without apparent proteinuria as well as 716 women without diabetes (control group) were examined by lateral thoracic and lumbar spine radiographs as well as dual-energy X-ray absorptiometry. Vertebral fractures were found in 26 (17.3%) and 158 (22.1%) subjects in the diabetic and control groups, respectively. Diabetic patients had higher absolute and age-matched (Z score) values of lumbar bone mineral density (L-BMD) than controls despite their significantly higher mean age. By receiver operating characteristic (ROC) analysis, the absolute L-BMD values for detecting vertebral fractures were higher and sensitivity and specificity were lower in diabetic patients than controls (0.816 g/cm2 vs. 0.716 g/cm2 and 66.0% vs. 74.8%, respectively). Logistic regression analysis adjusted for age, body weight, and height also showed that L-BMD was not significantly associated with the presence of vertebral fractures in diabetic patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.34-1.09 per standard deviation increase, P = 0.0954), in contrast to the significant association in controls (OR = 0.23, 95% CI 0.16-0.33, P < 0.0001). These results show that L-BMD is not sensitive enough to assess the risk of vertebral fractures in female diabetic patients and suggest that bone fragility not defined by BMD might be related to the risk of vertebral fractures in them.


A critical appraisal of the predictive value of in vitro chemosensitivity assays.
The ultimate value of a screening program based on the response of cell lines in vitro will depend on the demonstration of a strong correlation between in vitro and in vivo responses to cytotoxic drugs. However, marked discrepancies in the predictive value of in vitro chemosensitivity assays have been described, suggesting that factors other than the inherent chemosensitivity of tumor cells significantly influence the outcome of chemotherapy in vivo. These factors include the influence of drug pharmacokinetics and metabolism, together with numerous problems associated with the biology of solid tumors in vivo (e.g., drug penetration barriers, proliferation gradients, and microenvironmental conditions). These additional factors may be highly significant in explaining the site-dependent nature of the responses of solid tumors to cytotoxic drugs, the poor prediction of responses in experimental tumor models, and the differences in the responses of multicellular spheroids and monolayers. These discrepancies suggest that the selection of compounds for phase II clinical trials on the basis of disease-specific activity in vitro may be premature.


The Analgesic Efficacy of Nonsteroidal Anti-inflammatory Agents (NSAIDs) in Patients Undergoing Cesarean Deliveries: A Meta-Analysis.
Postoperative pain after cesarean delivery, which accounts for approximately 1 in 3 live births in the United States, can be severe in many patients. Nonsteroidal anti-inflammatory agents (NSAIDs) are potent analgesics that are effective in the treatment of postoperative pain. In this meta-analysis, we assessed the analgesic efficacy of NSAIDs in postoperative cesarean delivery patients. An electronic literature search of the Library of Medicine's PubMed, Cochrane CENTRAL, Scopus, and EMBASE databases was conducted in May 2013 and updated in January 2015 (Appendix, Supplemental Digital Content 1, http://links.lww.com/AAP/A174). Searches were limited to randomized controlled trials. The primary outcome variable was visual analog scale or numerical rating scale pain scores. Secondary outcomes included cumulative postoperative opioid consumption and opioid-related adverse effects (drowsiness/sedation, nausea, and vomiting). Data extraction was performed independently by 2 reviewers. Extracted data were input into Review Manager. Twenty-two randomized controlled trials compared a NSAID (n = 639) to a control (n = 674). Patients in the NSAID group versus control reported lower pain scores at 12 hours (P = 0.003) and at 24 hours (P < 0.001). Subgroup analysis showed a significant difference in pain scores at 24 hours, with patients receiving NSAIDs via intravenous/intramuscular (P < 0.001) route, but not the oral (P = 0.39) or rectal routes (P = 0.99). Significantly lower average pain scores were reported for pain with movement at 24 hours in the NSAID group (P = 0.001). Patients in the NSAID group versus controls consumed significantly less opioids (P < 0.001) and had significantly less drowsiness/sedation (P = 0.03), but there was no significant difference between the groups with regard to nausea or vomiting (P = 0.48 and P = 0.17, respectively). The perioperative use of NSAIDs in cesarean delivery patients will result in a significantly lower pain scores, less opioid consumption, and less drowsiness/sedation but no difference in nausea or vomiting compared to those who did not receive NSAIDs. Further research should address the optimal NSAID regimen and examine the effect of improved analgesia on patient-centered outcomes such as patient satisfaction and quality of breastfeeding.


A cation size effect on the framework structures in ABi2SeO3F5 (A = K and Rb): first examples of alkali metal bismuth selenite fluorides.
Two new centric alkali metal bismuth selenite fluorides, ABi2SeO3F5 (A = K and Rb), have been synthesized through a soft hydrothermal method. KBi2SeO3F5 crystallizes in an orthorhombic crystal system with the centric space group Pbcm possessing a three-dimensional (3D) network made up of SeO3 trigonal pyramids and asymmetric BiO3F5 polyhedra. As regards compound RbBi2SeO3F5, it crystallizes in a triclinic crystal system with a centric space group of P1[combining macron], which contains alternant two-dimensional (2D) [Bi2SeO3F5]∞1- layers separated by Rb+ cations. In terms of structure, the differences between KBi2SeO3F5 and RbBi2SeO3F5 originate from the size of alkali metal cations, which has a great influence on the framework geometry and the dimensionalities of crystals. The UV-vis diffuse reflectance spectroscopy study of powder samples indicates that the band gaps of KBi2SeO3F5 and RbBi2SeO3F5 are approximately 4.08 and 4.18 eV, respectively, which are the largest ones among the known bismuth selenites owing to the existence of alkali metal cations as well as fluorine anions in crystals. Furthermore, theoretical calculations show that the optical absorption of two compounds is mainly attributed to the contribution of BiOxFy polyhedra and [SeO3]2- anionic groups.


Graphene-based transition metal oxide nanocomposites for the oxygen reduction reaction.
The development of low cost, durable and efficient nanocatalysts to substitute expensive and rare noble metals (e.g. Pt, Au and Pd) in overcoming the sluggish kinetic process of the oxygen reduction reaction (ORR) is essential to satisfy the demand for sustainable energy conversion and storage in the future. Graphene based transition metal oxide nanocomposites have extensively been proven to be a type of promising highly efficient and economic nanocatalyst for optimizing the ORR to solve the world-wide energy crisis. Synthesized nanocomposites exhibit synergetic advantages and avoid the respective disadvantages. In this feature article, we concentrate on the recent leading works of different categories of introduced transition metal oxides on graphene: from the commonly-used classes (FeOx, MnOx, and CoOx) to some rare and heat-studied issues (TiOx, NiCoOx and Co-MnOx). Moreover, the morphologies of the supported oxides on graphene with various dimensional nanostructures, such as one dimensional nanocrystals, two dimensional nanosheets/nanoplates and some special multidimensional frameworks are further reviewed. The strategies used to synthesize and characterize these well-designed nanocomposites and their superior properties for the ORR compared to the traditional catalysts are carefully summarized. This work aims to highlight the meaning of the multiphase establishment of graphene-based transition metal oxide nanocomposites and its structural-dependent ORR performance and mechanisms.


Voltage dependence of subthreshold resonance frequency in layer II of medial entorhinal cortex.
The resonance properties of individual neurons in entorhinal cortex (EC) may contribute to their functional properties in awake, behaving rats. Models propose that entorhinal grid cells could arise from shifts in the intrinsic frequency of neurons caused by changes in membrane potential owing to depolarizing input from neurons coding velocity. To test for potential changes in intrinsic frequency, we measured the resonance properties of neurons at different membrane potentials in neurons in medial and lateral EC. In medial entorhinal neurons, the resonant frequency of individual neurons decreased in a linear manner as the membrane potential was depolarized between -70 and -55 mV. At more hyperpolarized membrane potentials, cells asymptotically approached a maximum resonance frequency. Consistent with the previous studies, near resting potential, the cells of the medial EC possessed a decreasing gradient of resonance frequency along the dorsal to ventral axis, and cells of the lateral EC lacked resonant properties, regardless of membrane potential or position along the medial to lateral axis within lateral EC. Application of 10 μM ZD7288, the H-channel blocker, abolished all resonant properties in MEC cells, and resulted in physiological properties very similar to lateral EC cells. These results on resonant properties show a clear change in frequency response with depolarization that could contribute to the generation of grid cell firing properties in the medial EC.


Two-dimensional picometer comb for three-dimensional reconstruction.
A two-dimensional (2D) picometer comb, a novel optical element made by picometer-differential four times exposed in two perpendicular directions, is proposed to generate the dot array projection pattern for three-dimensional (3D) shape reconstruction and other applications. Not only does a 2D picometer comb generate a stable light field distribution with extremely long depth of field and small divergence angle as a one-dimensional picometer comb, it also has new properties, such as periodicity of diffraction field in two perpendicular directions and high concentration of energy of points, which is particularly suitable for providing dot array structured light. We demonstrate that the diffraction field of a 2D picometer comb provides a solution for non-defocusing 3D reconstruction with a dot array. In fabrication of a 2D picometer comb, we can modulate the holography by changing the angle of two beams slightly, so its period can be measured at picometer accuracy. A 2D picometer comb can be made to any scale, then it can be integrated to mobile devices, such as a mobile phone, for 3D shape reconstruction. Furthermore, the concept of a 2D picometer comb would be applied to generate a picometer light field for opening the door of pico-optics in the future.


The use of antidepressants in novel combination therapies.
Antidepressant monotherapy is used more often than other therapies to achieve symptom remission in depressed patients; however, for patients resistant to antidepressants, other strategies are necessary. Many novel combination therapies have been proposed to treat resistant depression. The efficacy of combination therapies such as lithium augmentation of antidepressants is supported by a large amount of evidence including data from controlled trials. Nonetheless, anecdotal reports suggest that these combinations are underutilized. Data from studies of the use of the combination of atypical antipsychotics and selective serotonin reuptake inhibitors suggest that this is a particularly promising therapeutic avenue. However, more research is needed to corroborate these early results.


Acoustic cavitation generates molecular mercury(ii) hydroxide, Hg(OH)2, from biphasic water/mercury mixtures.
Emulsification of elemental mercury in aqueous solution in the form of grey particles occurs upon exposure to intense sound fields. We show the concomitant formation of molecular Hg(OH)2 in the solution phase reaching a saturation limit of 0.24 mM at 25 °C. The formation of Hg(OH)2 is consistent with the 'hot spot' model which suggests the formation of OH˙ as a result of acoustic cavitation; such radicals are proposed to combine with Hg to form the Hg(OH)2 species here characterised using voltammetry.


Seven-year survival following spinal cord injury.
This retrospective study of 5131 persons who sustained a spinal cord injury between 1973 and 1980 sought to determine the overall seven-year survival rate and the effect of several prognostic factors on survival. All study subjects had been treated at one of seven federally designated Model Regional Spinal Cord Injury Care Systems and each had survived at least 24 hours after injury. The cumulative seven-year survival was 86.7%. Advancing age at time of injury and being rendered a neurologically complete quadriplegic were significant prognostic factors. The cumulative seven-year survival among neurologically complete quadriplegics who were at least 50 years of age when injured, was only 22.7%. Spinal cord injury mortality rates ranged from 3.26 to 20.78 times higher than corresponding rates for nonspinal injured persons. Although mortality rates for spinal cord injury patients have declined dramatically since World War II, life expectancies for these patients are still substantially below normal.


'The way things are around here': organisational culture is a concept missing from New Zealand healthcare policy, development, implementation, and research.
Internationally, healthcare sectors are coming under increasing pressure to perform and to be accountable for the use of public funds. In order to deliver on stakeholder expectation, transformation will need to occur across all levels of the health system. Outside of health care it has been recognised for some time that organisational culture (OC) can have a significant influence on performance and that it is a mediator for change. The health sector has been slow to adopt organisational theory and specifically the benefits of understanding OC and impacts on performance. During a visit to health research units in the United Kingdom (UK) I realised the stark differences in the practice of health reform and its evaluation. OC is a firmly established concept within policy development, implementation and research in the UK. Unfortunately, the same cannot be said for New Zealand. There has been unrelenting reform and structural redesign, particularly of the primary healthcare sector under multiple governments over the past 20 to 30 years. However, there has been an underwhelming focus on the human aspects of organisational change. This seems set to continue and the aim of this viewpoint is to introduce the concept of OC and outline why New Zealand policy reformists and health services researchers should be thinking explicitly about OC. Culture is not solely the domain of the organisational scientist and current understandings of the influence of OC on performance are outlined in this commentary. Potential benefits of thinking about culture are argued and a proposed research agenda is presented.


Preclinical rationale for TGF-β inhibition as a therapeutic target for the treatment of myelofibrosis.
To assess the role of abnormal transforming growth factor-beta (TGF-β) signaling in the pathogenesis of primary myelofibrosis (PMF), the effects of the TGF-β receptor-1 kinase inhibitor SB431542 on ex vivo expansion of hematopoietic cells in cultures from patients with JAK2V617+-polycythemia vera (PV) or PMF (JAK2V617F+, CALRpQ365f+, or unknown) and from normal sources (adult blood, AB, or cord blood, CB) were compared. In cultures of normal sources, SB431542 significantly increased by 2.5-fold the number of progenitor cells generated by days 1-2 (CD34+) and 6 (colony-forming cells) (CB) and that of precursor cells, mostly immature erythroblasts, by days 14-17 (AB and CB). In cultures of JAK2V617F+-PV, SB431542 increased by twofold the numbers of progenitor cells by day 10 and had no effect on that of precursors cells by days 12-17 (∼fourfold increase in all cases). In contrast, SB431542 had no effect on the number of either progenitor or precursor cells in cultures of JAK2V617F+ and CALR pQ365fs+ PMF. These ontogenetic- and disease-specific effects were associated with variegation in the ability of SB431542 to induce CD34+ cells from AB (increased), CB (decreased), or PV and PMF (unaffected) into cycle and erythroblasts in proliferation (increased for AB and PV and unaffected for CB and PMF). Differences in expansion of erythroblasts from AB, CB, and PV were associated with differences in activation of TGF-β signaling (SHCY317, SMAD2S245/250/255, and SMAD1S/S/SMAD5S/S/SMAD8S/S) detectable in these cells by phosphoproteomic profiling. In conclusion, treatment with TGF-β receptor-1 kinase inhibitors may reactivate normal hematopoiesis in PMF patients, providing a proliferative advantage over the unresponsive malignant clone.


Myelodysplastic syndromes: therapy and outlook.
Myelodysplastic syndromes (MDS) are a diverse group of hematopoietic disorders characterized by dysplasia, peripheral cytopenias, and risk of progression to acute myeloid leukemia and death. In patients who are ineligible for potentially curative hematopoietic stem cell transplantation (HSCT), approved therapies such as lenalidomide, azacitidine, and decitabine are available for those who previously would have received supportive care alone. Each treatment can achieve hematologic improvement and enhance quality of life. Azacitidine is the only treatment to show a significant survival advantage in patients with higher-risk MDS compared with conventional care regimens. The treatment panorama has been further enhanced with immunosuppressive agents, growth factor support, and biologic response modifiers. Initial treatment decisions are based around HSCT eligibility and when best supportive care becomes insufficient. Transfusion dependence is associated with adverse outcomes and is an indication for possible treatment escalation.


Transfusion transmitted diseases in perioperative and intensive care settings.
Patients in the perioperative period and intensive care unit are commonly exposed to blood transfusion (BT). They are at increased risk of transfusion transmitted bacterial, viral and protozoal diseases. The risk of viral transmission has decreased steadily, but the risk of bacterial transmission remains same. Bacterial contamination is more in platelet concentrates than in red cells and least in plasma. The chances of sepsis, morbidity and mortality depend on the number of transfusions and underlying condition of the patient. Challenges to safe BT continue due to new emerging pathogens and various management problems. Strategies to restrict BT, optimal surgical and anaesthetic techniques to reduce blood loss and efforts to develop transfusion alternatives should be made. Literature search was performed using search words/phrases blood transfusion, transfusion, transfusion transmitted diseases, transfusion transmitted bacterial diseases, transfusion transmitted viral diseases, transfusion transmitted protozoal diseases or combinations, on PubMed and Google Scholar from 1990 to 2014.


A stepwise mechanism for the permeation of phloretin through a lipid bilayer.
The thermodynamics of interactions between phloretin and a phosphatidylcholine (PC) vesicle membrane are characterized using equilibrium spectrophotometric titration, stopped-flow, and temperature-jump techniques. Binding of phloretin to a PC vesicle membrane is diffusion limited, with an association rate constant greater than 10(8) M-1s-1, and an interfacial activation free energy of less than 2 kcal/mol. Equilibrium binding of phloretin to a vesicle membrane is characterized by a single class of high-affinity (8 micro M), noninteracting sites. Binding is enthalpy driven (delta H = -4.9 kcal/mol) at 23 degrees C. Analysis of amplitudes of kinetic processes shows that 66 +/- 3% of total phloretin binding sites are exposed at the external vesicle surface. The rate of phloretin movement between binding sites located near the external and internal interfaces is proportional to the concentration of un-ionized phloretin, with a rate constant of 5.7 X 10(4) M-1s-1 at 23 degrees C. The rate of this process is limited by a large enthalpic (9 kcal/mol) and entropic (-31 entropy units) barrier. An analysis of the concentration dependence of the rate of transmembrane movement suggests the presence of multiple intramembrane potential barriers. Permeation of phloretin through a lipid bilayer is modeled quantitatively in terms of discrete steps: binding to a membrane surface, translocation across a series of intramembrane barriers, and dissociation from the opposite membrane surface. The permeability coefficient for phloretin is calculated as 1.9 X 10(-3) cm/s on the basis of the model presented. Structure-function relationships are examined for a number of phloretin analogues.


[The role of free radicals oxidation in the deterioration of haemovascular homeostasis in aging].
Torty-two practically healthy subjects aged 60-80 and twenty-seven their younger counterparts aged 20-29 were investigated. The study involved investigation of interrelation between functional state of the endothelium, erythrocytes, platelets, and the state of free radicals oxidation indices. The results obtained showed the activation of free radicals oxidation processes in the group of older and old subjects in the decrease of antioxidant defence activity, this fact being corroborated by a statistically significant increase in the content of plasma malone dialdehyde, low level of superoxide dismutase, and the lack of adequate increment in catalase and glutathione in response to the increase in peroxidation processes. Moreover in the group of healthy older and old people, a deterioration of vasomotor function of the endothelium, a rise in erythrocytes and platelets aggregation activity, an increase in blood viscosity at various shift velocities were detected. The results of correlative analysis testify to the existance of interrelation between the deterioration of the indices of functional state of haemovascular homeustasis and uncompensated free radicals oxidation activity.


[Biological activity of a polar lipid of Clostridium butyricum spores].
A fraction of polar lipids was isolated from spores of the anaerobic bacterium Clostridium butyricum 35/11 exerting a noticeable radioprotective effect. The main biological activity of spore extracts was associated with this fraction. The fraction of polar lipids inhibited autolysis of the bacterial cell walls. The fraction was found to contain a phenolic glycolipid and a peptide component. The bacteriostatic and radiotherapeutic properties of the fraction are presumed to be due to its membranotropic activity.


Health care in the Soviet Union.
More nurses today have the opportunity to visit other countries and broaden their ideas of health care and nursing. Several colleagues and I have prepared a series of three articles that describe visits to the Soviet Union, China and Africa by nurses participating in exchange tours conducted by Professional Seminar Consultants of Albuquerque, New Mexico. During these two-week trips, American nurses were able to observe health care facilities and talk to health care providers in other countries. Although short visits such as these are not able to provide in-depth understanding of the health care systems or cultures involved, they have provided provocative ideas about how our own health care system differs from others. In some instances, our health care system seems the better one, but in many instances we were able to gain insights from our observations that may help us improve our own system of nursing and health care. This is the first in a series of three articles reporting professional exchange tours between American nurses and nurses of other countries. In this article, the health care system of the Soviet Union is discussed and compared to the United States' system of health care. From this comparison come several insights into ways for improving health care delivery.


Poisonous animal bites in the Israel Defense Forces.
Soldiers in field units of the Israel Defense Forces (IDF) are susceptible to injury by various poisonous animals during training and operations. Bites and envenomations by animals such as snakes, scorpions, and spiders can be painful and debilitating, and at times life-threatening. We have examined the extent of exposure of IDF soldiers to snake and arthropod bites and the morbidity resulting from these encounters. All reports of IDF soldiers who sought medical attention for snake or arthropod bites between the years 1993-1997 were reviewed at the IDF Medical Corps Headquarters. Monthly distribution of cases was noted for all years, and geographic distribution was studied for all 1997 cases. Over the period 1993-1997 there was a yearly rate of 32-52 physician visits per 100,000 soldiers due to snakebites (mean 43.6/100,000), and 1370-1729 physician visits per 100,000 soldiers due to arthropod bites (mean 1478/100,000). There is a clear overall increase in snake and arthropod bites during the spring and summer months, with a peak in snakebites in May and in arthropod bites in August. 58% of all snakebites in Israel were reported in the central region, with 33% occurring in the south, and 9% in the north of the country. No fatalities due to envenomations have been reported in the IDF in recent years. Poisonous animal species pose a significant threat to the soldiers of the IDF. Overall, envenomation is a common and widespread problem that has significant impact on the military medical system, especially during the spring and summer months. It is possible through institution of proper preventive measures to decrease the exposure of IDF personnel to this environmental hazard.


Resolving species boundaries in a recent radiation with the Angiosperms353 probe set: the Lomatium packardiae/L. anomalum clade of the L. triternatum (Apiaceae) complex.
Speciation not associated with morphological shifts is challenging to detect unless molecular data are employed. Using Sanger-sequencing approaches, the Lomatium packardiae/L. anomalum subcomplex within the larger Lomatium triternatum complex could not be resolved. Therefore, we attempt to resolve these boundaries here. The Angiosperms353 probe set was employed to resolve the ambiguity within Lomatium triternatum species complex using 48 accessions assigned to L. packardiae, L. anomalum, or L. triternatum. In addition to exon data, 54 nuclear introns were extracted and were complete for all samples. Three approaches were used to estimate evolutionary relationships and define species boundaries: STACEY, a Bayesian coalescent-based species tree analysis that takes incomplete lineage sorting into account; ASTRAL-III, another coalescent-based species tree analysis; and a concatenated approach using MrBayes. Climatic factors, morphological characters, and soil variables were measured and analyzed to provide additional support for recovered groups. The STACEY analysis recovered three major clades and seven subclades, all of which are geographically structured, and some correspond to previously named taxa. No other analysis had full agreement between recovered clades and other parameters. Climatic niche and leaflet width and length provide some predictive ability for the major clades. The results suggest that these groups are in the process of incipient speciation and incomplete lineage sorting has been a major barrier to resolving boundaries within this lineage previously. These results are hypothesized through sequencing of multiple loci and analyzing data using coalescent-based processes.


Salt and Water Transport in Reverse Osmosis Membranes: Beyond the Solution-Diffusion Model.
Understanding the salt-water separation mechanisms of reverse osmosis (RO) membranes is critical for the further development and optimization of RO technology. The solution-diffusion (SD) model is widely used to describe water and salt transport in RO, but it does not describe the intricate transport mechanisms of water molecules and ions through the membrane. In this study, we develop an ion transport model for RO, referred to as the solution-friction model, by rigorously considering the mechanisms of partitioning and the interactions among water, salt ions, and the membrane. Ion transport through the membrane is described by the extended Nernst-Planck equation, with the consideration of frictions between the species (i.e., ion, water, and membrane matrix). Water flow through the membrane is governed by the hydraulic pressure gradient and the friction between the water and membrane matrix as well as the friction between water and ions. The model is validated using experimental measurements of salt rejection and permeate water flux in a lab-scale, cross-flow RO setup. We then investigate the effects of feed salt concentration and hydraulic pressure on salt permeability, demonstrating strong dependence of salt permeability on feed salt concentration and applied pressure, starkly disparate from the SD model. Lastly, we develop a framework to analyze the pressure drop distribution across the membrane, demonstrating that cross-membrane transport dominates the overall pressure drop in RO, in marked contrast to the SD model that assumes no pressure drop across the membrane.


Connecting Through Dance: Understanding Conscious Clubbing Event Experiences.
Individuals abstaining from alcohol consumption frequently find themselves in contexts encouraging consumption, with limited alternative social interaction opportunities. Conscious clubbing events exclude alcohol and drugs, possibly providing valuable social connections, but little is known about event benefits. Twelve conscious clubbing event attendees and facilitators aged 25-55 from across Europe participated in semi-structured photo-elicitation interviews, which were analysed using thematic analysis. Findings suggested that conscious clubbing appears to enhance health, healing and growth, aiding recovery from substance dependency and trauma. Positioned as a modern ritual, symbolic and ritualistic preparations and experiences promoted storytelling and self-discovery. Connecting through synchronised but unchoreographed movement, participants engaged in powerful journeys and transformative experiences detached from life constraints. Inclusive digital and face-to-face conscious clubbing communities provided a sense of meaning and belonging away from substance use pressures and harms, particularly for those marginalised within society. Findings provide important and in-depth insights, including novel harm prevention implications. Future work should consider participatory barriers, event sustainability and misconceptions to increase event availability and participation.


Toxicological profiles of poisonous, edible, and medicinal mushrooms.
Mushrooms are a recognized component of the human diet, with versatile medicinal properties. Some mushrooms are popular worldwide for their nutritional and therapeutic properties. However, some species are dangerous because they cause toxicity. There are many reports explaining the medicinal and/or toxic effects of these fungal species. Cases of serious human poisoning generally caused by the improper identification of toxic mushroom species are reported every year. Different substances responsible for the fatal signs and symptoms of mushroom toxicity have been identified from various poisonous mushrooms. Toxicity studies of mushroom species have demonstrated that mushroom poisoning can cause adverse effects such as liver failure, bradycardia, chest pain, seizures, gastroenteritis, intestinal fibrosis, renal failure, erythromelalgia, and rhabdomyolysis. Correct categorization and better understanding are essential for the safe and healthy consumption of mushrooms as functional foods as well as for their medicinal use.


Bone density reduction in patients with Crohn disease and associations with demographic and disease variables: cross-sectional data from a population-based study.
The extent of bone density reduction in patients with Crohn disease is still being debated. The aim of this study was to examine bone mineral density (BMD) and factors associated with reduced BMD in a representative population of patients with Crohn disease aged between 20 and 70 years. BMD (using dual energy X-ray absorptiometry) was measured in spine and hip in 55 patients with Crohn disease recruited from the entire Crohn population (n = 96) in a defined area of southern Norway. Demographic and clinical data were also collected. The patients were compared with 52 age- and gender-matched healthy controls. Potential demographic and disease-related factors associated with BMD reduction were statistically tested with bi- and multivariate analyses. The BMD reduction in patients with Crohn disease was 7.1% (P = 0.02) in spine L1-4, 6.1% (P = 0.08) in femoral neck and 8.4% (P = 0.02) in total hip as compared with the controls. In total hip and femoral neck, age, body weight and gender were independently associated with reduced BMD, but in the spine only body weight. Among the disease-related variables, only ever use of prednisolone was independently associated with reduction in BMD but this only in the femoral neck. The spine and hip BMD reduction of 6%-8% is similar to that found in a comparable population-based study performed in another area in Norway. Among the disease-related variables tested for, only the use of prednisolone was independently associated with BMD reduction. However, the BMD reduction measured in this study indicates that disease-related mechanisms are involved.


Technique of transperitoneal laparoscopic adrenalectomy.
Adrenalectomy can be successfully and safely carried out with a laparoscopic technique, using standard instrumentation via a transperitoneal approach. We describe five tasks to be completed by the surgeon: (a) generation of pneumoperitoneum and port placement, (b) exposure of the adrenal gland, (c) dissection of the adrenal gland, (d) clipping of the adrenal vein, and (e) removal of the adrenal gland and fascial closure of port sites. Each step is described in detail for right and left adrenalectomy. Laparoscopic adrenalectomy is advocated on the same grounds as other laparoscopic procedure, namely, decreased postoperative pain and ileus, a better cosmetic result, decreased hospital stay, and a shorter convalescent period. Some other advantages of the laparoscopic technique are: minimal extent of dissection and excellent visibility and exposure of the adrenal gland.


Relation between Burnout and Sleep Problems in Nurses: A Systematic Review with Meta-Analysis.
Burnout can affect nurses' sleep quality. The aim of this study was to analyze the relationship between burnout syndrome and sleep problems in nurses. A systematic review with meta-analysis was performed. PubMed, CINAHL and Scopus databases were used. Some of the inclusion criteria were quantitative studies, in which the levels of burnout and sleep disorders were investigated in a sample of nurses using validated scales. A total of 12 studies were included. Sociodemographic variables did not influence the relation between burnout and sleep problems, except for being female. The environment and workplace violence, together with psychological traits and shifts, affect the probability of developing burnout and insomnia. The meta-analysis sample was n = 1127 nurses. The effect size of the correlation between burnout and sleep disorders was r = 0.39 (95% CI 0.29−0.48) with p < 0.001, indicating that the higher the level of burnout in nurses, the greater the presence of sleep disorders. The positive correlation between burnout and sleep disorders is a problem that must be addressed to improve the health of nurses. Developing turnicity strategies, using warmer lights in hospital units during night shifts and eliminating the fixed night shift could improve nurses' working conditions.


[Affection of myocardium in diabetes mellitus].
Echocardiography was performed in 67 patients with compensated diabetes mellitus (DM) type I and II. No signs of cardiovascular failure were noted. 20 patients have undergone myocardial scintigraphy. The patients were found to have hyperkinetic central hemodynamics resultant in DM type I from tachycardia, high rate of circulatory shortening of myocardial fibers, in DM type II from compensatory myocardial hypertrophy. In both diabetic types the function of myocardial relaxation was deteriorated as indicated by increased end diastolic volume and slow left ventricular relaxation. This evidences for initial cardiac failure. Myocardial scintigraphy registered perfusion defects in all the examinees, more profound in diabetes mellitus type II. The above findings explain the existence of marked coronarogenic and metabolic myocardial defects in DM.


Use of cycloserine-cefoxitin-fructose agar and L-proline-aminopeptidase (PRO Discs) in the rapid identification of Clostridium difficile.
The PRO Disc (Carr-Scarborough Microbiologicals, Inc., Decatur, Ga.) can be used to screen for L-proline-aminopeptidase produced by Clostridium difficile grown on cycloserine-cefoxitin-fructose agar (CCFA). Fifty stored isolates of C. difficile (48 toxin-positive and 2 toxin-negative isolates) and 47 fresh C. difficile isolates (39 toxin-positive and 8 toxin-negative isolates) were all PRO Disc positive. Other Clostridium species that were PRO Disc positive could be differentiated from C. difficile by failure to grow on CCFA, different colonial morphology on CCFA, or morphology upon Gram staining.


Effect of lowering dialysate sodium concentration on interdialytic weight gain and blood pressure in patients undergoing thrice-weekly in-center nocturnal hemodialysis: a quality improvement study.
Patients on in-center nocturnal hemodialysis therapy typically experience higher interdialytic weight gain (IDWG) than patients on conventional hemodialysis therapy. We determined the safety and effects of decreasing dialysate sodium concentration on IDWG and blood pressure in patients on thrice-weekly in-center nocturnal hemodialysis therapy. Quality improvement, pre-post intervention. 15 participants in a single facility. Participants underwent three 12-week treatment phases, each with different dialysate sodium concentrations, as follows: phase A, 140 mEq/L; phase B, 136 or 134 mEq/L; and phase A(+), 140 mEq/L. Participants were blinded to the exact timing of the intervention. IDWG, IDWG/dry weight (IDWG%), and blood pressure. Outcome data were obtained during the last 2 weeks of each phase and compared with mixed models. The fraction of sessions with adverse events (eg, cramping and hypotension) also was reported. IDWG, IDWG%, and predialysis systolic blood pressure decreased significantly by 0.6 ± 0.6 kg, 0.6% ± 0.8%, and 8.3 ± 14.9 mm Hg, respectively, in phase B compared with phase A (P < 0.05 for all comparisons). No differences in predialysis diastolic and mean arterial or postdialysis blood pressures were found (P > 0.05 for all comparisons). The proportion of treatments with intradialytic hypotension was low and similar in each phase (P = 0.9). In phase B compared with phase A, predialysis plasma sodium concentration was unchanged (P > 0.05), whereas postdialysis plasma sodium concentration decreased by 3.7 ± 1.9 mEq/L (P < 0.05). Modest sample size. Decreasing dialysate sodium concentrations in patients undergoing thrice-weekly in-center nocturnal hemodialysis resulted in a clinical and statistically significant decrease in IDWG, IDWG%, postdialysis plasma sodium concentration, and predialysis systolic blood pressure without increasing adverse events. Prolonged exposure to higher than required dialysate sodium concentrations may drive IDWG and counteract some of the purported benefits of "go-slow" (longer session length) hemodialysis.


Case Report: Application of whole exome sequencing for accurate diagnosis of rare syndromes of mineralocorticoid excess.
Syndromes of mineralocorticoid excess (SME) are closely related clinical manifestations occurring within a specific set of diseases. Overlapping clinical manifestations of such syndromes often create a dilemma in accurate diagnosis, which is crucial for disease surveillance and management especially in rare genetic disorders. Here we demonstrate the use of whole exome sequencing (WES) for accurate diagnosis of rare SME and report that p.R337C variation in the HSD11B2 gene causes progressive apparent mineralocorticoid excess (AME) syndrome in a South Indian family of Mappila origin.


Intrinsic Tuning of Poly(styrene-butadiene-styrene)-Based Self-Healing Dielectric Elastomer Actuators with Enhanced Electromechanical Properties.
The electromechanical properties of a thermoplastic styrene-butadiene-styrene (SBS) dielectric elastomer was intrinsically tuned by chemical grafting with polar organic groups. Methyl thioglycolate (MG) reacted with the butadiene block via a one-step thiol-ene "click" reaction under UV at 25 °C. The MG grafting ratio reached 98.5 mol % (with respect to the butadiene alkenes present) within 20 min and increased the relative permittivity to 11.4 at 103 Hz, with a low tan δ. The actuation strain of the MG-grafted SBS dielectric elastomer actuator was 10 times larger than the SBS-based actuator, and the actuation force was 4 times greater than SBS. The MG-grafted SBS demonstrated an ability to achieve both mechanical and electrical self-healing. The electrical breakdown strength recovered to 15% of its original value, and the strength and elongation at break recovered by 25 and 21%, respectively, after 3 days. The self-healing behavior was explained by the introduction of polar MG groups that reduce viscous loss and strain relaxation. The weak CH/π bonds through the partially charged (δ+) groups adjacent to the ester of MG and the δ- center of styrene enable polymer chains to reunite and recover properties. Intrinsic tuning can therefore enhance the electromechanical properties of dielectric elastomers and provides new actuator materials with self-healing mechanical and dielectric properties.


Applying linear interaction energy method for rational design of noncompetitive allosteric inhibitors of the sarco- and endoplasmic reticulum calcium-ATPase.
Noncompetitive inhibitors of sarco- and endoplasmic reticulum calcium-ATPase (SERCA) have important therapeutic value in the treatment of cancer, due to their ability to induce apoptosis in cancer cells in a proliferation-independent manner. Thapsigargin (TG) and its analogues are one such class of inhibitors that bind to a hydrophobic pocket located in the transmembrane region of SERCA near the biomembrane surface and interfere with calcium transport. The binding free energies of thapsigargin-based inhibitors of SERCA were computed using a novel linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model. A training set of 20 TG analogues was used to build a binding affinity model for estimating the free energy of binding for 18 new inhibitors with a root-mean-square (rms) error of 1.36 kcal/mol with respect to experimental data. For 15 out of the 18 inhibitors in the test set, the rms error was 1.02 kcal/mol, which is on the order of the accuracy level achieved by highly rigorous free energy of perturbation (FEP) or thermodynamic integration (TI) methods. On the basis of the analysis of the binding cavity at the interface of the membrane surface and the cytoplasmic region, we propose that side chains of TG derivatives at the O-8 position orient toward the cytoplasmic region through a hydrophobic channel. On the basis of this insight, four analogues of varying side chain length at the O-8 position with a charged moiety at the end were designed, tested with LIE methodology, and then validated experimentally for their SERCA inhibition activity. Low levels of rms error for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of SERCA by testing rationally designed lead compounds based on thapsigargin derivatization.


PRIMARY TUMOR LYMPHOVASCULAR INVASION NEGATIVELY AFFECTS SURVIVAL AFTER COLORECTAL LIVER METASTASIS RESECTION?
About 50% of the patients with colorectal adenocarcinoma will present with liver metastasis and 20% are synchronic. Liver resection is associated with improvement in survival in comparison to chemotherapy alone. To analyze the overall survival in patients submitted to liver resection of colorectal cancer metastasis and prognostic factors related to the primary and secondary tumors. A retrospective analysis of a prospectively maintained database regarding demographic, primary tumor and liver metastasis characteristics. There were 84 liver resections due to colorectal cancer metastasis in the period. The 5-year disease-free and overall survivals were 27.5% and 48.8% respectively. The statistically significant factors for survival were tumor grade (p=0.050), lymphovascular invasion (p=0.021), synchronous metastasis (p=0.020), as well as number (p=0.004), bilobar distribution (p=0.019) and diameter of the liver metastasis over 50 mm (p=0.027). Remained as independent negative predictive factors: lymphovascular invasion (HR=2.7; CI 95% 1.106-6.768; p=0.029), synchronous metastasis (HR=2.8; CI 95% 1.069-7.365; p=0.036) and four or more liver metastasis (HR=1.7; CI 95% 1.046-2.967; p=0.033). The resection of liver metastasis of colorectal adenocarcinoma leads to good survival rates. Lymphovascular invasion was the single prognostic factor related to the primary tumor. Synchronous disease and four or more metastasis were the most significant factors related to the secondary tumor.


[Search for optimal combinations of the hygienic and protective characteristics of body armors].
The protective composition of a body armor is generally characterized by two major parameters--the area and level of protection, i.e. resistance to bullets and fragments. These characteristics directly depend on the mass of a body armor and the sizes of the body's screening. The positive protective characteristics simultaneously have a negative impact on the most important hygienic indices of a body armor, such as convenience and easiness-to-use. The optimum combination of protective and performance characteristics of body armors makes a compromise between their mass and the level of protection.


Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s.
Cellular protein homeostasis depends on heat shock proteins 70 kDa (Hsp70s), a class of ubiquitous and highly conserved molecular chaperone. Key to the chaperone activity is an ATP-induced allosteric regulation of polypeptide substrate binding and release. To illuminate the molecular mechanism of this allosteric coupling, here we present a novel crystal structure of an intact human BiP, an essential Hsp70 in ER, in an ATP-bound state. Strikingly, the polypeptide-binding pocket is completely closed, seemingly excluding any substrate binding. Our FRET, biochemical and EPR analysis suggests that this fully closed conformation is the major conformation for the ATP-bound state in solution, providing evidence for an active release of bound polypeptide substrates following ATP binding. The Hsp40 co-chaperone converts this fully closed conformation to an open conformation to initiate productive substrate binding. Taken together, this study provided a mechanistic understanding of the dynamic nature of the polypeptide-binding pocket in the Hsp70 chaperone cycle.


[The syndrome of post-transfusion purpura].
Thrombocytopenic purpura occurred in two women aged 67 and 77 years, who earlier on had been pregnant, six and twelve days after blood transfusions. The platelet deficient phase lasted 16 and more than 50 days. Differentiation from other causes of thrombocytopenic haemorrhage was based on immunohaematologic findings. Both patients were negative for the platelet specific antigen PlA1 (Zwa). The platelet specific antibody (anti-PlA1) responsible for the purpura could be demonstrated and characterised immunologically.


Total daily physical activity and the risk of AD and cognitive decline in older adults.
Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273-0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). A higher level of total daily physical activity is associated with a reduced risk of AD.


Effects of incorporating germinated brown rice on the antioxidant properties of wheat flour chapatti.
Brown rice after germinating for 24 and 48 h was milled into flour and incorporated in whole wheat flour at a level of 10% to prepare chapattis. The objective was to use chapatti as a delivery vehicle for germinated brown rice. The flour blends and chapattis made from the flour blends were evaluated for their antioxidant properties. Incorporating germinated brown rice flour increased the total phenolic content of the flour blend from 1897 to 2144 µg FAE/g. The total flavonoids content increased significantly from 632.3 to1770.9 µg CAE/g and metal chelating activity significantly increased by 71.62%. Antioxidant activity increased significantly by the addition of brown rice flour and addition of 24- and 48-h germinated brown rice flour further increased the antioxidant activity significantly. The total phenolic content and total flavonoids content decrease significantly in all the blends after baking the flour into chapatti. A decrease of 3% to 29% was observed in the total phenolic content and a decrease of 25% to 42% was observed in the total flavonoids content. However, baking of the flour blends into chapatti increased the reducing power, metal chelating activity by three folds and antioxidant activity from 64% to 104%.


A Novel Technique for Infesting Field Sites with Encapsulated Eggs of Meloidogyne spp.
Eggs of Meloidogyne arenaria race 1 were encapsulated in calcium alginate for use as inoculum to infest peanut field plots. Some eggs within the capsules remained viable up to 10 weeks after preparation. A field site was successfully infested at peanut planting and (or) 6 weeks later. Dual applications of nematode inoculum (at planting and 6 weeks later) were superior to single applications (at planting or 6 weeks after planting). Field-site infestation levels at the end of the first year were related to the amount of inoculum dispersed and timing of the infestation (P = 0.001). Peanut yield was only slightly affected in the first year, but significant (P = 0.02) yield suppression occurred during the second year after field infestations. The negative relationship between the numbers of M. arenaria eggs and juveniles per 500 cm(3) soil in the fall and the percentage of peanut hull galled the second year was described by a quadratic model (P = 0.002, R(2) = 0.41).


Patterns of prescription dispensation and over-the-counter medication sales in Sweden during the COVID-19 pandemic.
On February 26th 2020, a high alert was issued in Sweden in response to the diagnosis of the first few coronavirus disease 2019 (COVID-19) cases in the country. Subsequently, a decreased supply of essential goods, including medical products, was anticipated. We aimed to explore the weekly patterns of prescription dispensing and over-the-counter (OTC) medication sales in Sweden in 2020 compared with previous years, to assess the influence of the government restrictions on medication sales, and to assess whether there is evidence of medication stockpiling in the population. Aggregated data on the weekly volume of defined daily doses (DDDs) of prescription medication dispensed and OTC sales from 2015 to 2020 were examined. From 2015-2019 data, the predicted weekly volume of DDDs for 2020 was estimated and compared to the observed volume for each ATC anatomical main group and therapeutic subgroup. From mid-February to mid-March 2020, there were increases in the weekly volumes of dispensed medication, peaking in the second week of March with a 46% increase in the observed versus predicted number of DDDs dispensed (16,440 vs 11,260 DDDs per 1000 inhabitants). A similar pattern was found in all age groups, in both sexes, and across metropolitan and non-metropolitan regions. In the same week in March, there was a 96% increase in the volume of OTC sold (2,504 vs 1,277 DDDs per 1000 inhabitants), specifically in ATC therapeutic subgroups including vitamins, antipyretics, painkillers, and nasal, throat, cough and cold preparations. Beginning in mid-February 2020, there were significant changes in the volume of prescription medication dispensed and OTC drugs sold. The weekly volume of DDDs quickly decreased following recommendations from public authorities. Overall, our findings suggest stockpiling behavior over a surge in new users of medication.


Drug Treatment of Venous Thromboembolism in the Elderly.
Half of all patients with acute venous thromboembolism are aged over 70 years; they then face the added hazard of an age-related increase in the incidence of major bleeding. This makes it even more important to weigh the balance of benefit and risk when considering anticoagulant treatment and treatment duration. Traditional treatment with a heparin (usually low molecular weight) followed by a vitamin K antagonist such as warfarin is effective but is often complicated, especially in the elderly. The direct-acting oral anticoagulants (DOACs), i.e. the thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban, are given in fixed doses, do not need laboratory monitoring, have fewer drug-drug interactions and are therefore much easier to take. Randomised trials, their meta-analyses and 'real-world' data indicate the DOACs are no less effective than warfarin (are non-inferior) and probably cause less major bleeding (especially intracranial). It seems the relative safety of DOACs extends to age above 65 or 70 years, although bleeding becomes more likely regardless of the chosen anticoagulant. Renal impairment, comorbidities (especially cancer) and interventions are special hazards. Ways to minimise bleeding include patient selection and follow-up, education about venous thromboembolism, anticoagulants, drug interactions, regular checks on adherence and avoiding needlessly prolonged treatment. The relatively short circulating half-lives of DOACs mean that time, local measures and supportive care are the main response to major bleeding. They also simplify the management of invasive interventions. An antidote for dabigatran, idarucizumab, was recently approved by regulators, and a general antidote for factor Xa inhibitors is in advanced development.


Response factor considerations for the quantitative analysis of western redcedar (Thuja plicata) foliar monoterpenes.
A method is described for quantitative analysis of monoterpenes in western redcedar (Thuja plicata) foliage by gas chromatography with flame ionization detection. Response factors for monoterpenes identified in redcedar are evaluated to determine similarities among monoterpene responses. Evaluation demonstrates that redcedar monoterpenes yield detector responses that fall into two groups. One monoterpene from each group is used as a standard for quantitative analysis. Redcedar monoterpenes are quantitated by comparing analyte response with the response factor of one of the standards in single-point calibrations. Homogenized foliage samples are extracted with ethyl acetate and the extracts passed through a solid phase extraction column of graphitized carbon to remove plant pigments. Method bias and repeatability are evaluated by fortifying foliage samples with (1S)-(+)-carvone and (1S)-(+)-2-carene and subjecting the samples to the extraction and analysis procedures. Detection limits are also assessed from fortified samples. Excellent recovery (> 95.0%) and precision (< 5%) are obtained from the analysis of 2-carene from fortified samples. Carvone recovery is approximately 80% with excellent precision (< 4%). The method limits of detection obtained from 2-carene and carvone fortified samples are 4.7 and 13.5 microg/g, respectively.


[Multiple trichoepithelioma with variable evolution of its lesions (malignancy and spontaneous remission)].
A case of Multiple Trichoepithelioma with extensive skin involvement without familial history is reported. Some of the lesions showed spontaneous remission over the years, and in two, the microscopcal examination, demonstrated malignant changes (Basal cell Epithelioma).


LIM Homeobox 9 knockdown by morpholino does not affect zebrafish retinal development.
LIM homeobox 9 (Lhx9) is a member of the LIM homeodomain transcription factor family, which expresses and functions in various vertebrate tissues, such as the gonads and pineal gland. Previous studies on lhx9 in zebrafish have mainly focused on the brain. However, little is known about the expression pattern of lhx9 during embryogenesis. Here, we detected lhx9 expression in zebrafish embryos using whole-mount in situ hybridization and found lhx9 expressed in heart, pectoral fin, and retina during their development in zebrafish. We then detailed the expression of lhx9 in retinal development. To further investigate the function of Lhx9 in retinogenesis, we performed morpholino (MO) knockdown experiments and found that upon lhx9 knockdown by MO, larvae presented normal eye development, retinal neural development, differentiation, proliferation, apoptosis, and responses to light stimulus. We not only elaborated the expression pattern of lhx9 in zebrafish embryogenesis, but we also demonstrated that lhx9 knockdown by morpholino does not affect the zebrafish retinal development, and our study provides data for further understanding of the role of Lhx9 in zebrafish retinal development.


On Putting an End to the Backlash Against Electrophysical Agents.
Electrophysical agents (EPAs) are core therapeutic interventions in academic physical therapy curricula around the world. They are used concomitantly with several other therapeutic interventions such as exercise, manual therapy techniques, medications, and surgery for the management of a wide variety of soft tissue disorders. Over the past decade, the practice of EPAs has been the subject of intense scrutiny in the U.S. This has been colored by some physical therapists publicly engaging in bashing rhetoric that has yet to be officially and publicly addressed by the guiding organizations which, together, regulate the practice of physical therapy in this country. Published in world renowned public media are unsubstantiated mocking remarks against the practice of EPAs and unethical allegations against its stakeholders. This rhetoric suggests that EPA interventions are "magical" treatments and that those practitioners who include them in their plans of care may be committing fraud. Such bashing rhetoric is in striking contradiction to the APTA's Guide to Physical Therapist Practice 4.0, which lists EPAs as one of its categories of interventions, the CAPTE's program accreditation policy, and the FSBPT's national licensing exam. The purpose of this commentary is to expose the extent of this discourse and to call to action the APTA, CAPTE, and FSBPT organizations, as well as physical therapists, with the aim at putting an end to this rhetoric.


Visual information processing in high-functioning individuals with autism spectrum disorders and their parents.
The authors assessed visual information processing in high-functioning individuals with pervasive developmental disorders (PDD) and their parents. The authors used tasks for contrast sensitivity, motion, and form perception to test visual processing occurring relatively early and late in the magnocellular-dorsal and parvocellular-ventral pathways. No deficits were found in contrast sensitivity for low or high spatial frequencies or for motion or form perception between individuals with PDD in comparison with a matched control group. Individuals with PDD performed equally with or better than controls on motion detection tasks. In addition, the authors did not find differences on any of the tasks between parents of the PDD group and matched control parents. These results indicate that high-functioning individuals with PDD and their parents are able to process visual stimuli that rely on early or late processing in the magnocellular-dorsal and parvocellular-ventral pathways as well as controls.


Foamy macrophages within lung granulomas of mice infected with Mycobacterium tuberculosis express molecules characteristic of dendritic cells and antiapoptotic markers of the TNF receptor-associated factor family.
Highly vacuolated or foamy macrophages are a distinct characteristic of granulomas in the lungs of animals infected with Mycobacterium tuberculosis. To date these have usually been considered to represent activated macrophages derived from monocytes entering the lesions from the blood. However, we demonstrate in this study that foamy macrophages express high levels of DEC-205, a marker characteristic of dendritic cells (DCs). In addition to high expression of the DEC-205 marker, these cells were characterized as CD11b(+)CD11c(high)MHC class II(high), and CD40(high), which are additional markers typically expressed by DCs. Up-regulation of CD40 was seen only during the early chronic stage of the lung disease, and both the expression of CD40 and MHC class II markers were down-regulated as the disease progressed into the late chronic phase. Foamy cells positive for the DEC-205 marker also expressed high levels of TNFR-associated factor-1 (TRAF-1), TRAF-2, and TRAF-3, markers associated with resistance to apoptosis. These data indicate that in addition to the central role of DCs in initiating the acquired immune response against M. tuberculosis infection, they also participate in the granulomatous response.


Urticaria and COVID-19: A review.
The first cases of the coronavirus disease (COVID-19) appeared in Wuhan, China, in December 2019. COVID-19 was declared a pandemic in March 2020. Cutaneous manifestations are among the heterogenous clinical features of the disease, and urticaria is one of the most common skin manifestations reported in COVID-19. We reviewed the literature available regarding COVID-19-associated urticaria. A literature search in the PubMed and Scopus databases was conducted, till the cut-off date of 24th July 2020, using the following terms: "skin" or "cutaneous" or "urticaria" or "urticarial," and "COVID-19" or coronavirus disease. The search resulted in 502 publications. In this review, 30 articles with a total of 202 patients with COVID-19-associated urticaria were included. Patient age ranged from 2 months to 84 years. Gender was reported in 149 patients; of these 96 (64%) were females, and 53 (36%) were males. Of the 105 patients with a determined onset of the disease, 58 (55%) presented with rash preceding or concurrently with the classic COVID-19 symptoms. Urticarial rash was mainly either generalized or distributed on the trunk. Associated respiratory symptoms, level of care, medications used, comorbidities, and duration, and distribution and timeline of urticarial rash were summarized. In this article, we present a review of literature on COVID-19-associated urticaria, which would enable dermatologists and other clinicians to diagnose COVID-19 early in the onset of disease, and prevent viral spread. Additionally, this may also pave the way for further studies on this topic.


Social housing enhances acquisition of task set independently of environmental enrichment: A longitudinal study in the Barnes maze.
Human studies suggest that healthy social relationships benefit cognition, yet little is known about the underlying neural mechanisms of this protective effect. In rodents, studies on acute isolation and environmental enrichment (EE) confirm the importance of social exposure. Despite the widely recognized importance of sociality, however, rodent models have yet to explore the independent contributions of social housing divorced of other forms of enrichment. This study dissociates the effects of social and physical enrichment on spatial learning and memory from adulthood to old age. Rats were placed in either single or group housing, provided with ample enrichment, and tested at three time points on several phases/versions of the Barnes maze (BM) (standard, retention probes, variable location, and reversal). We found that sustained social housing enhanced cognitive flexibility, as evidenced by superior acquisition of task set (standard BM), adaptability to a new task set (variable BM), and improved reversal learning (reversal BM). Long-term retention (BM retention probes) of spatial memory was unaffected by housing conditions. Recent studies from our lab, including this report, are the first to show that social housing confers cognitive benefits beyond those of physical enrichment. Importantly, our experimental design is ideal for exploring the neural underpinnings of this socially induced cognitive protection. Understanding how sociality influences cognition will be invaluable to translational models of aging, neuropsychiatric disease, and neurological injury.


Palliative care in liver disease: what does good look like?
The mortality rate from chronic liver disease in the UK is rising rapidly, and patients with advanced disease have a symptom burden comparable to or higher than that experienced in other life-limiting illnesses. While evidence is limited, there is growing recognition that care of patients with advanced disease needs to improve. Many factors limit widespread provision of good palliative care to these patients, including the unpredictable trajectory of chronic liver disease, the misconception that palliative care and end-of-life care are synonymous, lack of confidence in prescribing and lack of time and resources. Healthcare professionals managing these patients need to develop the skills to ensure effective delivery of core palliative care, with referral to specialist palliative care services reserved for those with complex needs. Core palliative care is best delivered by the hepatology team in parallel with active disease management. This includes ensuring that discussions about disease trajectory and advance care planning occur alongside active management of disease complications. Liver disease is strongly associated with significant social, psychological and financial hardships for patients and their carers; strategies that involve the wider multidisciplinary team at an early stage in the disease trajectory help ensure proactive management of such issues. This review summarises the evidence supporting palliative care for patients with advanced chronic liver disease, presents examples of current best practice and provides pragmatic suggestions for how palliative and disease-modifying care can be run in parallel, such that patients do not miss opportunities for interventions that improve their quality of life.


Impact of regulatory variation across human iPSCs and differentiated cells.
Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.


The evaluation of CYP2B6 inhibition by artemisinin antimalarials in recombinant enzymes and human liver microsomes.
Artemisinin-based combination therapy (ACT) is the recommended treatment of uncomplicated P.falciparum malaria by the World Health Organisation (WHO). Some artemisinin compounds and anti-retroviral drugs have been shown to be metabolized by CYP2B6. In the African clinical settings, the likelihood of co-administration of ACTs and antiretroviral drugs is higher than elsewhere, posing the risk of drug-drug interactions (DDIs). This study aimed to investigate whether artemisinin compounds inhibit CYP2B6 activity in vitro using recombinant CYP2B6 (rCYP2B6) and human liver microsomes (HLM). Values for IC50 and Ki were determined by kinetic analyses using non-linear regression. In vitro to in vivo extrapolations of the likelihood of DDIs where done using a static [I]/Ki approach. Artemisinin and artemether were shown to inhibit CYP2B6 in vitro through a partial mixed type of inhibition, while dihydroartemisinin did not inhibit the enzymatic activity. IC50 values for artemisinin were 9.5 and 9.1 µM for rCYP2B6 and HLM, respectively, after 30 min of incubation. Corresponding values for artemether were 7.5 and 5.4 µM. Artemisinin did not show any time-dependency or requirement of NADPH in its mechanism, indicating a reversible mode of inhibition. Based on the [I]/Ki approach using rCYP2B6, the risk of DDIs for artemisinin was indicated to be medium to high, while artemether had a low risk. The findings indicate a potential but moderate risk of DDIs in the co-administration of artemisinin or artemether with efavirenz in the co-treatment of malaria and HIV/AIDS.


Release of endothelium-derived relaxing factor after subarachnoid hemorrhage.
The purpose of this study was to determine the cause of the loss of endothelium-dependent relaxation observed in chronic cerebral vasospasm. A bioassay system was developed to measure the release of endothelium-derived relaxing factor (EDRF) from canine basilar arteries. Subarachnoid hemorrhage (SAH) was induced in dogs by two injections of autologous blood into the cisterna magna. Angiograms were performed on the 7th day after SAH to check the presence of chronic vasospasm. The animals were sacrificed on the 8th day, and in vitro experiments were performed on rings harvested from the basilar artery. These confirmed loss of endothelium-dependent relaxation in response to bradykinin and arginine vasopressin in the group with SAH. The basilar arteries were perfused with modified Krebs-Ringer solution. The perfusate was bioassayed with a ring of coronary artery without endothelium (bioassay ring). The release of the EDRF was detected by relaxation of the bioassay ring contracted with prostaglandin F2 alpha. Arginine vasopressin and bradykinin added to the perfusate upstream of the basilar artery caused concentration-dependent release of the EDRF. The direct effect of these peptides on the smooth muscle of the bioassay ring was to cause contraction. The release of the EDRF was identical in basilar arteries from the control and the SAH groups. These results indicate that the release of the EDRF is not impaired during chronic vasospasm, and thus that the loss of the endothelium-dependent relaxation is due to a decreased transfer of the EDRF or a reduced responsiveness of the smooth muscle to the factor.


AIDS drugs & the pharmaceutical industry: a need for reform.
The pharmaceutical industry has long enjoyed substantial profits despite increased requirements for drug approval and various attempts to regulate the industry. Drug companies have avoided effective regulation by blaming high prices on the costs of research and development. The search for drugs effective in combatting HIV and AIDS related illnesses has provided a stark background on which to view the actions and justifications of drug companies. Despite increased cooperation between government and the drug industry and expedited approval of several useful drugs, these drugs are still prohibitively expensive. This Article explores the history and economics of the drug industry and proposes a system of national price regulation for all drugs.


The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis.
Follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. During development, expression of Fstl1 is already found in cleavage stage embryos and becomes gradually restricted to mesenchymal elements of most organs during subsequent development. Knock down experiments in chicken and zebrafish demonstrated a role as a BMP antagonist in early development. To investigate the role of Fstl1 during mouse development, a conditional Fstl1 KO allele as well as a Fstl1-GFP reporter mouse were created. KO mice die at birth from respiratory distress and show multiple defects in lung development. Also, skeletal development is affected. Endochondral bone development, limb patterning as well as patterning of the axial skeleton are perturbed in the absence of Fstl1. Taken together, these observations show that Fstl1 is a crucial regulator in BMP signalling during mouse development.


Identification and specification of the mouse skeletal stem cell.
How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.


Naturalization of central European plants in North America: species traits, habitats, propagule pressure, residence time.
The factors that promote invasive behavior in introduced plant species occur across many scales of biological and ecological organization. Factors that act at relatively small scales, for example, the evolution of biological traits associated with invasiveness, scale up to shape species distributions among different climates and habitats, as well as other characteristics linked to invasion, such as attractiveness for cultivation (and by extension propagule pressure). To identify drivers of invasion it is therefore necessary to disentangle the contribution of multiple factors that are interdependent. To this end, we formulated a conceptual model describing the process of invasion of central European species into North America based on a sequence of "drivers." We then used confirmatory path analysis to test whether the conceptual model is supported by a statistical model inferred from a comprehensive database containing 466 species. The path analysis revealed that naturalization of central European plants in North America, in terms of the number of North American regions invaded, most strongly depends on residence time in the invaded range and the number of habitats occupied by species in their native range. In addition to the confirmatory path analysis, we identified the effects of various biological traits on several important drivers of the conceptualized invasion process. The data supported a model that included indirect effects of biological traits on invasion via their effect on the number of native range habitats occupied and cultivation in the native range. For example, persistent seed banks and longer flowering periods are positively correlated with number of native habitats, while a stress-tolerant life strategy is negatively correlated with native range cultivation. However, the importance of the biological traits is nearly an order of magnitude less than that of the larger scale drivers and highly dependent on the invasion stage (traits were associated only with native range drivers). This suggests that future research should explicitly link biological traits to the different stages of invasion, and that a failure to consider residence time or characteristics of the native range may seriously overestimate the role of biological traits, which, in turn, may result in spurious predictions of plant invasiveness.


The role of pharmacies in the care of drug users: what has changed in ten years. The case of a Swiss region.
This article assesses changes over 10 years in the role of pharmacies in the care of drug misusers--needle/syringe provision and methadone treatment supervision--in the Swiss French-speaking Canton of Vaud (636,000 inhabitants, 238 pharmacies). A review of data collected in four surveys (1991, 1994, 1996, 2003) on the provision of sterile material (and methadone treatment supervision in 2003) including all the pharmacists of the Canton of Vaud was conducted, as well as a review of data of the monitoring of needle exchange programmes introduced since 1996 in this canton, and of methadone treatment statistics. In 2003, interviews with pharmacists complemented the survey. Pharmacies play an important role in the 'frontline' services to drug misusers: the provision of needles/syringes to drug users by pharmacies remains important in spite of a decrease in the provision of sterile material by them since the advent of needle exchange programmes, and they are included in the supervision of two thirds of the methadone treatments. However, they do not feel integrated enough in the network of care to drug misusers and ask for more training and better recognition of their role.


Cell-to-cell transfer of interferon-induced antiproliferative activity.
Interferon-treated cells rapidly and efficiently transferred the antiproliferative activity of interferon to untreated cells. This phenomenon was not due to the carry-over of interferon by the interferon-treated cells. Thus, to evoke an antiproliferative state, interferon did not directly contact each cell in a population. The results suggest a novel mechanism by which interferon may indirectly regulate cell growth, and suggests that cells other than those of the immune system may play a role in controlling tumor growth in tissue where cell-to-cell contact occurs.


Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions.
Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12) with either subcutaneous morphine (10 mg/kg) or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1), consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL) and infralimbic (IL) cortex, nucleus accumbens (NAc) core, dorsomedial caudate-putamen (CPU), basolateral amygdala (BLA) and central nucleus of the amygdala (CNA) but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc), motor outputs (CPU), and associative learning (PL, IL, BLA) and stress pathways (CNA).


Expression Pattern of MicroRNA-21 during the Liver Ischemia/Reperfusion.
Ischemia/reperfusion (I/R) injury in cadaveric liver transplantation is not avoidable. Liver I/R injury is an important phenomenon in hepatic damage. MicroRNA-21 (miR-21) plays an important role in I/R injury. The present study aimed to determine the expression pattern of miR-21 in liver I/R injury/recovery and its correlation with the immunologic transmission signals pathways several days post-reperfusion. In an animal model for I/R in the liver, 40 male Balb/c mice were divided into 3 groups. The animals were monitored for 3 and 24 hours, and also for 4, 7, 14, and 28 days post-reperfusion. Liver tissue damage was assessed by histopathology. The plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total antioxidant capacity (TAC) levels were measured with enzymatic assays. MiR-21, programmed cell death 4 (PDCD4) mRNA, T-cell-restricted intracellular antigen 1 (TIA1) mRNA, and fas ligand (FASL) mRNA expression levels were measured; using reverse transcription-polymerase chain reaction (RT-PCR) at different times after the reperfusion in liver tissue and blood. Histopathology and plasma ALT, AST, ALP, and TAC levels confirmed liver damage induced by I/R injury. MiR-21 increased by twofold in the liver tissue and on the inflammatory phase after 24 hours of reperfusion; it then continued to decrease up to day 7 post-reperfusion. Afterward, it continued to rise slightly up to day 14 post-reperfusion. This trend was in parallel with the recovery of the liver damage. MiR-21 expression level in the liver and blood is a predictor of the extent of I/R injury.


Phytoremediation of petroleum hydrocarbons in tropical coastal soils. II. Microbial response to plant roots and contaminant.
The goal of this study was to understand the interaction between plants and microorganisms during petroleum-hydrocarbon bioremediation in Pacific Islands coastal soils. Total bacteria and hydrocarbon-degrading microorganisms population dyanamics were examined in the rhizospheres of tropical trees and shrubs, which were evaluated for their phytoremediation potential in a greenhouse experiment. The respective and combined effects of plant roots and diesel contaminant on the microbial populations were determined in relation to diesel fuel depletion. An increase in the grading populations size of the hydrocarbon-degrading populations of microbes, elicited by rhizodeposition, is generally regarded as conducive to an enhanced degradation of petroleum hydrocarbon pollutants in vegetated soil. The soil was a coastal sandy loam (pH 7.8) which was artificially contaminated with 10 g of No. 2 diesel fuel/kg soil or left uncontaminated. The pots were irrigated with fertilizer and 1% NaCl. The enumerations were carried out in the contaminated and uncontaminated rhizospheres of three trees, kiawe (Prosopis pallida), milo (Thespesia populnea), and kou (Cordia subcordata) and three shrubs, beach naupaka (Scaevola sericea), false sandalwood (Myoporum sandwicense), and oleander (Nerium oleander). Unplanted control soils were included in the experiment. Total bacteria and phenanthrene-degrading bacteria were enumerated on plates. Diesel- and pristane-degrading microorganisms were enumerated by the most-probable-number technique in tissue-culture plates. All four types of microorganisms responded to the rhizosphere of the 6 plants in uncontaminated soil and to the diesel contaminant in unplanted soil. In contaminated rhizospheres, no effect of the plant on the hydrocarbon-degrader numbers was visible. Total bacteria responded more to the plant roots than to the contaminant. The phenanthrene-degrading bacteria and pristane-degrading microorganisms were more influenced by the contaminant than by the plants. The diesel-degrading microorganisms were equally stimulated by the plants and the contaminant. The numbers of hydrocarbon degraders were similar in the contaminated rhizospheres of the three effective plants (kiawe, kou, and milo) and in those of the three ineffective shrubs. The results suggest the quality of the rhizodeposition is plant-dependent and governs the type of diesel-degrader populations that will be enhanced by a given plant. In the proposed phytoremediation-benefit model plant roots maintain high levels of hydrocaron degraders in uncontaminated soil. When the root enters a contaminated zone of soil, those hydrocarbon degraders that prefer the contaminant would switch to the contaminant as a carbon source, effectively removing the hydrocarbons. If the root exudates and the contaminant are equally attractive to the hydrocarbon degraders, the contaminant degradaton would be less effective.


Audit system on quality of breast cancer diagnosis and treatment (QT): results from the survey on screen-detected lesions in Italy, 2004.
Within this survey, conducted by the Italian Group for Mammography Screening (GISMa), individual data are collected yearly on more than 50% of all screen-detected operated lesions in Italy. In 2004, overall results show a good diagnosis and treatment quality and an improving trend over time. Critical issues have been identified in waiting times, compliance to the recommendations on not performing frozen section examination on small lesions and on performing specimen X-ray. Pre-operative diagnosis has reached an acceptable level, but room for improvement still exists. The sentinel lymph node technique (SLN) was performed on the axilla in almost 70% of screen-detected invasive cancers, avoiding a large number of potentially harmful dissections. On the other hand, potential overuse of SLN deserves further investigation. The detailed results have been distributed to local and regional screening programmes in order to enable multidisciplinary discussion and the identification of appropriate solutions to any problems documented by the data. Specialist Breast Units with adequate case volumes would provide the best setting for effective audits leading to quality improvement.