Surveillance of deaths caused by arboviruses in Brazil: from dengue to chikungunya.
Did death occur DUE TO dengue, or in a patient WITH dengue virus infection? It seems a matter of semantics, but in fact, it underscores how challenging it is to distinguish whether the disease contributed to death, or was itself the underlying cause of death. Can a death be attributed to chikungunya virus, when some deaths occur after the acute phase? Did the virus decompensate the underlying diseases, leading to death? Did prolonged hospitalisation lead to infection, resulting in the patient's progression to death? Were there iatrogenic complications during patient care? The dengue question, for which there has not yet been a definitive response, resurfaces prominently under the chikungunya surveillance scenario. We are facing an epidemic of a disease that seems to be more lethal than previously thought. The major challenge ahead is to investigate deaths suspected of occurring due to arbovirus infections and to understand the role of each infection in the unfavourable outcome.


Comparison of cell viability methods for human mesenchymal/stromal stem cells and human A549 lung carcinoma cells after freeze-thaw stress.
For the safety and efficacy of frozen cell therapy products, determination of cellular viability is key. However, results of cell viability measurements do not only depend on the cell line or on the inflicted stress, but also on the assay used, making inter-experimental comparisons difficult. The aim of this study was thus to assess commonly used viability assays in clinically relevant human mesenchymal/stromal stem cells and human A549 lung carcinoma cells. Post freeze-thaw stress viability and proliferation were evaluated under different conditions using trypan blue, acridine orange/DAPI stain, alamarBlue, ATP, and neutral red assays. Significant differences in cell viability between metabolic assays were observed, likely due to their distinct intrinsic detection mechanisms. Membrane-integrity based assays generally overestimated cell viabilities in this study. Furthermore, noticeable differences in inter-assay sensitivities were observed. These differences highlight that cell viability methods should be meticulously selected and their associated results carefully interpreted in a relevant context to ensure reliable conclusions. Indeed, although cell membrane integrity based assays are a popular choice to determine cellular quality attributes after freezing and thawing, we demonstrate that metabolic assays may be more suitable in this context.


Enzootic bovine leukosis.
The author emphasizes the significance of enzootic bovine leukosis in Canada. He describes in detail diagnostic methods, various types of the disease and methods of transmission. Various aspects of the disease in Canada are compared with those in other countries. Prevention and control are discussed in a Canadian context and include the current policies of the Government of Canada in relationship to this disease. The possibility of developing a certification program for herds free of the disease is also discussed. The paper includes incidence in various parts of Canada.


Influence of glucose and dissolved oxygen concentrations on yields of Escherichia coli B in dialysis culture.
Yields of Escherichia coli B grown on glucose were determined in dialysis and non-dialysis culture. The molar growth yields were compared under conditions of excess glucose and oxygen as well as glucose- and oxygen-limiting conditions. The molar growth yields on glucose (YG) were determined for different periods during growth in non-dialysis cultures. A rapid decrease of YG was observed and growth ceased even in the presence of high concentrations of glucose and dissolved oxygen in the culture liquid. The decrease in YG was delayed in dialysis cultures where a high YG could be maintained at very high cell concentrations. The inhibition of growth depended on the accumulation of end-products of fermentative degradation of glucose. These products interfered with the oxidative phosphorylation. A large proportion of the glucose was fermented even in the presence of high concentrations of dissolved oxygen in the culture liquid. A decrease in the growth yield per g glucose was also observed.


[Venous aneurysmatic malformation of the chest wall as a rare cause of pulmonary embolism--a case report].
This is a case report about a 66-year old man with recurrent pulmonary embolisms. Phlebography revealed a monstrous venous aneurysm of the right chest wall with several venous dilatations and calcification as the source of the embolism. Radiological embolisation and surgical ligation of the large aneurysmatic neck were performed. No further embolism episodes were registered under anticoagulation during the 23 months of the postoperative follow-up investigation.


Surface Activation by Single Ru Atoms for Enhanced High-Temperature CO2 Electrolysis.
Cathodic CO2 adsorption and activation is essential for high-temperature CO2 electrolysis in solid oxide electrolysis cells (SOECs). However, the component of oxygen ionic conductor in the cathode displays limited electrocatalytic activity. Herein, stable single Ruthenium (Ru) atoms are anchored on the surface of oxygen ionic conductor (Ce0.8Sm0.2O2-δ, SDC) via the strong covalent metal-support interaction, which evidently modifies the electronic structure of SDC surface for favorable oxygen vacancy formation and enhanced CO2 adsorption and activation, finally evoking the electrocatalytic activity of SDC for high-temperature CO2 electrolysis. Experimentally, SOEC with the Ru1/SDC-La0.6Sr0.4Co0.2Fe0.8O3-d cathode exhibits a current density as high as 2.39 A cm-2 at 1.6 V and 800 °C. This work expands the application of single atom catalyst to the high-temperature electrocatalytic reaction in SOEC and provides an efficient strategy to tailor the electronic structure and electrocatalytic activity of SOEC cathode at the atomic scale.


Gender differences in naphthalene metabolism and naphthalene-induced acute lung injury.
Humans are widely exposed to polycyclic aromatic hydrocarbons, commonly found in cigarette smoke and diesel exhaust. These can undergo site- and cell-specific metabolism to cytotoxic intermediates. Metabolism of naphthalene and Clara cell cytotoxicity have been extensively studied in male animals. To address whether male and female mice are equally susceptible to naphthalene, mice were injected with naphthalene, and lungs were examined 1, 2, 3, 6, and 24 h after treatment. By analysis of acute injury using differential permeability to fluorescent nuclear dyes and high-resolution histopathology, injury in female mice was found to be more extensive, occur earlier, and include permeable cells in proximal airways, including airway bifurcations. HPLC analysis of the products of cytochrome P-450 (CYP)-mediated metabolism in microdissected airways indicated that although both genders produced a predominance of products from CYP2F2, female mice produced more naphthalene dihydrodiol in distal airways, the primary sites of injury. We conclude that there are clear gender differences in susceptibility to naphthalene-induced injury and that differences in metabolism of naphthalene may play a role in elevated susceptibility in female mice.


A transition-based joint model for disease named entity recognition and normalization.
Disease named entities play a central role in many areas of biomedical research, and automatic recognition and normalization of such entities have received increasing attention in biomedical research communities. Existing methods typically used pipeline models with two independent phases: (i) a disease named entity recognition (DER) system is used to find the boundaries of mentions in text and (ii) a disease named entity normalization (DEN) system is used to connect the mentions recognized to concepts in a controlled vocabulary. The main problems of such models are: (i) there is error propagation from DER to DEN and (ii) DEN is useful for DER, but pipeline models cannot utilize this. We propose a transition-based model to jointly perform disease named entity recognition and normalization, casting the output construction process into an incremental state transition process, learning sequences of transition actions globally, which correspond to joint structural outputs. Beam search and online structured learning are used, with learning being designed to guide search. Compared with the only existing method for joint DEN and DER, our method allows non-local features to be used, which significantly improves the accuracies. We evaluate our model on two corpora: the BioCreative V Chemical Disease Relation (CDR) corpus and the NCBI disease corpus. Experiments show that our joint framework achieves significantly higher performances compared to competitive pipeline baselines. Our method compares favourably to other state-of-the-art approaches. Data and code are available at https://github.com/louyinxia/jointRN. email@example.com.


The Affinity of Elongated Membrane-Tethered Ligands Determines Potency of T Cell Receptor Triggering.
T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I and II pMHC molecules. The dimensions of membrane-tethered anti-CD3 and pMHC molecules were progressively increased by insertion of different extracellular domains. In agreement with previous studies, elongation of pMHC molecules or low-affinity anti-CD3 scFv caused progressive loss of T cell activation. However, elongation of high-affinity ligands (BC3 and OKT3 scFv) did not abolish TCR phosphorylation and T cell activation. Mutation of key amino acids in OKT3 to reduce binding affinity to CD3 resulted in restoration of topological dependence on T cell activation. Our results show that high-affinity TCR ligands can effectively induce TCR triggering even at large interspatial distances between T cells and APCs.


Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice.
Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations provide a unique model to examine altered Ca homeostasis in selectively vulnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, while calcium was gradually depleted from the cytoplasm and intact mitochondria. In oculomotor neurons, no degenerative changes, vacuolization, or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited no degenerative changes, but did exhibit unique membrane-enclosed organelles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of degeneration associated with minimally changed calcium and ample calbindin-D28K and/or parvalbumin.


Comparative Analysis of Stress Induced Gene Expression in Caenorhabditis elegans following Exposure to Environmental and Lab Reconstituted Complex Metal Mixture.
Metals are essential for many physiological processes and are ubiquitously present in the environment. However, high metal concentrations can be harmful to organisms and lead to physiological stress and diseases. The accumulation of transition metals in the environment due to either natural processes or anthropogenic activities such as mining results in the contamination of water and soil environments. The present study used Caenorhabditis elegans to evaluate gene expression as an indicator of physiological response, following exposure to water collected from three different locations downstream of a Swedish mining site and a lab reconstituted metal mixture. Our results indicated that the reconstituted metal mixture exerted a direct stress response in C. elegans whereas the environmental waters elicited either a diminished or abrogated response. This suggests that it is not sufficient to use the biological effects observed from laboratory mixtures to extrapolate the effects observed in complex aquatic environments and apply this to risk assessment and intervention.


Circadian clock-controlled regulation of cGMP-protein kinase G in the nocturnal domain.
The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mammalian SCN. Signaling via the cGMP-PKG pathway is required for light- or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMP-PKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by approximately 3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide (alphaODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GC-PKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMP-PKG. Inhibition of the cGMP-PKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMP-PKG-necessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GC-cGMP-PKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by light-GLU-activated GC-cGMP-PKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.


OGT: a short overview of an enzyme standing out from usual glycosyltransferases.
O-GlcNAcylation is a highly dynamic post-translational modification whose level depends on nutrient status. Only two enzymes regulate O-GlcNAcylation cycling, the glycosyltransferase OGT (O-GlcNAc transferase) and the glycoside hydrolase OGA (O-GlcNAcase), that add and remove the GlcNAc moiety to and from acceptor proteins, respectively. During the last 30 years, OGT has emerged as a master regulator of cell life with O-GlcNAcylation being found in viruses, bacteria, insects, protists and metazoans. The study of OGT in different biological systems opens new perspectives for understanding this enzyme in many kingdoms of life. In this review, we summarize recent and older findings regarding the distribution of OGT in living organisms.


The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH.
The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.


A simple test for predisposition to LDL oxidation based on the fluorescence development during copper-catalyzed oxidative modification.
When human low density lipoprotein (LDL) obtained from 10 volunteers was incubated in air at 37 degrees C in the presence of various concentrations of copper, an increase in fluorescence was observed with emission maximum at 430 nm when excitation was performed at 360 nm. The fluorescence increase was inhibited by ethylenediamine tetraacetic acid and by 4-methyl-2,6-di-tert-butylphenol. The fluorescence was found to be tightly bound to the protein moiety. Furthermore, Cu2+ modification of LDL was associated with a decrease in the reactive amino groups of apolipoprotein B and in the uptake of the lipoprotein by rabbit fibroblasts. Under our conditions, the fluorescence increase showed two consecutive periods; an inhibition period during which the fluorescence increased only weakly, and a propagation period with a rapid increase in fluorescence that was linear for at least 5 h. Both periods were influenced by copper concentration. The study also shows that the extent of fluorescence generated upon LDL oxidation varied greatly in the volunteers. Thus, while the results demonstrate that the fluorescence increase may likely monitor the extent of the apoB derivatization, the calculation of the fluorescence development rate of the propagation period together with the duration of the inhibition period may constitute a quantitative measurement of the susceptibility of apoB to be derivatized.


The effect of vitrification after warming on the expressions of p38, CDK1, and cyclin B in immature goat oocytes followed by in vitro maturation.
The combination of vitrification techniques and in vitro maturation can reduce oocyte competence. Mitogen-activated protein kinase and maturation-promoting factor are significant in oocyte meiotic maturation regulation. This study aimed to analyze vitrification's effect, after warming followed by in vitro maturation, on the expressions of protein 38 (p38), cyclin-dependent kinase 1 (CDK1), and cyclin B and oocyte maturation level. Immature goat oocytes were soaked in vitrification and warming solutions. The procedure was followed by in vitro maturation and in vitro maturation without post-warming vitrification as a control. These oocytes, along with their cumulus, were vitrified using hemistraw in liquid nitrogen. Oocyte maturation was carried out in a maturation medium that was added with 10 μg/mL of FSH, 10 μg/mL of LH, and 1 μg/mL E2 for 22 h. The expressions of p38, CDK1, and cyclin B were observed using immunocytochemical methods, which were assessed semiquantitatively according to the modified Remmele method. The oocyte maturation level was observed using the aceto-orcein staining method based on the achievement of chromosomes up to the metaphase II stage and/or the formation of the polar body I. p38 expression in vitrified oocytes after warming, followed by in vitro maturation, increased insignificantly (p≥0.05), with the acquisition of 3.91±2.69 and 2.69±0.50 in the control oocytes. CDK1 expression in vitrified oocytes decreased significantly (p≤0.05) after warming, followed by in vitro maturation, with the acquisition of 2.73±1.24 and 7.27±4.39 in the control oocytes. Cyclin B expression in vitrified oocytes decreased insignificantly (p≥0.05) after warming, followed by in vitro maturation, with the acquisition of 3.09±1.4 and 4.18±2.61 in the control oocytes. The proportion of vitrified oocyte maturation levels after warming, followed by in vitro maturation, decreased significantly (p≤0.05), with the acquisition of 45.45% and 77.27% in the control oocytes. This study concluded that vitrification after warming resulted in an insignificant increase in p38 expression, a significant decrease in CDK1 expression, an insignificant decrease in cyclin B expression, and a significant reduction in oocyte maturation levels.


Features of health care interventions associated with reduced services and spending.
This study examines 14 independent and diverse health care interventions funded under the second round of Health Care Innovation Awards by CMS to determine if any organizational, model, or implementation features were strongly associated with the programs' estimated impacts on total expenditures, hospitalizations, or emergency department visits. We estimated program impacts using awardee-specific difference-in-differences models based on Medicare and Medicaid enrollment and claims data for treatment and matched comparison groups from 2012 to 2018. We used 2 analytic approaches to identify program features associated with favorable impacts. The first method identified program characteristics that were common among programs that had estimated reductions in costs and service use and uncommon among those that did not. The second approach compared median impacts among awardees with a given distinguishing feature with median impacts among awardees that lacked the characteristic. Of the 23 program features examined, 7 were associated with favorable estimated impacts: 3 intervention components (behavioral health, telehealth, and health information technology) and 4 program design and organizational characteristics (having prior experience implementing similar programs, targeting patients with substantial nonmedical needs in addition to medical problems, being focused on individual patient care rather than transforming provider practice, and using nonclinical staff as frontline providers of the intervention). Innovative health care service delivery models with 2 or more of these 7 identified features were more likely than programs without them to reduce Medicare and Medicaid beneficiaries' needs for costly health care services.


Increased risk of precocious puberty in internationally adopted children in Denmark.
Studies have indicated that internationally adopted children have an increased risk of developing precocious puberty, but no epidemiologic risk estimates have previously been calculated. We aimed to assess the risk of developing precocious puberty in intercountry adoptees, children immigrating with their family, and descendants of immigrants living in Denmark. Patients who were registered with the diagnosis of precocious puberty during the period 1993-2001 were identified through the national patient registry. The background population of children born from 1983 to 2001 were identified through the unique Danish Civil Registration System and subsequently categorized as being Danish (N = 1,062,333), adopted (N = 10,997), immigrating with their family (N = 72,181), or being descendants of immigrants (N = 128,152). The incidence rate ratio of precocious puberty was estimated by log-linear Poisson regression. All rate ratios were adjusted for age and its interaction with gender and calendar year. P values were based on likelihood ratio tests, and 95% confidence intervals were calculated by Wald's test. In the study period, 655 children developed precocious puberty during 5,627,763 person-years at risk. Adopted children were followed during 39,978 person-years at risk, during which 45 girls and 6 boys developed precocious puberty. The risk of developing precocious puberty was significantly increased 10 to 20 times in adopted girls compared with girls with Danish background. The risk of developing precocious puberty depended on the country of origin. In children immigrating with their family, the risk of developing precocious puberty was only marginally increased. Older age at adoption significantly increased the risk of precocious puberty in adoptees independent of region of origin. The incidence rate ratio was significantly higher in children adopted after the age of 2. In children immigrating with their family, we found no effect of age at migration. In this large, nationwide, register-based study including 655 cases of precocious puberty, we found that intercountry boys and girls were 10 to 20 times more likely to develop precocious puberty compared with the Danish reference group. Older age at adoption significantly increased the risk of precocious puberty. Uncertainty of the exact age is a well-known problem in adopted children, and systematic underestimation of age might bias the result. However, using the worst-case scenario that all children who according to the Danish Civil Registration System were adopted after 2 years of age were in fact 1 year older, we still observed a highly increased risk of precocious puberty associated with adoption and especially with adoption after 2 years of age. Surprisingly, the risk of precocious puberty was not increased in the large group of children adopted from Korea. One case of precocious puberty was identified among Korean children, whereas > 20 cases of precocious puberty would have been expected if the risk for a Korean child was at the same level as observed among adopted children from India and South America. In the study population, 99% of Korean children were adopted before 2 years of age, which may contribute to explaining our finding. In Korea, children appointed for adoption are often living in foster care settings from birth to adoption, whereas most other countries are reported to take care of the children in orphanages before adoption. It can only be speculated whether a relation between preadoption living conditions and later risk of precocious puberty exists. Genetic factors play a key role in the timing of puberty, and large variations in age at menarche are observed worldwide. Age at menarche is reported to be in the same age range in South Korea as in well-off populations in other parts of the world, indicating that the different risk of precocious puberty observed between Korean and other adoptees probably cannot be explained by genetic factors alone. The finding that the risk of precocious puberty was significantly increased among adoptees in contrast to what was seen in children immigrating with their families contradicts a direct effect of migration. An increasing number of studies have shown long-term effects of certain prenatal and postnatal growth patterns, including advancement in pubertal maturation after poor intrauterine growth and catch-up growth during childhood. Different growth patterns and dietary habits between adoptees and children immigrating with their families might contribute to explain our findings. It has been hypothesized that stressful psychosocial factors in infancy and childhood may lead to earlier pubertal maturation. In general, adoptees have experienced several traumatic life events, and it may be speculated that these events alter the susceptibility for developing precocious puberty. Foreign-adopted children originating from regions other than Korea had a 15- to 20-fold increased risk of precocious puberty compared with Danish-born children, whereas adoptees originating from Korea had no increased risk of precocious puberty. In addition, children immigrating with their families had no increased risk of precocious puberty. The effect of country of origin might be explained by genetic factors or by different environmental exposures and living conditions in the different countries. Older age at adoption increased the risk for premature onset of puberty, which may suggest that environmental factors influence the risk of precocious pubertal development in adopted children.


Steps in tailoring a text messaging-based smoking cessation program for young adults.
Steps to develop or refine text messaging-based interventions are largely missing from the literature. Here, the authors describe steps in refining Stop My Smoking USA, a text messaging-based smoking cessation program for smokers 18-25 years old. Research activities included the following: needs assessment focus groups (n = 35); a content advisory team to affirm message acceptability (n = 10); and two beta tests to confirm technological feasibility (n = 12 and 28, respectively). Various recruitment strategies were tested to identify the optimal methods to reach young adult smokers ready to quit. Each stage of the refinement process yielded new insights, resulting in improved message content and tone, an effective recruitment strategy, and the identification and subsequent resolution of technology challenges. Findings suggest that young adults prefer messages that provide concrete behavioral strategies to overcome cravings, and which are positive in tone. Craigslist was the most efficient recruitment method and yielded a sample that was racially and economically diverse. Despite a successful beta test of initial technological feasibility, extensive problems were subsequently experienced in a beta test of the technological feasibility of the entire program. Iterative program refinement and adaptation on the basis of user input is necessary to ensure salience, while extensive field testing is required to ensure proper functioning of technology-based programs.


Synergistic action of sodium selenite and N-acetylcysteine in acetaminophen-induced liver damage.
Acetaminophen (AAP) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis in both humans and experimental animals. In this study, we investigated whether selenium (Se) and N-acetylcysteine (NAC), alone or in combination, are protective against AAP toxicity in mice. At the beginning of the experiment, blood samples were taken from 10 of 350 mice. Then, the remaining mice were randomly allocated into four groups, each consisting of 35 animals. The 1st group received a single administration of AAP by gavage at a dose of 600 mg/kg-bw, p.o. The 2nd group (AAP-Se) was treated with sodium selenite (0.5 mg Se/kg-bw, p.o.) one hour after ingestion of AAP. The 3rd group (AAP-NAC) ingested AAP, 1.5 h later followed by NAC (500 mg/kg-bw, p.o.). The 4th group (AAP-Se-NAC) was given sodium selenite and NAC, 1 and 1.5 h after administration of AAP, respectively. From each group, blood samples of seven mice for each time point were taken at 4, 8, 24, and 48 h after AAP toxicity. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels were measured. Compared with AAP group, the levels of ALT were lower after AAP ingestion in AAP-NAC, AAP-Se, and AAP-Se-NAC groups at the 8th hour. ALT, AST, and LDH levels in AAP-Se-NAC group were 50% of the levels of other groups starting form the 4th hour of toxicity. It is concluded that protection against AAP hepatotoxicity using a combination of Se and NAC is better than that found with either agent alone.


Human B1 Cells are the Main Blood Group A-Specific B Cells That Have a Moderate Correlation With Anti-A Antibody Titer.
Anti-carbohydrate antibody responses, including those of anti-blood group ABO antibodies, are yet to be thoroughly studied in humans. Because anti-ABO antibody-mediated rejection is a key hurdle in ABO-incompatible transplantation, it is important to understand the cellular mechanism of anti-ABO responses. We aimed to identify the main human B cell subsets that produce anti-ABO antibodies by analyzing the correlation between B cell subsets and anti-ABO antibody titers. Blood group A-binding B cells were analyzed in peritoneal fluid and peripheral blood samples from 43 patients undergoing peritoneal dialysis and 18 healthy volunteers with blood group B or O. The correlation between each blood group A-specific B cell subset and anti-A antibody titer was then analyzed using Pearson's correlation analysis. Blood group A-binding B cells were enriched in CD27+CD43+CD1c- B1, CD5+ B1, CD11b+ B1, and CD27+CD43+CD1c+ marginal zone-B1 cells in peripheral blood. Blood group A-specific B1 cells (P=0.029 and R=0.356 for IgM; P=0.049 and R=0.325 for IgG) and marginal zone-B1 cells (P=0.011 and R=0.410 for IgM) were positively correlated with anti-A antibody titer. Further analysis of peritoneal B cells confirmed B1 cell enrichment in the peritoneal cavity but showed no difference in blood group A-specific B1 cell enrichment between the peritoneal cavity and peripheral blood. Human B1 cells are the key blood group A-specific B cells that have a moderate correlation with anti-A antibody titer and therefore constitute a potential therapeutic target for successful ABO-incompatible transplantation.


The importance of detecting cytomegalovirus infections in studies evaluating new therapies for severe sepsis.
Cytomegalovirus infection is present in the majority of the population and is associated with substantial morbidity and mortality in immunocompromised patients. Recently, this viral infection has also been reported in nonimmunocompromised critically ill patients. We hypothesize that active cytomegalovirus infection may confound survival outcomes in severe sepsis trials. Scenarios based on three published studies on activated protein C were used as real examples for statistical simulations looking for how much bias in favor of or against activated protein C would be observed in single-arm studies (scenario 1), phase II trials (scenario 2A/2B), and phase III trials (scenario 3A/3B). Scenario 1 simulations evaluated a single-arm study and demonstrated that confounding biases could cause an absolute decrease of 5.7% to an increase of 6.1% on mortality rates of similar studies. Scenarios 2A and 3A evaluated phase II and III trials assuming that activated protein C is truly effective; they showed that trials with an imbalance on the proportion of active cytomegalovirus infection between study arms could lead to false-negative rates (β errors) in up to 25% of phase II trials and up to 42% of phase III trials. Scenarios 2B and 3B assumed that activated protein C was truly ineffective; they showed that imbalanced cytomegalovirus infection between arms would cause false-positive rates (α errors) in up to 5% of phase II and up to 7% of all phase III trials. The inclusion of an imbalanced proportion of patients with active cytomegalovirus infection may severely compromise the reliability of outcome results of severe sepsis trials independent of their design. Even randomized trials could have a much higher probability of false-negative rates for a new therapy than designed. Future severe sepsis trials should consider including active cytomegalovirus infection as a prospective covariate.


Alpha-glucosidase inhibitors from Millettia conraui.
A new geranylated isoflavone, 7-O-geranyl-6-methoxypseudobaptigenin (1) was isolated from the stem barks of Millettia conraui, along with known compounds 5-methoxydurmillone (2), conrauinone A (3), beta-amyrine (4), sitosterol (5), 3-O-beta-D-glucopyranosyl sitosterol (6) and n-docosanol (7). Compounds 1 and 4 showed a significant alpha-glucosidase inhibitory activity. The structures of the compounds were determined by analysis of their spectroscopic data.


Bosnian and Soviet refugees' experiences with health care.
Studies of refugees in the United States rarely address health the first few years following resettlement in part because the refugees become subsumed under the foreign-born or immigrant category. A national study reaffirmed the so-called healthy immigrant effect, but fewer sick days and less physician use may actually reflect access problems, economic concerns, and health beliefs or practices that clash with American health care. Because statistics may mask differences in health and why people seek professional care, it is important to combine qualitative and quantitative approaches. This study examined health, illness, and health care use patterns of refugees in Northern California using a database analysis, a medical record review, and an ethnographic study of the Bosnian and former Soviet Union refugee communities. This article describes some ethnographic findings from participant observation, semistructured interviews, and focus groups, with an emphasis on people's experiences with health care, health risk behaviors, and self-care.


The political implications of epigenetics Emerging narratives and ideologies.
Epigenetics, which is just beginning to attract public attention and policy discussion, challenges conventional understanding of gene-environment interaction and intergenerational inheritance and perhaps much more besides. Does epigenetics challenge modern political ideologies? I analyzed the narratives of obesity and epigenetics recently published in the more liberal New York Times and the more conservative Wall Street Journal. For the years 2010 through 2014, 50 articles on obesity and 29 articles on epigenetics were identified, and elements in their causal narratives were quantitatively analyzed using a well described narrative policy framework. The narratives on obesity aligned with the two newspapers' reputed ideologies. However, the narratives on epigenetics aligned with neither ideology but freely mixed liberal and conservative elements. This small study may serve as a starting point for broader studies of epigenetics as it comes to affect political ideologies and, in turn, public policies. The narrative mix reported here could yet prove vulnerable to ideological capture, or, more optimistically, could portend the emergence of a "third-way" narrative using epigenetics to question atomistic individualism and allowing for less divisiveness in public-health domains such as obesity.


Studies of IgE-dependent histamine releasing factors: heterogeneity of IgE.
Nasal lavage fluids from unstimulated individuals contain a histamine-releasing factor (HRF) similar to those which we have previously described from macrophages, platelets, and from blister fluids obtained during the late cutaneous reaction. The nasal HRF was partially purified by ion-exchange chromatography and gel filtration. Although some m.w. heterogeneity was observed, the majority of the HRF eluted at an apparent m.w. range of 15,000 to 30,000. This partially purified HRF induced histamine release from basophils of certain individuals. Histamine release occurred via a mechanism which is IgE-dependent in that: basophils desensitized by exposure to anti-IgE in the absence of calcium no longer respond to HRF, and desensitization with HRF reduces responsiveness to anti-IgE; and removal of IgE from the basophil surface by using lactic acid renders cells unresponsive to HRF. We have further defined this IgE dependence and have shown that the reason that only selected basophil donors respond to HRF is due to a previously unrecognized, functional heterogeneity of IgE. Thus, passive sensitization using sera from responders restored the responsiveness of acid-stripped basophils and conferred responsiveness to basophils of a nonresponder with naturally unoccupied IgE receptors. Sera from nonresponders failed to do this even though similar numbers of IgE molecules were put onto the basophil surface in each case. This property of responder sera was due to IgE because both heating sera at 56 degrees C for 2 hr and passage of sera over anti-IgE-Sepharose (which removes greater than 90% of the IgE) markedly reduced the ability of sera to induce responsiveness, and because an excess of either purified IgE myeloma or purified penicillin-specific IgE antibody from a nonresponder competitively inhibited the ability of IgE from responder sera to induce responsiveness to HRF. We conclude that nasal lavage fluids contain an HRF which induces basophil histamine release in a specific, IgE-dependent fashion but only from individuals with the appropriate type of IgE. Because we have shown that basophils are recruited into the nose during the late-phase reaction, we suggest that nasal HRF may induce these cells to release histamine and other mediators which could contribute to the symptomatology of the late-phase reaction.


Absorption of light in a single vertical nanowire and a nanowire array.
Both a single III-V semiconductor nanowire and an array of such nanowires have shown promise for solar cell applications. However, the correspondence between the optical properties of the single nanowire and the nanowire array has not been studied. Here, we perform electromagnetic modeling of InP nanowires to study this relationship. We find that a single nanowire can show at an absorption peak, a remarkably high absorption cross-section that is more than 50 times the geometrical cross-section. With optimization of the diameter of the single nanowire, the short-circuit current density is 30 times higher than in a bulk solar cell. With such a strong absorption, we predict an apparent efficiency >500% for the single nanowire solar cell. In contrast, we show that an efficient nanowire array solar cell cannot rely on strong absorption just through the absorption peak. Instead, the nanowires need to be packed rather closely to enhance the absorption of the full solar spectrum. At the optimum diameter for the nanowire array, neighboring nanowires compete strongly for absorption of incident photons at the absorption peak, which limits the absorption per nanowire by a factor of 18. As a result, the single InP nanowire is optimized at a diameter of 110 nm while the nanowires in the array are optimized at a considerably larger diameter of 180 nm. Importantly, we show analytically the coupling efficiency of incident light into the fundamental HE11 guided mode and consecutive absorption of the mode in the nanowires. With that analysis, we explain that a single nanowire shows two different absorption pathways-one through coupling into the guided mode and another by coupling into the nanowire through the sidewall. This analytical analysis also shows at which period the neighboring nanowires in an array start to compete for absorption of incident photons.


Effect of light-emitting diodes therapy (LEDT) on knee extensor muscle fatigue.
The purpose of this study was to evaluate the effects of light-emitting diodes therapy (LEDT) on quadriceps muscle fatigue by using torque values from the isokinetic dynamometer as an outcome measure. Light therapy is considered an innovative way to prevent muscle fatigue. Although positive results have been obtained in animal models and in clinical experiments, no results are available on the effects of this therapeutic modality on human performance studies with isokinetic dynamometry. Seventeen healthy and physically active male volunteers were included in a crossover randomized double-blinded placebo-controlled trial. They performed two sessions of an isokinetic fatigue test (30 maximal concentric knee flexion-extension contractions; range of motion, 90 degrees; angular velocity, 180 degrees per second) after LEDT or placebo treatment. Maximal knee extensor muscle isokinetic voluntary contractions were performed before (PRE-MVC) and after (POST-MVC) the fatigue test. LEDT treatment was performed with a multidiode cluster probe (34 red diodes of 660 nm, 10 mW; 35 infrared diodes of 850 nm, 30 mW) at three points of the quadriceps muscle, with a total irradiating dose of 125.1 J. No differences were observed in the PRE-MVC between LEDT (284.81 ± 4.52 Nm) and placebo (282.65 ± 52.64 Nm) treatments. However, for the POST-MVC, higher torques (p = 0.034) were observed for LEDT (237.68 ± 48.82 Nm) compared with placebo (225.68 ± 44.14 Nm) treatment. LEDT treatment produced a smaller maximal isometric torque decrease after high-intensity concentric isokinetic exercise, which is consistent with an increase in performance.


The bipolar spectrum: a review of current concepts and implications for the management of depression in primary care.
Family physicians inevitably encounter patients with bipolar disorders, often when the patient is depressed. For most of these patients, the attendant elevations in mood fall short of mania. Such milder periods of expansive mood, hypomanias, may go unrecognized unless the physician specifically queries the patient to uncover them. In addition, patients with bipolar disorders often manifest other distinctive characteristics. An understanding of these hints of bipolarity is helpful to clinicians treating depressive illness. Patients with bipolar disorders are at risk for treatment complications caused by the administration of antidepressants without the concurrent use of mood stabilizers, such as lithium carbonate, valproate sodium, and carbamazepine. Such complications include exacerbation of hypomania or mania, induction of refractory states, and, perhaps, rapid cycling or mixed states. We review current issues in classification of bipolar disorders and emphasize the importance of identifying hypomania. An introduction to the concept of affective temperaments and a brief review of treatment strategies and treatment complications are included.


Driving biology: The effect of standardized wound management on wound biomarker profiles.
The timing of coverage of an open wound is based on heavily on clinical gestalt. DoD's Surgical Critical Care Initiative created a clinical decision support tool that predicts wound closure success using clinical and biomarker data. The military uses a regimented protocol consisting of serial washouts and debridements. While decisions around wound closure in civilian centers are subject to the same clinical parameters, preclosure wound management is, generally, much more variable. We hypothesized that the variability in management would affect local biomarker expression within these patients. We compared data from 116 wounds in 73 military patients (MP) to similar data from 88 wounds in 78 civilian patients (CP). We used Wilcoxon rank-sum tests to assess concentrations of 32 individual biomarkers taken from wound effluent. Along with differences in the debridement frequency, we focused on these local biomarkers in MP and CP at both the first washout and the washout performed just prior to attempted closure. On average, CP waited longer from the time of injury to closure (21.9 days, vs. 11.6 days, p < 0.0001) but had a similar number of washouts (3.86 vs. 3.44, p = 0.52). When comparing the wound effluent between the two populations, they had marked biochemical differences both when comparing the results at the first washout and at the time of closure. However, in a subset of civilian patients whose average number of days between washouts was never more than 72 hours, these differences ceased to be significant for most variables. There were significant differences in the baseline biochemical makeup of wounds in the CP and MP. These differences could be eliminated if both were treated under similar wound care paradigms. Variations in therapy affect not only outcomes but also the actual biochemical makeup of wounds. Therapeutic, level IV.


Enkephalin knockdown in the central amygdala nucleus reduces unconditioned fear and anxiety.
The endogenous opioid enkephalins (ENK) are highly expressed in the central nucleus of the amygdaloid complex (CeA) where several lines of evidence point to a potential role in the modulation of fear and anxiety. In this study, we aimed to assess the role of CeA ENK using local injections of a lentiviral vector expressing a short hairpin RNA (shRNA) targeting ENK in Sprague-Dawley rats. We injected this vector in the CeA and a 56% downregulation of ENK mRNA was observed in animals when compared with scrambled shRNA animals. Anxiety-like behaviors were also assessed using the elevated plus maze and social interaction test. There was an increase in exploration of open arms of the elevated plus maze in ENK knockdown animals compared with controls, but no change in social interaction. In addition, we used the contextual fear conditioning procedure to assess fear expression and learning in these animals. There was a reduction in freezing induced by acute shocks during the training procedure. Interestingly, associative learning was not affected, and ENK knockdown animals displayed an equivalent freezing when re-exposed to the conditioning chamber 48 h later. These results contrast with knockout mice studies, which ascribed anxiolytic properties to ENK, and they demonstrate the need for a thorough understanding and characterization of neuroanatomically distinct ENK pathways.


Excited state structural dynamics of 4-cyano-4'-hydroxystilbene: deciphering the signatures of proton-coupled electron transfer using ultrafast Raman loss spectroscopy.
The photo-initiated proton-coupled electron transfer (PCET) process plays a crucial role in the context of light harvesting in various biological and chemical systems. Molecular model systems are typically employed to understand the mechanisms underlying the functioning of complex biological systems. Some molecular dyads based on the PCET property have been particularly designed to achieve efficient sunlight-to-fuel production. Organic photoacids are potential sources for such applications since they exhibit an enhancement in their acidity upon photoexcitation, facilitating the mimicking of some of the biological processes. p-Hydroxybenzylideneimidazolinone (p-HBI), an organic photoacid, is a key chromophore in green fluorescent protein, which exhibits green emission due to excited state proton transfer. Herein, we investigate the structural changes and dynamics of 4-cyano-4'-hydroxystilbene (CHSB), an analogue of p-HBI, in the presence of an external base, t-butylamine (TBA), using the techniques of ultrafast transient absorption, emission and ultrafast Raman loss spectroscopy. Femtosecond fluorescence up-conversion measurements of the CHSB-TBA adduct reveal a precursor-successor relationship between the ∼420 and ∼530 nm emission bands, which implies that the adduct evolves predominantly through an electron-proton transferred state. Further, Raman measurements show a clear distinction in the dynamics of the C[double bond, length as m-dash]C stretch of CHSB in the presence and absence of TBA in terms of the amplitude growth (0.45 ps vs. instantaneous) and the central frequency (1584 vs. 1523 cm-1).


Signalling pathways involved in hypertonicity- and acidification-induced activation of Na+/H+ exchange in trout hepatocytes.
In trout hepatocytes, hypertonicity and cytosolic acidification are known to stimulate Na+/H+ exchanger (NHE) activity, which contributes to recovery of cell volume and intracellular pH (pHi), respectively. The present study investigated the signalling mechanisms underlying NHE activation under these conditions. Exposing trout hepatocytes to cariporide, a specific inhibitor of NHE-1, decreased baseline pHi, completely blocked the hypertonicity-induced increase of pHi and reduced the hypertonicity-induced proton secretion by 80%. Changing extracellular pH (pHe) above and below normal values, and allowing cells to adjust pHi accordingly, significantly delayed alkalinization during hypertonic exposure, whereas following an acid load an enhanced pHi recovery with increasing pHe was seen. Chelating Ca2+, and thereby preventing the hypertonicity-induced increase in intracellular Ca2+ ([Ca2+]i), significantly diminished hypertonic elevation of pHi, indicating that Ca2+ signalling might be involved in NHE activation. A reduction in alkalinization and proton secretion was also observed in the presence of the protein kinase A (PKA) inhibitor H-89 or the calmodulin (CaM) inhibitor calmidazolium. A complete inhibition of hypertonic- and acidification-induced changes of pHi concurrent with an increase in hypertonically induced proton efflux was seen with the protein kinase C (PKC) inhibitor chelerythrine. Recovery of pHi following sodium propionate addition was reduced by more than 60% in the presence of cariporide, was sensitive to PKA inhibition, and tended to be reduced by CaM inhibition. In conclusion, we showed that NHE-1 is the main acid secretion mechanism during hypertonicity and recovery following acid loading. In addition, Ca2+-, PKA- and CaM-dependent pathways are involved in NHE-1 activation for recovery of cell volume and pHi. On the other hand, PKC appeared to have an impact on NHE-independent pathways affecting intracellular acid-base homeostasis.


Effects of vaccination on the acute-phase protein response and measures of performance in growing beef calves.
Two experiments were conducted to evaluate the influence of vaccination on the acute-phase protein (APP) reaction (Exp. 1 and 2) and measures of performance (Exp. 2) in growing beef calves. In Exp. 1, the APP reaction was assessed in newly weaned steers administered 1 of 3 treatments (n = 8 steers/treatment), consisting of 1) Mannheimia haemolytica vaccine (One Shot; Pfizer Inc., New York, NY), 2) Clostridium vaccine (UltraBac 7; Pfizer, Inc.), or 3) saline-injected control. Blood samples for the evaluation of APP concentrations were collected on d 0, 1, 3, 5, 7, 10, and 14 and steer BW measured on d 0 and 21 relative to treatment administration. Plasma concentrations of haptoglobin (Hp) increased (P < 0.05) in vaccinated but not control calves and reached a peak on d 3 and 5 for steers receiving Mannheimia haemolytica and Clostridium vaccine, respectively. Plasma concentrations of ceruloplasmin (Cp) and fibrinogen (Fb) increased (P < 0.05) in all calves after treatment administration and Fb concentrations were greatest (P < 0.01) in calves receiving Mannheimia haemolytica vaccine on d 3 and 5 compared with the other treatments. There were no treatment effects (P = 0.44) on 21-d steer ADG (0.43 kg/d; SEM = 0.082). In Exp. 2, 23 heifers were randomly assigned to 2 treatments: 1) vaccinated (Mannheimia haemolytica vaccine (One Shot; n = 12) and 2) saline control (n = 11). After vaccination, blood samples were collected for determination of APP concentrations on d 0, 3, 6, 9, 12, and 15. During this period, individual heifer DMI was measured using an automated feed intake measuring system (Model 4000E; GrowSafe Systems Ltd., Airdrie, Alberta, Canada). Initial and final shrunk BW did not differ (P > 0.36) among treatments. On d 1, plasma Cp concentrations increased (P < 0.01) sharply in vaccinated heifers but not control heifers and were greater (P < 0.05) in vaccinated vs. control heifers on d 3, 6, 9, and 12 relative to injection. Daily DMI did not differ (P = 0.66) among treatments (average = 9.1 kg/d; SEM = 0.34); however, ADG and G:F were greater (P ≤ 0.05) for control vs. vaccinated heifers (1.14 vs. 0.87 kg/d and 0.13 and 0.10 kg, respectively; SEM = 0.064 and 0.011). These data indicate that within a 2 wk period after vaccination, beef calves experience an acute-phase protein response, which may result in reduced ADG and feed efficiency.


Life-time risk factors and progression of carotid atherosclerosis in young adults: the Cardiovascular Risk in Young Finns study.
The aim of this study is to evaluate whether childhood risk factors are associated with a 6-year change in carotid intima-media thickness (IMT) in young adulthood independent of the current risk factors. The Cardiovascular Risk in Young Finns cohort consisted of 1809 subjects who were followed-up for 27 years since baseline (1980, age 3-18 years) and having carotid IMT measured both in 2001 and 2007. Cardiovascular risk factors were assessed repeatedly since childhood. A genotype risk score was calculated using 17 newly identified genetic variants associating with cardiovascular morbidity. The number of childhood risk factors (high LDL-cholesterol, low HDL-cholesterol, high blood pressure, obesity, diabetes, smoking, low physical activity, infrequent fruit consumption) was associated with a 6-year change in adulthood IMT. In subjects with 0, 1, 2, and > or =3 childhood risk factors, IMT [mean (95% CI)) increased by 35 (28-42), 46 (40-52), 49 (41-57), and 61 (49-73) microm (P = 0.0001). This association remained significant when adjusted for adulthood risk score and genotype score (P = 0.007). Of the individual childhood variables, infrequent fruit consumption ((beta (95% CI) for 1-SD change -5(-9 to -1), P = 0.03) and low physical activity (-6(-10 to -2), P = 0.01) were associated with accelerated IMT progression after taking into account these variables assessed in adulthood. These findings indicate that children with risk factors have increased atherosclerosis progression rate in adulthood, and support the idea that the prevention of atherosclerosis by means of life style could be effective when initiated in childhood.


Biodegradable Polymer with Hydrolysis-Induced Zwitterions for Antibiofouling.
Persistent protein resistance is critical for marine antibiofouling. We have prepared copolymer of 2-methylene-1,3-dioxepane (MDO), tertiary carboxybetaine ester (TCB), and 7-methacryloyloxy-4-methylcoumarin (MAMC) via radical ring-opening polymerization, where MDO, TCB, and MAMC make the polymer degradable, protein resistible, and photo-cross-linkable, respectively. Our study shows that the polymer can well adhere to the substrate with controlled degradation and water adsorption rate in artificial seawater (ASW). Particularly, the polymer film can generate zwitterions via surface hydrolysis in ASW. Quartz crystal microbalance with dissipation measurements reveal that such hydrolysis-induced zwitterionic surface can effectively resist nonspecific protein adsorption. Moreover, the surface can inhibit the adhesion of marine bacteria Pseudomonas sp. and Vibrio alginolyticus as well as clinical bacterium Escherichia coli.


Comparative properties of five human ovarian adenocarcinoma cell lines.
We describe the derivation of three human ovarian carcinoma cell lines and the comparison of their properties with two previously described cell lines of like histology (SKOV-3 and CAOV-3). Two of the new lines (HOC-1 and HOC-7) were derived from separate ascites tumors (at 9-month intervals) of a patient with well-differentiated serous adenocarcinoma of the ovary. The third new line, HEY, was derived from a human ovarian cancer xenograft (HX-62) originally grown from a peritoneal deposit of a patient with moderately differentiated papillary cystadenocarcinoma of the ovary. The cell lines demonstrated differential ability to grow in semisolid culture and as xenografts in immunologically deprived CBA/CJ mice. Dose-response curves were generated for clonogenic cell survival of cells exposed to common chemotherapeutic agents; one of the lines (HEY) shows a degree of resistance to the alkylating agent cis-diamminedichloroplatinum(II) (cis-platinum). Common karyological features included structural abnormalities of chromosomes 3 and 11. Heterogeneity of expression of ovarian tumor-associated antigens was documented.


Clinical features and management of children with primary ciliary dyskinesia in England.
In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). Multi-centre service evaluation of the English National Management PCD Service. Four nationally commissioned PCD centres in England. 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF. Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV1) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae. We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV1. Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice.


Interaction of YB-1 with human immunodeficiency virus type 1 Tat and TAR RNA modulates viral promoter activity.
Transcriptional regulation of the human immunodeficiency virus type 1 (HIV-1) genome is mediated by viral and cellular factors. TAR, an unusual RNA regulatory element with a stem-bulge-loop structure at the 5' ends of all nascent viral transcripts is critical for HIV-1 transcription. TAR is the target for Tat, a viral transcription factor encoded early in the HIV-1 life-cycle and essential for gene expression. Evidence demonstrating the interaction of a cellular ssDNA/RNA binding protein, YB-1, with TAR through a region which is important for Tat interaction is presented. Interestingly, results from protein-protein interaction studies revealed that YB-1 can also form a complex with Tat. Results from mapping experiments suggest that while the region spanning aa 125-203 within YB-1 is essential for its association with TAR, a truncated YB-1 spanning aa 1-125 can weakly bind to Tat. Functionally, overexpression of full-length YB-1 enhanced Tat-induced activation of the HIV-1 minimal promoter containing TAR sequences, whereas mutant YB- 1 with no ability to bind to Tat and TAR failed to affect Tat-mediated activation. Expression of mutant YB-1(1-125), which binds to Tat but not RNA, decreased Tat-mediated enhancement of virus transcription. These observations suggest that while full-length YB-1 may function as a facilitator and, by interaction with both Tat and TAR, increase the level of Tat:TAR association, mutant YB-1 with no TAR binding activity, by complexing with Tat, may prevent Tat interaction with TAR. The importance of these findings in light of the proposed mechanism of Tat function is discussed.


Discharge from a palliative care unit: prevalence and related factors from a retrospective study in Japan.
Selecting a place for end-of-life care is an important issue for patients with cancer. In this study we conducted a retrospective analysis on the prevalence of discharge from a palliative care unit (PCU) and explored factors related to discharge based on individual-level data from 5 years of experience at the Tokyo Metropolitan Toshima Hospital PCU. We retrospectively collected information on patients and families from the admission database of the PCU. We calculated the prevalence of patients discharged from the PCU and explored the factors related to discharge using bivariate and multivariate analysis. The subjects were 498 terminal patients with cancer. The overall discharge rate was 33%. For subjects who were admitted for symptom control, the discharge rate was 54%. The duration of the period from referral to death (odds ratio [OR] = 4.98, p < 0.001), Eastern Cooperative Oncology Group Performance States [ECOG PS]_OR = 0.51, p = 0.003), problems with oral intake (OR = 0.41, p = 0048), presence of nausea (OR = 0.41, p = 0.046), experience of radiation therapy (OR = 0.27, p = 0.003), and patient's anxiety for family (OR = 0.35, p = 0.029) were independent related factors for discharge from the PCU, according to logistic regression. Early referral to the PCU and development of alleviation methods for symptoms such as nausea and anxiety and depression are important for promoting discharge and would contribute to the patient's quality of life at the end of life.


G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension.
-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein beta3 subunit gene (GNB3) induces formation of a splice variant (Gbeta3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (chi2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105+/-7, 109+/-16, and 128+/-28 mm Hg (mean+/-SD) for CC, CT, and TT, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein beta3 subunit gene in the causation of essential hypertension.


Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action.
Trigonella foenum-graecum (fenugreek) seeds have been documented as a traditional plant treatment for diabetes. In the present study, the antidiabetic properties of a soluble dietary fibre (SDF) fraction of T. foenum-graecum were evaluated. Administration of SDF fraction (0 x 5 g/kg body weight) to normal, type 1 or type 2 diabetic rats significantly improved oral glucose tolerance. Total remaining unabsorbed sucrose in the gastrointestinal tract of non-diabetic and type 2 diabetic rats, following oral sucrose loading (2 x 5 g/kg body weight) was significantly increased by T. foenum-graecum (0 x 5 g/kg body weight). The SDF fraction suppressed the elevation of blood glucose after oral sucrose ingestion in both non-diabetic and type 2 diabetic rats. Intestinal disaccharidase activity and glucose absorption were decreased and gastrointestinal motility increased by the SDF fraction. Daily oral administration of SDF to type 2 diabetic rats for 28 d decreased serum glucose, increased liver glycogen content and enhanced total antioxidant status. Serum insulin and insulin secretion were not affected by the SDF fraction. Glucose transport in 3T3-L1 adipocytes and insulin action were increased by T. foenum-graecum. The present findings indicate that the SDF fraction of T. foenum-graecum seeds exerts antidiabetic effects mediated through inhibition of carbohydrate digestion and absorption, and enhancement of peripheral insulin action.


Production and characterization of hyaluronic acid microparticles for the controlled delivery of growth factors using a spray/dehydration method.
Hyaluronic acid is the main polysaccharide present in the connective tissue. Besides its structural function as backbone of the extracellular matrix, hyaluronic acid plays staple roles in several biological processes including the modulation of inflammation and wound healing processes. The application of hyaluronic acid in regenerative medicine, either as cells and/or drug/growth factors delivery vehicles, relies on its ability to be cross-linked using a plethora of reactions, producing stable hydrogels. In this work, we propose a novel method for the production of hyaluronic acid microparticles that presents several advantages over others that have been used. Basically, droplets of hyaluronic acid solution produced with a nozzle are collected in an isopropanol dehydration bath, and stabilized after crosslinking with adipic acid dihydrazide, using a cabodiimide-based chemistry. The size and morphology of the hyaluronic acid microparticles produced by this method varied with the molecular weight and concentration of the hyaluronic acid solution, the nozzle chamber pressure, the distance between the nozzle and the crosslinking solution, and the number of crosslinking steps. The degree of crosslinking of the hyaluronic acid microparticles produced was tunable and allowed to control the rate of the degradation promoted by hyaluronidase. Moreover, the particles were loaded with platelet lysate, a hemoderivative rich in cytokines with interest for regenerative medicine applications. The hyaluronic acid microparticles showed potential to bind selectively to positively charged molecules, as the factors present in the platelet lysate. It is envisioned that these can be further released in a sustained manner by ion exchange or by the degradation of the hyaluronic acid microparticles matrix promoted by extracellular matrix remodeling.


Effects of Cryptosporidium muris (strain MCR) infection on gastric mucosal mast cells in mice.
The responses of gastric mucosal mast cells (GMMCs) to infection with coccidian protozoa, Cryptosporidium muris, in mice were examined during primary and challenge infections. Each of three-week old ICR SPF mice was orally inoculated with a single dose of 2 x 10(6) oocysts of C. muris (strain MCR). After oocyst shedding ceased, the mice were orally challenged with a single dose of 2 x 10(6) oocysts of the same species. GMMCs reached a peak on days 20-30 postinoculation (PI) in number, and decreased thereafter. An increase on days 20-30 post-challenge-infection (PCI) was also observed. The mice showed, on the whole, normal profiles of oocyst shedding in droppings. The number of the cells of uninfected control mice remained constant. Judging from the above results, it is suggested that mastocytosis correlate with expulsion of C. muris in primary infection and the defense mechanism of challenge infection.


Neurologic perspectives of otosclerosis.
Of 500 patients with roentgenographically verified otosclerosis, 230 had vestibular manifestations. Because of its frequency in general practice, otosclerosis has a major impact on the differential diagnosis of vertigo and related symptoms. The vestibular syndrome encompasses the full symptomatic spectrum common to diseases of the vestibular system, from episodic violent rotational vertigo to a sense of almost continuous imbalance, and cannot usually be distinguished from idiopathic endolymphatic hydrops. Otosclerosis is easy to diagnose when vestibular symptoms occur in conjunction with conductive or mixed hearing loss and a normal tympanic membrane that excludes middle ear disease. However, in approximately one-third of patients with a hearing loss that is purely sensorineural, the diagnosis can be confirmed only by compound-motion tomography of the petrous bones.


Differences in price of flavoured and non-flavoured tobacco products sold in the USA, 2011-2016.
Limited data exist on whether there is differential pricing of flavoured and non-flavoured varieties of the same product type. We assessed price of tobacco products by flavour type. Retail scanner data from Nielsen were obtained for October 2011 to January 2016. Universal product codes were used to classify tobacco product (cigarettes, roll-your-own cigarettes (RYO), little cigars and moist snuff) flavours as: menthol, flavoured or non-flavoured. Prices were standardised to a cigarette pack (20 cigarette sticks) or cigarette pack equivalent (CPE). Average prices during 2015 were calculated overall and by flavour designation. Joinpoint regression and average monthly percentage change were used to assess trends. During October 2011 to January 2016, price trends increased for menthol (the only flavour allowed in cigarettes) and non-flavoured cigarettes; decreased for menthol, flavoured and non-flavoured RYO; increased for flavoured little cigars, but decreased for non-flavoured and menthol little cigars; and increased for menthol and non-flavoured moist snuff, but decreased for flavoured moist snuff. In 2015, average national prices were US$5.52 and US$5.47 for menthol and non-flavoured cigarettes; US$1.89, US$2.51 and US$4.77 for menthol, non-flavoured and flavoured little cigars; US$1.49, US$1.64 and US$1.78 per CPE for menthol, non-flavoured and flavoured moist snuff; and US$0.93, US$1.03 and $1.64 per CPE flavoured, menthol and non-flavoured RYO, respectively. Trends in the price of tobacco products varied across products and flavour types. Menthol little cigars, moist snuff and RYO were less expensive than non-flavoured varieties. Efforts to make flavoured tobacco products less accessible and less affordable could help reduce tobacco product use.


Poliovirus and non-polio-enterovirus environmental surveillance in Parma within the "Global Polio Eradication Program" (GPEI).
Environmental surveillance of poliovirus plays an essential role in GPEI both for the detection of WTP and VDPV circulation in endemic areas and for monitoring their absence in polio-free countries. Since 2005 to 2018, in Parma, 642 wastewater samples were collected from the two wastewater treatment plants and analyzed according to the WHO Guidelines. All isolates supposed being poliovirus were sent to ISS reference laboratory for molecular characterization while NPEV only refer to samples up to 2016. Positivity was obtained in 68% of samples without significant difference between the two treatment plants. Six polioviruses (1.4%) were detected, all characterized as Sabin-like: 4 of them (66.7%) were type 3 and 2 (33.3%) type 1. Coxsackieviruses B mainly recurred among NPEV (85%) while residual 15% was Echoviruses. B4 was the most frequent Coxsackie serotype isolated (31%) while, among Echovirus, Echo 7 and Echo 11 prevail (both 23%). As OPV isn't used in Italy since 2002, recovery of Sabin-like polioviruses indicates the possibility of poliovirus reintroduction, considering also the important exposure to migratory flows. Finally, monitoring the environmental circulation of NPEV, could compensate for the lack of a surveillance system of the infections they cause.


Reduced reflection from roughened hyperbolic metamaterial.
We show that roughened surfaces of hyperbolic metamaterials scatter light preferentially inside the media, resulting in a very low reflectance. This phenomenon of fundamental importance, demonstrated experimentally in arrays of silver nanowires grown in alumina membranes, is consistent with a broad-band singularity in the density of photonic states. It paves the road to a variety of applications ranging from the stealth technology to high-efficiency solar cells and photodetectors.


Economic cost of smoking and secondhand smoke exposure in the Gulf Cooperation Council countries.
The economic cost of smoking has been determined in many high-income countries as well as at a global level. This paper estimates the economic cost of smoking and secondhand smoke (SHS) exposure in the six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates), for which no detailed study exists. We used data from the Global Burden of Diseases Study 2016 and the cost-of-illness approach to estimate direct costs (healthcare expenditures) and indirect costs (productivity losses due to morbidity and mortality). Indirect cost was estimated with and without the inclusion of musculoskeletal disorders, using the human capital approach. Total cost of smoking and SHS was estimated to be purchasing power parity (PPP)$ 34.5 billion in 2016, equivalent to 1.04% of the combined gross domestic product (GDP). SHS accounted for 20.4% of total cost. The highest proportion of indirect cost resulted from smoking in men and middle-aged people. The main causes of morbidity cost from smoking and SHS were chronic respiratory diseases and type 2 diabetes mellitus, respectively. Cardiovascular diseases were the main contributor to mortality cost for both smoking and exposure to SHS. Including musculoskeletal disorders increased total cost to PPP$ 41.3 billion (1.25% of the combined GDP). The economic cost of smoking and SHS in the GCC states is relatively low compared with other high-income countries. Scaling-up implementation of evidence-based policies will prevent the evolution of a tobacco epidemic with its negative consequences for health and public finances.


v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: alteration of AU-rich element-binding proteins.
Sphingosine kinase 1 (SPHK1) is overexpressed in solid tumors and leukemia. However, the mechanism of SPHK1 overexpression by oncogenes has not been defined. We found that v-Src-transformed NIH3T3 cells showed a high SPHK1 mRNA, SPHK1 protein and SPHK enzyme activity. siRNA of SPHK1 inhibited the growth of v-Src-NIH3T3, suggesting the involvement of SPHK1 in v-Src-induced oncogenesis. v-Src-NIH3T3 showed activations of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH(2)-terminal kinase. Their inhibition suppressed SPHK1 expression in v-Src-NIH3T3, whereas their overexpression increased SPHK1 mRNA in NIH3T3. Unexpectedly, the nuclear run-on assay and the promoter analysis using 5'-promoter region of mouse SPHK1 did not show any significant difference between mock- and v-Src-NIH3T3. Furthermore, the half-life of SPHK1 mRNA in mock-NIH3T3 was nearly 15 min, whereas that of v-Src-NIH3T3 was much longer. Examination of two AU-rich region-binding proteins, AUF1 and HuR, that regulate mRNA decay reciprocally, showed decreased total AUF1 protein associated with increased tyrosine-phosphorylated form and increased serine-phosphorylated HuR protein in v-Src-NIH3T3. Modulation of AUF1 and HuR by their overexpression or siRNA revealed that SPHK1 mRNA in v-Src- and mock-NIH3T3 was regulated reciprocally by these factors. Our results showed, for the first time, a novel mechanism of v-Src-induced SPHK1 overexpression.


[Iron-deficient anemia, anemia of chronic disease or mixed anemia: how to determine the diagnosis?].
The diagnosis of pure iron-deficient anemia or anemia of chronic disease is easy. However, in mixed situations, conventional laboratory tests for iron status are influenced by the inflammatory response and their diagnostic accuracy may be undermined. New tests are available but grey zones and diagnostic uncertainties sometimes remain. The objective of this article is to give an overview of the current diagnostic tools for the evaluation of the iron metabolism and to provide a practical diagnostic algorithm for the evaluation of iron-deficient anemia.


Comparison of T2-Weighted Imaging, DWI, and Dynamic Contrast-Enhanced MRI for Calculation of Prostate Cancer Index Lesion Volume: Correlation With Whole-Mount Pathology.
The objective of our study was to investigate the comparative effectiveness of different MRI sequences for the estimation of index lesion volume in patients with prostate cancer (PCa) compared with ground truth volume measured on whole-mount pathology. Patients with PCa underwent multiparametric MRI (mpMRI) on a 3-T MRI scanner before radical prostatectomy. Forty PCa index lesions were identified and outlined on histology by a pathologist. Two radiologists who were informed about the presence of PCa but were not aware of lesion outlines on histology worked in consensus to delineate PCa lesions on T2-weighted imaging, apparent diffusion coefficient (ADC) maps, and early-phase dynamic contrast-enhanced MRI (DCE-MRI). The lesion volumes from different mpMRI sequences and the percentage of volume underestimation compared with pathology were calculated and correlated with volume at pathology. The repeated-measures ANOVA with the posthoc Bonferroni test was performed to evaluate whether the difference between the estimated tumor volumes was statistically significant. The mean PCa lesion volume estimated from pathology, T2-weighted imaging, DWI (ADC maps), and DCE-MRI were 4.61 ± 4.99 (SD) cm3, 2.03 ± 2.96 cm3, 1.81 ± 2.76 cm3, and 3.48 ± 4.06 cm3, respectively. The lesion volumes on T2-weighted images (p = 0.000002), ADC maps (p = 0.000003), and DCE-MR images (p = 0.004412) were significantly lower than those from pathology. PCa lesion volume was significantly underestimated on T2-weighted images, ADC maps, and DCE-MR images compared with pathology by 54.98% ± 22.60% (mean ± SD), 58.59% ± 18.58%, and 18.33% ± 30.11%, respectively; underestimation using T2-weighted imaging (p = 1.01 × 10-11) and DWI (p = 2.94 × 10-11) was significantly higher than underestimation using DCE-MRI. Correlations between lesion volume estimated on T2-weighted images, ADC maps, and DCE-MR images with pathology were 0.91 (p = 9.03 × 10-16), 0.86 (p = 7.32 × 10-13), and 0.93 (p = 8.22 × 10-18), respectively. DCE-MRI performed better than T2-weighted imaging and DWI for estimation of index PCa volume and therefore can be preferred over these other two sequences for volume estimation.


Tinea capitis in adults in southern Taiwan.
We report the clinicomycologic study of 27 culture-proven cases of tinea capitis from southern Taiwan during the years 1988 to 1990. The series is notable for its predominance of adults (63%), of women (89%), and of Trichophyton violaceum infection (74%). The age distribution was clearly bimodal; the median age was 6 years for children and 56 years for adults (older than 18 years). Whether or not these findings represent a new trend of tinea capitis in southern Taiwan remains to be determined. Clinically, our cases of black-dot ringworm caused by T. violaceum often presented with subtle changes of scaling, hair loss, and black dots. The keys to the correct diagnosis are (1) a high clinical index of suspicion with careful inspection of the scalp for the presence of black dots, and (2) microscopic examination and culturing of the black dots or plucked hairs.


The burden of osteoporosis in California, 1998.
This study estimates the cost of osteoporosis in California, including health care services and the value of lives lost prematurely to the disease. Costs are estimated for diagnoses of "osteoporosis" and for the proportion of spine, forearm, hip and other fractures that are caused by the disease. The additional costs resulting from a secondary diagnosis of osteoporosis are also included. Osteoporosis accounted for over $2.4 billion in direct health care costs in 1998, and over $4 million in lost productivity resulting from premature death. Most of the cost results from hip fractures and other fractures. In fact, only 15% of costs are for people with a diagnosis of "osteoporosis" per se, and, of this group, most of the costs are associated with a secondary, not a primary diagnosis. The disease is largely a diagnosis of older white women: three-quarters of the hospitalization costs are incurred by women, 80% of those hospitalized are white, and three-quarters are over age 65 years. As would be expected, Medicare pays for most of the hospital care -- almost three-fourths of the total. Nursing home care represents the largest cost for people with osteoporosis, accounting for 59% of the money spent treating the disease.


Adjustment of ocean color sensor calibration through multi-band statistics.
The band-by-band vicarious calibration of on-orbit satellite ocean color instruments, such as SeaWiFS and MODIS, using ground-based measurements has significant residual uncertainties. This paper applies spectral shape and population statistics to tune the calibration of the blue bands against each other to allow examination of the interband calibration and potentially provide an analysis of calibration trends. This adjustment does not require simultaneous matches of ground and satellite observations. The method demonstrates the spectral stability of the SeaWiFS calibration and identifies a drift in the MODIS instrument onboard Aqua that falls within its current calibration uncertainties.


H-2 polymorphisms are more uniformly distributed than allozyme polymorphisms in natural populations of house mice.
Patterns of H-2 and allozyme polymorphism in natural populations of house mice from Europe, North Africa and South America were analyzed. The purpose of the analysis was to determine whether H-2 and allozyme polymorphisms were similarly distributed both geographically and temporally in wild mice. Two subspecies of house mice, Mus musculus domesticus and M. m. musculus were sampled and the polymorphisms of two H-2 class I genes, H-2K and H-2D, and 34 allozyme-encoding genes were surveyed. The three kinds of analyses that were conducted included a hierarchical gene diversity analysis, an analysis of the effects of barriers to gene flow, and an analysis of similarity networks. Each of the comparisons demonstrated that H-2 polymorphisms were more uniformly distributed than allozyme polymorphisms and provided additional evidence that H-2 and allozyme polymorphisms are subject to different evolutionary pressures. The analysis of similarity networks also demonstrated that H-2 genes provide little information about the phylogeny of wild mice.


[Detection and treatment of persons with arterial hypertension].
By screening unogranized and organized male population, groups of individuals with relatively stable arterial pressure were chosen, which accounted for approximately 70% of all those with increased pressure. Three groups were formed among persons with increased arterial pressure; one received intensive hypotensive therapy on a multistage schedule and two were placed under observation, one being examined once in 2 months and the other once in 6 months. Two-year follow-up and treatment showed that long-term hypotensive therapy on a multistage schedule leads to a statisticaly reliable reduction of arterial pressure in individuals with relatively stable and moderate hypertension as compared to the initial level and to the pressure in the control group. In planning hypertension control it should be borne in mind that 1/4 of patients discontinue treatment in the first year.


Northern Hemisphere plant disjunctions: a window on tertiary land bridges and climate change?
This botanical briefing examines how molecular systematics has contributed to progress in understanding the history of Tertiary relict genera, i.e. those that that now occur disjunctly in parts of Eurasia and N America, and how progress in understanding Southern Hemisphere biogeography paradoxically makes unravelling Northern Hemisphere biogeography more complex. Tertiary relict floras comprise genera of warm wet climates that were once circumboreal in distribution but are now confined to E Asia, south-eastern and western N America, and SW Eurasia. The intercontinental disjunctions among these genera have long been believed to result from land connections between Eurasia and N America, across Beringia and the N Atlantic. This view is reassessed in the light of new evidence for long dispersal of propagules across oceans being responsible for many plant disjunctions involving southern continents. The impact of molecular dating, which has been very different in Southern and Northern Hemisphere biogeography, is discussed. For N America-Eurasia disjunctions involving Tertiary relict floras, land connections remain the more likely cause of disjunctions but data from fossils or infraspecific variation will be required to exclude long-dispersal explanations for disjunctions in any individual genus. Molecular dating of divergence between disjunctly distributed Tertiary relict floras can tell us which palaeoclimatic or palaeogeographic events impacted on them, and how, but only if migration over land and vicariance can be proved and molecular dating is sufficiently accurate.


Isolation, Identification and Pharmacological Effects of Mandragora autumnalis Fruit Flavonoids Fraction.
Since ancient times, Mandragora autumnalis has been used as a traditional medicinal plant for the treatment of numerous ailments. In light of this, the current study was designed to isolate and identify the chemical constituents of the flavonoids fraction from M. autumnalis ripe fruit (FFM), and evaluate its DPPH scavenging, anti-lipase, cytotoxicity, antimicrobial and antidiabetic effects. An ethyl acetate extract of M. autumnalis was subjected to a sequence of silica gel column chromatography using different eluents with various polarities. The chemical structures of the isolated compounds were identified using different spectral techniques, including 1H NMR and 13C NMR. FFM's anti-diabetic activity was assessed using a glucose transporter-4 (GLUT4) translocation assay, as well as an inhibition against α-amylase and α-glucosidase using standard biochemical assays. The FFM anti-lipase effect against porcine pancreatic lipase was also evaluated. Moreover, FFM free radical scavenging activity using the DPPH test and antimicrobial properties against eight microbial strains using the micro-dilution method were also assessed. Four flavonoid aglycones were separated from FFM and their chemical structures were identified. The structures of the isolated compounds were established as kaempferol 1, luteolin 2, myricetin 3 and (+)-taxifolin 4, based on NMR spectroscopic analyses. The cytotoxicity test results showed high cell viability (at least 90%) for up to 1 mg/mL concentration of FFM, which is considered to be safe. A dose-dependent increase in GLUT4 translocation was significantly shown (p < 0.05) when the muscle cells were treated with FFM up to 0.5 mg/mL. Moreover, FFM revealed potent α-amylase, α-glucosidase, DPPH scavenging and porcine pancreatic lipase inhibitory activities compared with the positive controls, with IC50 values of 72.44 ± 0.89, 39.81 ± 0.74, 5.37 ± 0.41 and 39.81 ± 1.23 µg/mL, respectively. In addition, FFM inhibited the growth of all of the tested bacterial and fungal strains and showed the greatest antibacterial activity against the K. pneumoniae strain with a MIC value of 0.135 µg/mL. The four flavonoid molecules that constitute the FFM have been shown to have medicinal promise. Further in vivo testing and formulation design are needed to corroborate these findings, which are integral to the pharmaceutical and food supplement industries.


Lymphokine production by cultured human T cells transformed by human T-cell leukemia-lymphoma virus-I.
Cell-free conditioned media from human T cells transformed by human T-cell leukemia-lymphoma virus (HTLV-I) were tested for the production of soluble biologically active factors, including several known lymphokines. The cell lines used were established from patients with T-cell leukemia-lymphoma and from human umbilical cord blood and bone marrow leukocytes transformed by HTLV-I in vitro. All of the cell lines liberated constitutively one or more of the 12 biological activities assayed. These included macrophage migration inhibitory factor (MIF), leukocyte migration inhibitory factor (LIF), leukocyte migration enhancing factor (MEF), macrophage activating factor (MAF), differentiation inducing factor (DIF), colony stimulating factor (CSF), eosinophil growth and maturation activity (eos. GMA), fibroblast activating factor (FAF), gamma-interferon and, in rare instances, T-cell growth factor (TCGF). Some cell lines produced interleukin 3 (IL-3), platelet-derived growth factor (PDGF), or B-cell growth factors (BCGF). Such cells should prove useful for the production of lymphokines and as sources of specific messenger RNA's for their genetic cloning.


A Steric-Repulsion-Driven Clutch Stack of Triaryltriazines: Correlated Molecular Rotations and a Thermoresponsive Gearshift in the Crystalline Solid.
We report that a newly developed type of triaryltriazine rotor, which bears bulky silyl moieties on the para position of its peripheral phenylene groups, forms a columnar stacked clutch structure in the crystalline phase. The phenylene units of the crystalline rotors display two different and interconvertible correlated molecular motions. It is possible to switch between these intermolecular geared rotational motions via a thermally induced crystal-to-crystal phase transition. Variable-temperature solid-state 2H NMR measurements and X-ray diffraction studies revealed that the crystalline rotor is characterized by a vertically stacked columnar structure upon introducing a bulky Si moiety with bent geometry as the stator. The structure exhibits correlated flapping motions via a combination of 85° and ca. 95° rotations between 295 and 348 K, concurrent with a negative entropy change (ΔS‡ = -23 ± 0.3 cal mol-1 K-1). Interestingly, heating the crystal beyond 348 K induces an anisotropic expansion of the column and lowers the steric congestion between the adjacent rotators, thus altering the correlated motions from a flapping motion to a correlated 2-fold 180° rotation with a lower entropic penalty (ΔS‡ = -14 ± 0.5 cal mol-1 K-1). The obtained results of our study suggest that the intermolecular stacking of the C3-symmetric rotator driven by the steric repulsion of the bulky stator represents a promising strategy for producing various correlated molecular motions in the crystalline phase. Moreover, direct and reversible modulation of the intermolecularly correlated rotation is achieved via a thermally induced crystal-to-crystal phase transition, which operates as a gearshift function at the molecular level.


Characterization of Uniformity in Nb/NbxSi1-x/Nb Josephson Junctions.
The uniformity of the barriers in Josephson junctions (JJs) is a critical parameter in determining performance and operating margins for a wide variety of superconducting electronic circuits. We present an automated measurement system capable of measuring individual JJs across a 1 × 1 cm die at both ambient temperature and 4 K. This technique allows visualization of the spatial variation over a large area of the critical electrical properties of the junctions and allows for the direct correlation between room-temperature (RT) resistance and low temperature properties. The critical current variation of NbxSi1-x (x = 15%) barriers is found to be about 2.6% (one standard deviation) for 1024 junctions across an individual die and only weakly correlates with RT resistance measurements.


A randomized controlled trial of distress tolerance treatment for smoking cessation.
We previously developed a distress tolerance (DT)-based treatment that showed promising results for smokers with a history of early lapse. In the current study, we conducted a randomized controlled trial of this DT treatment for a general population of smokers not limited to those with a history of early lapse. We randomized 116 participants (41% female) to DT or standard treatment (ST). Both treatments included 1 individual session during Week 1 followed by 7 group sessions during Weeks 2-9 (quit date at Session 4), two 20-min phone sessions, and 8 weeks of transdermal nicotine patch. Results indicated no significant differences between conditions in the primary outcome of biochemically verified 7-day point prevalence smoking abstinence or in time to 1st lapse. Verified abstinence rates in DT were 38.7%, 38.7%, 46.77%, 40.32%, 20.9%, and 17.7% versus 40.7%, 37.0%, 53.7%, 44.4%, 33.3%, and 22.2% in ST at 1, 2, 4, 8, 13, and 26 weeks postquit, respectively. Additionally, we found no significant moderators of treatment efficacy and few differences in treatment process variables. These findings stand somewhat in contrast to those in our previous study and other recent studies of similar acceptance-based treatments. However, differences in methodology, inclusion of nicotine replacement therapy in both treatment conditions, and strict inclusion-exclusion criteria that excluded many smokers with affective vulnerabilities may underlie this discrepancy. Future research should evaluate the utility of DT and other acceptance-based treatments in populations with affective vulnerabilities who might specifically benefit from a DT-based approach. (PsycINFO Database Record


High throughput trapping and arrangement of biological cells using self-assembled optical tweezer.
Lately, a fiber-based optical tweezer that traps and arranges the micro/nano-particles is crucial in practical applications, because such a device can trap the biological samples and drive them to the designated position in a microfluidic system or vessel without harming them. Here, we report a new type of fiber optical tweezer, which can trap and arrange erythrocytes. It is prepared by coating graphene on the cross section of a microfiber. Our results demonstrate that thermal-gradient-induced natural convection flow and thermophoresis can trap the erythrocytes under low incident power, and the optical scattering force can arrange them precisely under higher incident power. The proposed optical tweezer has high flexibility, easy fabrication, and high integration with lab-on-a-chip, and shows considerable potential for application in various fields, such as biophysics, biochemistry, and life sciences.