Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking.
We have previously reported that platelet-derived growth factor (PDGF) receptor mutants that lack high affinity binding sites for phosphatidylinositol 3-kinase (PI 3-kinase) fail to concentrate in juxtanuclear vesicular structures after activation with PDGF. We have now identified the point in the endocytic pathway at which PI 3-kinase binding sites are required. Receptor internalization from the plasma membrane, measured as the acquisition of acid resistance of prebound 125I-PDGF, was only slightly decreased in cells expressing a PDGF receptor mutant (F5) lacking PI 3-kinase, GTPase-activating protein (GAP), phospholipase C gamma, and Syp binding sites but not expressing mutants where any of these individual sites were restored nor expressing a mutant lacking exclusively PI 3-kinase binding sites. In contrast, the extent of down-regulation of PDGF binding sites from the cell surface after prolonged incubation with PDGF as well as the degradation of [35S]methionine-labeled receptor were markedly reduced in cells expressing the F5 mutant, mutants restored in GAP, phospholipase C gamma, or Syp binding sites or expressing the mutant exclusively lacking PI 3-kinase binding sites but not in cells expressing the mutant where PI 3-kinase binding sites were restored. Inhibition of PI 3-kinase activity with wortmannin caused a dramatic decrease in the rates of down-regulation and degradation of wild-type receptors. These results suggest that PI 3-kinase binding sites are not required for internalization of PDGF receptor but are required to divert the PDGF receptor to a degradative pathway. Furthermore, the requirement for PI 3-kinase binding sites on the receptor appears to be due to a requirement for PI 3-kinase catalytic activity.


Effect of vasodilation by milrinone, a phosphodiesterase III inhibitor, on vasospastic arteries after a subarachnoid hemorrhage in vitro and in vivo: effectiveness of cisternal injection of milrinone.
Cerebral vasospasm remains a major cause of morbidity and mortality. Milrinone, a bipyridine phosphodiesterase III inhibitor, is a potent member of the inodilator class of cardiac agents for vasospasm and is injected intra-arterially or intracisternally. There have been no studies investigating the duration of action (context-sensitive half-life) of milrinone for vasospasm or the most effective route of administration (intra-arterial versus intracisternal). We examined the effects of intracisternal and intra-arterial injection of milrinone on chronic cerebral vasospasm in dogs. A double-hemorrhage canine model was used. In a preliminary isometric tension study of canine vasospastic basilar arteries, the vasodilatory effects of milrinone were examined 7 days after an initial injection of blood. Milrinone was injected intracisternally (0.1 mg, 0.47 mmol/L) or intra-arterially (0.3 mg/kg, 1.2 mmol/L), and angiograms were performed 30, 60, 120, 180, 240, 300, and 360 minutes later on day 7. Milrinone produced concentration-dependent vasodilation and was effective intracisternally, resulting in significant dilation until 180 minutes after injection and a tendency for dilation until 240 minutes. The effect of intra-arterial injection was not as significant compared with an intracisternal injection, resulting in significant dilation only at 180 minutes after intra-arterial injection. Intracisternal injection of milrinone was more effective than intra-arterial injection for chronic cerebral vasospasm in dogs because intracisternal injection produced a higher concentration in vasospastic arteries (0.034-0.068 mmol/L intracisternally versus 0.016 mmol/L intra-arterially).


Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration.
The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15- basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium.


Epidemiology of snakebites in Kuwait.
Fifty-two confirmed cases of snakebites in Kuwait were recorded during 2015-2019. The male:female ratio was almost 2:1 and 84.6% of the victims were between 1 and 20 y of age and 14.4% were >30 y. Snakebites peaked in October (23.1%) and July (17.3%), with the lowest number of recorded cases in March.


Single Cesium Lead Halide Perovskite Nanocrystals at Low Temperature: Fast Single-Photon Emission, Reduced Blinking, and Exciton Fine Structure.
Metal-halide semiconductors with perovskite crystal structure are attractive due to their facile solution processability, and have recently been harnessed very successfully for high-efficiency photovoltaics and bright light sources. Here, we show that at low temperature single colloidal cesium lead halide (CsPbX3, where X = Cl/Br) nanocrystals exhibit stable, narrow-band emission with suppressed blinking and small spectral diffusion. Photon antibunching demonstrates unambiguously nonclassical single-photon emission with radiative decay on the order of 250 ps, representing a significant acceleration compared to other common quantum emitters. High-resolution spectroscopy provides insight into the complex nature of the emission process such as the fine structure and charged exciton dynamics.


Can we use digital life-log images to investigate active and sedentary travel behaviour? Results from a pilot study.
Active travel such as walking and cycling has potential to increase physical activity levels in sedentary individuals. Motorised car travel is a sedentary behaviour that contributes to carbon emissions. There have been recent calls for technology that will improve our ability to measure these travel behaviours, and in particular evaluate modes and volumes of active versus sedentary travel. The purpose of this pilot study is to investigate the potential efficacy of a new electronic measurement device, a wearable digital camera called SenseCam, in travel research. Participants (n = 20) were required to wear the SenseCam device for one full day of travel. The device automatically records approximately 3,600 time-stamped, first-person point-of-view images per day, without any action required by the wearer. Participants also completed a self-report travel diary over the same period for comparison, and were interviewed afterwards to assess user burden and experience. There were a total of 105 confirmed journeys in this pilot. The new SenseCam device recorded more journeys than the travel diary (99 vs. 94). Although the two measures demonstrated an acceptable correlation for journey duration (r = 0.92, p < 0.001) self-reported journey duration was over-reported (mean difference 154 s per journey; 95% CI = 89 to 218 s; 95% limits of agreement = 154 ± 598 s (-444 to 752 s)). The device also provided visual data that was used for directed interviews about sources of error. Direct observation of travel behaviour from time-stamped images shows considerable potential in the field of travel research. Journey duration derived from direct observation of travel behaviour from time-stamped images appears to suggest over-reporting of self-reported journey duration.


Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.
To elucidate the functions of the serine/threonine kinase Akt/PKB in vivo, we generated mice lacking both akt1 and akt2 genes. Akt1/Akt2 double-knockout (DKO) mice exhibit severe growth deficiency and die shortly after birth. These mice display impaired skin development because of a proliferation defect, severe skeletal muscle atrophy because of a marked decrease in individual muscle cell size, and impaired bone development. These defects are strikingly similar to the phenotypes of IGF-1 receptor-deficient mice and suggest that Akt may serve as the most critical downstream effector of the IGF-1 receptor during development. In addition, Akt1/Akt2 DKO mice display impeded adipogenesis. Specifically, Akt1 and Akt2 are required for the induced expression of PPARgamma, the master regulator of adipogenesis, establishing a new essential role for Akt in adipocyte differentiation. Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation. These functions of Akt were uncovered despite the observed lower level of Akt activity mediated by Akt3 in Akt1/Akt2 DKO cells, suggesting that a critical threshold level of Akt activity is required to maintain normal cell proliferation, growth, and differentiation.


Solitary extramedullary plasmacytoma of the bladder: a case report and literature.
Plasmacytoma is a rare B-lymphocyte neoplastic disorder that usually presents as the generalized disease multiple myeloma. Less than 5% of the cases present as a solitary mass of monoclonal plasma cells in the bone or soft tissue. Although solitary extramedullary plasmacytoma (SEP) may arise in any organ, it rarely involves the urinary bladder. A 67-year-old male without a history of multiple myeloma presented with urinary frequency and nocturia; he was later diagnosed with SEP of the bladder. The patient was initially treated with a course of radiation therapy without symptomatic improvement; therefore a chemotherapy regimen consisting of lenalidomide and dexamethasone was subsequently given for six cycles. SEP usually carries a better prognosis and higher cure rate than solitary plasmacytoma of bone, as SEP is radiation sensitive. The role of adjuvant chemotherapy in the treatment of SEP that is resistant to radiation therapy is not clear, since most of the recommendations have been derived from the experience of head and neck SEP. The literature also lacks recommendations for choice of a chemotherapy regimen and surveillance of isolated bladder plasmacytoma. Here we present the first case of a radiation-resistant solitary plasmacytoma of the bladder that was successfully treated with lenalidomide and dexamethasone with successful clinical remission.


Structural basis of adhesive binding by desmocollins and desmogleins.
Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.


Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health.
Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15-60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30-45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity.


Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity.
Neuroligins are postsynaptic cell adhesion proteins that bind specifically to presynaptic membrane proteins called neurexins. Mutations in human neuroligin genes are associated with autism spectrum disorders in some families. The nematode Caenorhabditis elegans has a single neuroligin gene (nlg-1), and approximately a sixth of C. elegans neurons, including some sensory neurons, interneurons and a subset of cholinergic motor neurons, express a neuroligin transcriptional reporter. Neuroligin-deficient mutants of C. elegans are viable, and they do not appear deficient in any major motor functions. However, neuroligin mutants are defective in a subset of sensory behaviors and sensory processing, and are hypersensitive to oxidative stress and mercury compounds; the behavioral deficits are strikingly similar to traits frequently associated with autism spectrum disorders. Our results suggest a possible link between genetic defects in synapse formation or function, and sensitivity to environmental factors in the development of autism spectrum disorders.


HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term.
HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4(+) T cells were characterized by a higher frequency of gamma interferon (IFN-γ) production, perforin(+)/CD107a(+) expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer-positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-γ-producing CD4(+) T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-γ production, supporting the notion of a persistent immune dysfunction in HIV-specific CD4(+) T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions.


Hydrogen encapsulation in a silicon clathrate type I structure: Na5.5(H2)2.15Si46: synthesis and characterization.
A hydrogen-encapsulated inorganic clathrate, which is stable at ambient temperature and pressure, has been prepared in high yield. Na5.5(H2)2.15Si46 is a sodium-deficient, hydrogen-encapsulated, type I silicon clathrate. It was prepared by the reaction between NaSi and NH4Br under dynamic vacuum at 300 degrees C. The Rietveld refinement of the powder X-ray diffraction data is consistent with the clathrate type I structure. The type I clathrate structure has two types of cages where the guest species, in this case Na and H2, can reside: a large cage composed of 24 Si, in which the guest resides in the 6d crystallographic position, and a smaller one composed of 20 Si, in which the guest occupies the 2a position. Solid-state 23Na, 1H, and 29Si MAS NMR confirmed the presence of both sodium and hydrogen in the clathrate cages. 23Na NMR shows that sodium completely fills the small cage and is deficient in the larger cage. The 1H NMR spectrum shows a pattern consistent with mobile hydrogen in the large cage. 29Si NMR spectrum is consistent with phase pure type I clathrate framework. Elemental analysis is consistent with the stoichiometry Na5.5(H2.15)2Si46. The sodium occupancy was also examined using spherical aberration (Cs) corrected scanning transmission electron microscopy (STEM). The high-angle annular dark-field (HAADF) STEM experimental and simulated images indicated that the Na occupancy of the large cage, 6d sites, is less than 2/3, consistent with the NMR and elemental analysis.


Sedentary and active: self-reported sitting time among marathon and half-marathon participants.
Emerging evidence suggests that combined physical activity (PA) and inactivity may be more important for chronic disease risk than PA alone. A highly active yet highly sedentary population is needed to study this interaction. The present purpose is to describe the sitting habits of a group of recreational runners and determine if sitting varies with reported training duration or anticipated running velocity. Marathon and half-marathon participants completed the Multicontext Sitting Time Questionnaire and reported peak training duration, anticipated finishing time, and demographic information. Sitting time was described across 5 contexts for workdays and nonworkdays. Total sitting time was analyzed by tertiles of training duration and anticipated event running velocity. 218 participants took part in this study. Median reported training time was 6.5 hours per week. Median total sitting time was higher on workdays than nonworkdays (645 and 480 minutes, respectively, P < .0001). Total sitting time was not associated with training duration or anticipated event running velocity. These results suggest that recreational distance runners are simultaneously highly sedentary and highly active, supporting independence of sedentary behaviors and moderate- to vigorous-intensity PA. This population may provide the characteristics needed to study the joint effects of active and sedentary behaviors on health outcomes.


Cancer mortality by country of birth, sex, and socioeconomic position in Sweden, 1961-2009.
In 2010, cancer deaths accounted for more than 15% of all deaths worldwide, and this fraction is estimated to rise in the coming years. Increased cancer mortality has been observed in immigrant populations, but a comprehensive analysis by country of birth has not been conducted. We followed all individuals living in Sweden between 1961 and 2009 (7,109,327 men and 6,958,714 women), and calculated crude cancer mortality rates and age-standardized rates (ASRs) using the world population for standardization. We observed a downward trend in all-site ASRs over the past two decades in men regardless of country of birth but no such trend was found in women. All-site cancer mortality increased with decreasing levels of education regardless of sex and country of birth (p for trend <0.001). We also compared cancer mortality rates among foreign-born (13.9%) and Sweden-born (86.1%) individuals and determined the effect of education level and sex estimated by mortality rate ratios (MRRs) using multivariable Poisson regression. All-site cancer mortality was slightly higher among foreign-born than Sweden-born men (MRR = 1.05, 95% confidence interval 1.04-1.07), but similar mortality risks was found among foreign-born and Sweden-born women. Men born in Angola, Laos, and Cambodia had the highest cancer mortality risk. Women born in all countries except Iceland, Denmark, and Mexico had a similar or smaller risk than women born in Sweden. Cancer-specific mortality analysis showed an increased risk for cervical and lung cancer in both sexes but a decreased risk for colon, breast, and prostate cancer mortality among foreign-born compared with Sweden-born individuals. Further studies are required to fully understand the causes of the observed inequalities in mortality across levels of education and countries of birth.


High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.
In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.


Oral glucose tolerance test significantly impacts the prevalence of abnormal glucose tolerance among Indian women with polycystic ovary syndrome: lessons from a large database of two tertiary care centers on the Indian subcontinent.
To estimate the prevalence of abnormal glucose tolerance (AGT) among Indian women with polycystic ovary syndrome (PCOS) and analyze the role of oral glucose tolerance (OGTT) test on its estimation. Cross-sectional clinical study. Tertiary care center. A total of 2,014 women with PCOS diagnosed on the basis of the Rotterdam 2003 criteria were enrolled, and the data of 1,746 subjects were analyzed. In addition to recording clinical, biochemical, and hormone parameters, a 75 g OGTT was administered. Prevalence of AGT and impact of age, body mass index (BMI), family history, and OGTT on its prevalence. The mean age of subjects was 23.8 ± 5.3 years, with a mean BMI of 24.9 ± 4.4 kg/m(2). The overall prevalence of AGT was 36.3% (6.3% diabetes and 30% impaired fasting plasma glucose/impaired glucose tolerance) using American Diabetes Association criteria. The glucose intolerance showed a rising trend with advancing age (30.3%, 35.4%, 51%, and 58.8% in the second, third, fourth, and fifth decades, respectively) and increasing BMI. Family history of diabetes mellitus was present in 54.6% (953/1,746) subjects, and it did not correlate with any of the studied parameters except waist circumference and BMI. Sensitivity was better with 2-hour post-OGTT glucose values as compared with fasting plasma glucose, since using fasting plasma glucose alone would have missed the diagnosis in 107 (6.1%) subjects. We conclude that AGT is high among young Indian women with PCOS and that it is not predicted by family history of type 2 DM. OGTT significantly improves the detection rate of AGT among Indian women with PCOS.


The collaborative search by tag-based user profile in social media.
Recently, we have witnessed the popularity and proliferation of social media applications (e.g., Delicious, Flickr, and YouTube) in the web 2.0 era. The rapid growth of user-generated data results in the problem of information overload to users. Facing such a tremendous volume of data, it is a big challenge to assist the users to find their desired data. To attack this critical problem, we propose the collaborative search approach in this paper. The core idea is that similar users may have common interests so as to help users to find their demanded data. Similar research has been conducted on the user log analysis in web search. However, the rapid growth and change of user-generated data in social media require us to discover a brand-new approach to address the unsolved issues (e.g., how to profile users, how to measure the similar users, and how to depict user-generated resources) rather than adopting existing method from web search. Therefore, we investigate various metrics to identify the similar users (user community). Moreover, we conduct the experiment on two real-life data sets by comparing the Collaborative method with the latest baselines. The empirical results show the effectiveness of the proposed approach and validate our observations.


Analysis of the RNA of Potato yellow vein virus: evidence for a tripartite genome and conserved 3'-terminal structures among members of the genus Crinivirus.
Double-stranded RNA preparations produced from potato plants graft-inoculated with a Peruvian isolate of Potato yellow vein virus (PYVV; genus Crinivirus, family Closteroviridae) contain five RNA species denoted RNA 1, RNA 2, RNA 3, x and y of approximately 8, 5.3, 3.8, 2.0 and 1.8 kbp, respectively. The complete nucleotide sequences of PYVV RNAs 1, 2 and 3 and Northern hybridization analysis showed that PYVV RNA 1 contained the replication module and an additional open reading frame (p7), while two distinct species, RNAs 2 and 3, contain the Closteroviridae hallmark gene array. Pairwise comparisons and phylogeny of genome-encoded proteins showed that PYVV shares significant homology with other criniviruses but is most closely related to the Trialeurodes vaporariorum-vectored Cucumber yellows virus. Secondary structure prediction of the 3'-untranslated regions of all three PYVV RNAs revealed four conserved stem-loop structures and a 3'-terminal pseudoknot structure, also predicted for all fully characterized members of the genus Crinivirus and some members of the genera Closterovirus and Ampelovirus.


Odor sensitivity impairment: a behavioral marker of psychological distress?
Enhanced odor sensitivity, particularly toward threat-related cues, may be adaptive during periods of danger. Research also suggests that chronic psychological distress may lead to functional changes in the olfactory system that cause heightened sensitivity to odors. Yet, the association between self-reported odor sensitivity, objective odor detection, and affective psychopathology is currently unclear, and research suggests that persons with affective problems may only be sensitive to specific, threat-related odors. The current study compared adults with self-reported odor sensitivity that was described as functionally impairing (OSI; n = 32) to those who reported odor sensitivity that was non-impairing (OS; n = 17) on affective variables as well as quantitative odor detection. Increased anxiety sensitivity, trait anxiety, depression, and life stress, even while controlling for comorbid anxiety and depressive disorders, was found for OSI compared to OS. While OSI, compared to OS, demonstrated only a trend increase in objective odor detection of a smoke-like, but not rose-like, odor, further analysis revealed that increased detection of that smoke-like odor was positively correlated with anxiety sensitivity. These findings suggest that persons with various forms of psychological distress may find themselves significantly impaired by an intolerance of odors, but that self-reported odor sensitivity does not necessarily relate to enhanced odor detection ability. However, increased sensitivity to a smoke-like odor appears to be associated with sensitivity to aversive anxiogenic stimuli. Implications for the pathophysiology of fear- and anxiety-related disorders are discussed.


Organic molecules in the Sheepbed Mudstone, Gale Crater, Mars.
The Sample Analysis at Mars (SAM) instrument on board the Mars Science Laboratory Curiosity rover is designed to conduct inorganic and organic chemical analyses of the atmosphere and the surface regolith and rocks to help evaluate the past and present habitability potential of Mars at Gale Crater. Central to this task is the development of an inventory of any organic molecules present to elucidate processes associated with their origin, diagenesis, concentration, and long-term preservation. This will guide the future search for biosignatures. Here we report the definitive identification of chlorobenzene (150-300 parts per billion by weight (ppbw)) and C2 to C4 dichloroalkanes (up to 70 ppbw) with the SAM gas chromatograph mass spectrometer (GCMS) and detection of chlorobenzene in the direct evolved gas analysis (EGA) mode, in multiple portions of the fines from the Cumberland drill hole in the Sheepbed mudstone at Yellowknife Bay. When combined with GCMS and EGA data from multiple scooped and drilled samples, blank runs, and supporting laboratory analog studies, the elevated levels of chlorobenzene and the dichloroalkanes cannot be solely explained by instrument background sources known to be present in SAM. We conclude that these chlorinated hydrocarbons are the reaction products of Martian chlorine and organic carbon derived from Martian sources (e.g., igneous, hydrothermal, atmospheric, or biological) or exogenous sources such as meteorites, comets, or interplanetary dust particles. First in situ evidence of nonterrestrial organics in Martian surface sediments Chlorinated hydrocarbons identified in the Sheepbed mudstone by SAM Organics preserved in sample exposed to ionizing radiation and oxidative condition.


Relationship between dietary patterns and COPD: a systematic review and meta-analysis.
Findings from previous studies reporting on the associations between chronic obstructive pulmonary disease (COPD) and various dietary patterns have been inconsistent. This review aims to summarise the evidence on the strength of the association between dietary patterns and the prevalence and incidence of COPD. We conducted a comprehensive search of seven databases between 1 January 1980 and 30 November 2019. Two reviewers independently reviewed each manuscript through the screening, selection, data extraction and quality assessment stages. Data from eight observational studies that met the inclusion criteria were extracted and random-effects meta-analysis was subsequently conducted. Eight observational studies (all eight reporting on healthy dietary patterns and three on unhealthy dietary patterns) met the inclusion criteria and data were extracted to include in the meta-analysis. Consumption of a healthy dietary pattern was associated with a lower risk of COPD (pooled OR 0.88, 95% CI 0.82-0.94). Consumption of unhealthy dietary patterns was associated with a higher risk of COPD (OR 1.22, 95% CI 0.84-1.76); however, the results were not statistically significant and had high heterogeneity (I2=91%). Our results suggests that healthy dietary patterns are associated with a lower prevalence of COPD, while unhealthy dietary patterns are not. More studies, particularly adequately powered longitudinal studies, are needed to further elucidate the effects of healthy and unhealthy dietary patterns on risk of COPD.


Theoretical investigation on guiding IR light in hollow-core metallic fiber with corrugated inner surface.
Hollow metallic fibers (HMFs) are in general lossy primarily owing to the fact that the guided transverse-magnetic (TM) light sustains a relatively high propagation loss. In this paper, we propose a type of practical hollow-core metallic fiber (HMF) with longitudinally corrugated inner surface for transmitting infrared (IR) light. Simulation results show that the loss of the fundamental TM mode can be easily reduced by 50~100 times compared to a HMF without surface corrugation. In contrast to the traditional HMF with a dielectric coating, it is shown that the loss of the fundamental TM mode in the proposed HMF is relatively insensitive to the corrugation layer thickness or equivalently the operating frequency.


Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial.
To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed by a booster dose at age 12 months. Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 SETTING: Four centres in the United Kingdom and one centre in Malta. Healthy infants aged 6-12 weeks followed up until age 24 months. In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months. MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >-0.35. The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥ 1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age. MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib-MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children.Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov).


Induction of Mycobacterium Tuberculosis Lipid-Specific T Cell Responses by Pulmonary Delivery of Mycolic Acid-Loaded Polymeric Micellar Nanocarriers.
Mycolic acid (MA), a major lipid component of Mycobacterium tuberculosis (Mtb) cell wall, can be presented by the non-polymorphic antigen presenting molecule CD1b to T cells isolated from Mtb-infected individuals. These MA-specific CD1b-restricted T cells are cytotoxic, produce Th1 cytokines, and form memory populations, suggesting that MA can be explored as a potential subunit vaccine candidate for TB. However, the controlled elicitation of MA-specific T cell responses has been challenging due to difficulties in the targeted delivery of lipid antigens and a lack of suitable animal models. In this study, we generated MA-loaded micellar nanocarriers (MA-Mc) comprised of self-assembled poly(ethylene glycol)-bl-poly(propylene sulfide; PEG-PPS) copolymers conjugated to an acid sensitive fluorophore to enhance intracellular delivery of MA to phagocytic immune cells. Using humanized CD1 transgenic (hCD1Tg) mice, we found these nanobiomaterials to be endocytosed by bone marrow-derived dendritic cells (DCs) and localized to lysosomal compartments. Additionally, MA-Mc demonstrated superior efficacy over free MA in activating MA-specific TCR transgenic (DN1) T cells in vitro. Following intranasal immunization, MA-Mc were primarily taken up by alveolar macrophages and DCs in the lung and induced activation and proliferation of adoptively transferred DN1 T cells. Furthermore, intranasal immunization with MA-Mc induced MA-specific T cell responses in the lungs of hCD1Tg mice. Collectively, our data demonstrates that pulmonary delivery of MA via PEG-PPS micelles to DCs can elicit potent CD1b-restricted T cell responses both in vitro and in vivo and MA-Mc could be explored as subunit vaccines against Mtb infection.


Bacterial diversity in a deep-subsurface clay environment.
The presence of bacteria in a deep clay sediment was analyzed in a 20-m-long core horizontally drilled from a mine gallery at a depth of 224 m in the Boom clay formation (Mol, Belgium). This clay deposit is the result of a marine sedimentary process that occurred 35 million years ago. Bacterial activities were estimated by measuring respiration on [14C]glucose. Using the same samples, universal primers for the genes coding for eubacterial 16S rRNA were used to amplify extracted DNA. PCR products were then cloned, sequenced, and analyzed by molecular phylogeny. Our data showed a decrease in bacterial densities as a function of distance from the gallery, with few bacteria detectable by culture at more than 80 cm from the gallery wall. PCR experiments showed the presence of bacteria in all samples, and phylogenetic analyses were then used to tentatively identify these organisms. Because of low bacterial densities in deep clay samples, direct counts and enumeration of viable bacteria on diverse culture media remained negative. All experiments, both cultures and PCR, demonstrated the difficulty of analyzing samples that contain only a few poorly active bacteria as it is difficult to avoid a small contamination by active bacteria during sampling. Since the porosity of the Boom clay formation is less than the expected size of bacteria, it is possible that some of the bacteria present in this 35-million-year-old deep clay deposit derive from cells initially trapped during the sedimentation process.


Family support as a mediator of change in sexual risk-taking attitudes among orphaned adolescents in rural Uganda.
Prior studies demonstrated the effect of family-based economic empowerment intervention Suubi on reducing attitudes approving sexual risk-taking behavior among orphaned adolescents in Uganda. To understand mechanisms of change, the article examines the effect of Suubi intervention on family support variables and their role in mediating the change in adolescents' attitudes toward sexual risk-taking. The Suubi study used a cluster-randomized experimental design with three waves, and included 283 orphaned adolescents from 15 primary schools in Rakai, Uganda. First, using mixed-effects models, the study tested for the effect of intervention on family support variables. Second, using mediation analysis, the study examined whether the change in sexual risk-taking attitudes was mediated by the change in family support. Compared with adolescents from the control group, at wave 2, adolescents in the treatment group reported higher levels of perceived support from caregivers, were more willing to talk to caregivers about their problems, and felt more comfortable talking about sexual risk behaviors with their caregivers. Mediation analysis demonstrated that the improvement in perceived support from caregivers at wave 2 accounted for 16.8% of the reduction in adolescents' attitudes toward sexual risk-taking behavior at wave 3 (z = -2.21, p < .05). A family-based economic empowerment intervention Suubi may have the potential to increase family support to orphaned adolescents. Interventions aimed at strengthening existing social networks and improving connectedness with surviving family members may be critical in preventing sexual risk-taking behavior among orphaned adolescents in Uganda, which is characterized by low resources.


Multi-targeted tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: an era of individualized therapy.
Multi-targeted tyrosine kinase inhibitors (TKIs) have played an increasingly important role in the treatment of non-small cell lung cancer (NSCLC). Many recently published phase III trials have shown bittersweet efficacies of these drugs. How to optimize the efficacies of TKIs has been a hot topic in the era of individualized therapy. In this article, we review the up-to-dated advances in research on the application of TKIs for NSCLC treatment.


Lineage selection and the evolution of multistage carcinogenesis.
A wide array of proto-oncogenes and tumour suppressor genes are involved in the prevention of cancer. Each form of cancer requires mutations in a characteristic group of genes, but no single group controls all cancers. This lack of generality shows that the control of cancer is not an ancient, fixed property of cells. By contrast, it supports a dynamic evolutionary model, whereby genetic controls over unregulated cell growth are recruited independently through evolutionary time in different tissues within different taxa. The complexity of this genetic control can be predicted from a population genetic model of lineage selection driven by the detrimental fitness effects of cancer. Cancer occurs because the genetic control of cell growth is vulnerable to somatic mutations (or 'hits'), particularly in large, continuously dividing tissues. Thus, compared to small rodents, humans must have evolved more complex genetic controls over cell growth in at least some of their tissues because of their greater size and longevity; an expectation relevant to the application of mouse data to humans. Similarly, the 'two-hit' model so successfully applied to retinoblastoma, which originates in a small embryonic tissue, is unlikely to be generally applicable to other human cancers; instead, more complex scenarios are expected to dominate, with complexity depending upon a tissue's size and its pattern of proliferation.


The current landscape of European registries for rare endocrine conditions.
Objective To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions. Methods Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. Results Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. Conclusion Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.


An evaluation of GO annotation retrieval for BioCreAtIvE and GOA.
The Gene Ontology Annotation (GOA) database http://www.ebi.ac.uk/GOA aims to provide high-quality supplementary GO annotation to proteins in the UniProt Knowledgebase. Like many other biological databases, GOA gathers much of its content from the careful manual curation of literature. However, as both the volume of literature and of proteins requiring characterization increases, the manual processing capability can become overloaded. Consequently, semi-automated aids are often employed to expedite the curation process. Traditionally, electronic techniques in GOA depend largely on exploiting the knowledge in existing resources such as InterPro. However, in recent years, text mining has been hailed as a potentially useful tool to aid the curation process. To encourage the development of such tools, the GOA team at EBI agreed to take part in the functional annotation task of the BioCreAtIvE (Critical Assessment of Information Extraction systems in Biology) challenge. BioCreAtIvE task 2 was an experiment to test if automatically derived classification using information retrieval and extraction could assist expert biologists in the annotation of the GO vocabulary to the proteins in the UniProt Knowledgebase. GOA provided the training corpus of over 9000 manual GO annotations extracted from the literature. For the test set, we provided a corpus of 200 new Journal of Biological Chemistry articles used to annotate 286 human proteins with GO terms. A team of experts manually evaluated the results of 9 participating groups, each of which provided highlighted sentences to support their GO and protein annotation predictions. Here, we give a biological perspective on the evaluation, explain how we annotate GO using literature and offer some suggestions to improve the precision of future text-retrieval and extraction techniques. Finally, we provide the results of the first inter-annotator agreement study for manual GO curation, as well as an assessment of our current electronic GO annotation strategies. The GOA database currently extracts GO annotation from the literature with 91 to 100% precision, and at least 72% recall. This creates a particularly high threshold for text mining systems which in BioCreAtIvE task 2 (GO annotation extraction and retrieval) initial results precisely predicted GO terms only 10 to 20% of the time. Improvements in the performance and accuracy of text mining for GO terms should be expected in the next BioCreAtIvE challenge. In the meantime the manual and electronic GO annotation strategies already employed by GOA will provide high quality annotations.


Computer aided tool for diagnosis of ENT pathologies using digital signal processing of speech and stroboscopic images.
The development of computer software and other technologies greatly facilitates the evaluation of pathological voice patients. This fact allows to reduce exploration time, improves the reproducibility of results and creates the possibility of test protocol standardization needed for the intercommunication between the different voice specialists. The proposed application encompasses the most important aspects which should be taken into account regarding dysphonic patients. It is a multidimensional scope which involves subjective questionnaires and perceptual, aerodynamic, acoustic and stroboscopic evaluations. In this system, the authors have designed and created simple tools for recording and automatic acoustic analysis for the acquisition and edition of stroboscopic images. The purpose is to work with all necessary tools running on a single application, without having to export and import data from other computer programs. Therefore, the objective is to synthetize the basic voice and the exploration of the vocal folds, simplifying it through the design of a program which helps us to analyze step-by-step each aspect of the vocal pathology. The evaluation of the tool has been performed by the otolaryngologists through periodical (medical) appointments on 25 patients for one year a year, and the results are promising either for the professionals as well as for the patients which receive a detailed report with the objective information concerning the features of their voice and vocal cords.


Neural Responsiveness to Reward as an Index of Depressive Symptom Change Following Cognitive-Behavioral Therapy and SSRI Treatment.
Reward positivity (RewP), a neurophysiologic index of reward responsivity, is consistently reduced in participants with depression and, to a lesser extent, anxiety. It remains unknown, however, whether RewP can be altered as psychiatric symptoms change with treatment. The current study addressed this question by examining differences in RewP within patients before and after 12 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral therapy (CBT). We also examined the utility of RewP as a predictor of symptom change during CBT and SSRI treatment. Participants were recruited between 2014 and 2017 and included adults with a primary DSM-5 anxiety or depressive disorder (n = 63) and healthy controls (n = 25). At baseline and 12 weeks, participants completed a monetary award task while electroencephalogram (EEG) was recorded. Between EEG sessions, patients completed CBT or SSRI treatment. At baseline, higher levels of depressive symptoms were associated with a more attenuated RewP. We found no significant differences between patients and healthy controls in the degree of RewP change across the 12 weeks; however, among patients, the extent of increase in RewP robustly correlated with the extent of decline in depressive (t = -2.21, P = .03) and anxiety (t = -2.57, P = .02) symptoms following CBT and SSRI treatment. Additionally, a more attenuated RewP at baseline predicted a greater reduction in depressive symptoms following treatment with SSRIs (t = -2.04, P < .05), but not after CBT. These findings highlight neural responsiveness to reward as both a mechanism and a predictor of depressive symptom change that may be used serve as an objective index of symptom improvement. ClinicalTrials.gov identifier: NCT01903447.


Trapping single molecules by dielectrophoresis.
We have trapped single protein molecules of R-phycoerythrin in an aqueous solution by an alternating electric field. A radio frequency voltage is applied to sharp nanoelectrodes and hence produces a strong electric field gradient. The resulting dielectrophoretic forces attract freely diffusing protein molecules. Trapping takes place at the electrode tips. Switching off the field immediately releases the molecules. The electric field distribution is computed, and from this the dielectrophoretic response of the molecules is calculated using a standard polarization model. The resulting forces are compared to the impact of Brownian motion. Finally, we discuss the experimental observations on the basis of the model calculations.


Conjugated equine estrogen and risk of benign proliferative breast disease: a randomized controlled trial.
Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease, a condition that is associated with increased risk of breast cancer. We tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI CEE trial, 10,739 postmenopausal women were randomly assigned to 0.625 mg/d of CEE or to placebo. Baseline and annual breast examinations and mammograms were required. We identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated histological sections, and subjected them to standardized central review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. A total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease (HR = 2.11, 95% CI = 1.58 to 2.81). For benign proliferative breast disease without atypia, the HR was 2.34 (95% CI = 1.71 to 3.20), whereas for atypical hyperplasia, it was 1.12 (95% CI = 0.53 to 2.40). Risk varied little by levels of baseline characteristics. Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.


Antiviral flavonoids from Mosla scabra.
An ethanolic extract and ethyl acetate fraction (EFMS) prepared from Mosla scabra showed potential inhibition against influenza viruses. The compounds isolated from EFMS were elucidated to be ursolic acid (1), 5-hydroxy-6,7-dimethoxyflavone (2), 5-hydroxy-7,8-dimethoxyflavone (3), apigenin (4) and acacetin (5) based on their spectral analysis. Compounds 2, 3, 4 and 5 showed significant anti-influenza viruses activities. Compared with ribavirin, EFMS appeared to have similar efficacy against influenza viruses, was considered to be less toxic and may warrant further evaluation as a possible agent for the treatment of influenza.


Analgesic activity of Ugni molinae (murtilla) in mice models of acute pain.
Leaf extracts of Ugni molinae Turcz. (Myrtaceae) are used in Chilean folk medicine as analgesic and anti-inflammatory. The antinociceptive effect of dichloromethane (DCM), ethyl acetate (EA) and methanol (ME) leaf extracts was assessed by intraperitoneal, oral and topical administration in writhing, tail flick, and tail formalin tests in mice. The extracts showed a dose-dependent antinociceptive activity in all the assays under different administration routes. The ED(50) values for the different tests for the DCM, EA, ME extract and reference drug (ibuprofen) were as follows. Writhing test in acetic acid (i.p. administration): 0.21, 0.37, 1.37 and 0.85mg/kg, respectively; tail flick test (oral administration): 199, 189, 120 and 45.9mg/kg. The EC(50) values for tail flick test were (topical administration): 2.0, 0.35, 1.4 and 8.2% (w/v), respectively; and the topical analgesic effects were (formalin assay) 75.5, 77.5, 31.6 and 76.5%, respectively. Ugni molinae extracts produce antinociception in chemical and thermal pain models through a mechanism partially linked to either lipooxygenase and/or cyclooxygenase via the arachidonic acid cascade and/or opioid receptors. Flavonoid glycosides and triterpenoids have been isolated from the plant and can be associated with the observed effect. Our results corroborate the analgesic effects of Ugni molinae, and justify its traditional use for treating pain.


Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer.
Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.


The size and shape of the optic disc in normal human eyes.
We studied the size, shape, and configuration of connective tissue of the optic disc in normal eye-bank eyes from 60 adults. The mean vertical and horizontal disc diameters were 1.88 and 1.77 mm, respectively. These figures are larger than most estimates of disc diameter using clinical image analysis methods. Within our sample, larger eyes did not have larger discs. The normal variation in disc diameter is sufficient to explain the normal variation in cup-disc ratio. The optic discs of blacks were larger and more oval than those of whites, though the axial lengths of the eyes in the two groups were not significantly different. Women's eyes and discs were smaller than those of men, possibly explaining the smaller cup-disc ratio in women. Larger optic discs and optic nerves have more optic nerve fibers than do smaller discs and nerves. Oblique insertions of the disc were detected in 18% of eyes. These were predominantly centered in the inferior disc and were more commin in white women.


Acute stent recoil and optimal balloon inflation strategy: an experimental study using real-time optical coherence tomography.
Our aim was to evaluate stent expansion and acute recoil at deployment and post-dilatation, and the impact of post-dilatation strategies on final stent dimensions. Optical coherence tomography (OCT) was performed on eight bare metal platforms of drug-eluting stents (3.0 mm diameter, n=6 for each) during and after balloon inflation in a silicone mock vessel. After nominal-pressure deployment, a single long (30 sec) vs. multiple short (10 sec x3) post-dilatations were performed using a non-compliant balloon (3.25 mm, 20 atm). Stent areas during deployment with original delivery systems were smaller in stainless steel stents than in cobalt-chromium and platinum-chromium stents (p<0.001), whereas subsequent acute recoil was comparable among the three materials. At post-dilatation, acute recoil was greater in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001), resulting in smaller final stent areas in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001). In comparison between conventional and latest-generation cobalt-chromium stents, stent areas were not significantly different after both deployment and post-dilatation. With multiple short post-dilatations, acute recoil was significantly improved from first to third short inflation (p<0.001), achieving larger final area than a single long inflation, despite stent materials/designs (p<0.001). Real-time OCT revealed significant acute recoil in all stent types. Both stent materials/designs and post-dilatation strategies showed a significant impact on final stent expansion.


The incidence and risk factors of associated acute myocardial infarction (AMI) in acute cerebral ischemic (ACI) events in the United States.
To determine the association between myocardial infarction (AMI) and clinical outcome in patients with primary admissions diagnosis of acute cerebral ischemia (ACI) in the US. Data from Nationwide Inpatient Sample (NIS) was queried from 2002-2011 for inpatient admissions of patients with a primary diagnosis of ACI with and without AMI using International Classification of Diseases, Ninth Revision, Clinical Modification coding (ICD-9). A multivariate stepwise regression analysis was performed to assess the correlation between identifiable risk factors and clinical outcomes. During 10 years the NIS recorded 886,094 ACI admissions with 17,526 diagnoses of AMI (1.98%). The overall cumulative mortality of cohort was 5.65%. In-hospital mortality was associated with AMI (aOR 3.68; 95% CI 3.49-3.88, p≤0.0001), rTPA administration (aOR 2.39 CI, 2.11-2.71, p<0.0001), older age (aOR 1.03, 95% CI, 1.03-1.03, P<0.0001) and women (aOR 1.06, 95% CI 1.03-1.08, P<0.0001). Overall, mortality risk declined over the course of study; from 20.46% in 2002 to 11.8% in 2011 (OR 0.96, 95% CI 0.95-0.96, P<0.0001). Survival analysis demonstrated divergence between the AMI and non-AMI sub-groups over the course of study (log-rank p<0.0001). Our study demonstrates that although the prevalence of AMI in patients hospitalized with primary diagnosis of ACI is low, it negatively impacts survival. Considering the high clinical burden of AMI on mortality of ACI patients, a high quality monitoring in the event of cardiac events should be maintained in this patient cohort. Whether prompt diagnosis and treatment of associated cardiovascular diseases may improve outcome, deserves further study.


Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).
Dose responses to two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), in induction of glutathione S-transferase placental form positive liver cell foci (GST-P+ foci) and DNA adduct formation in the liver were examined in male F344 rats. Beginning 2 weeks after a single diethylnitrosamine (DEN) injection (200 mg/kg, i.p.), rats received MeA alpha C or PhIP in the diet at various doses for 6 weeks. All rats were subjected to two-thirds partial hepatectomy (PH) 1 weeks after the test agents were added to the diet and were killed 8 weeks after DEN initiation. MeA alpha C (100, 200, 400 and 800 p.p.m.) significantly increased numbers and areas of GST-P+ foci over control levels in all dose groups with a clear dose-response. In contrast, PhIP (50, 100, 200 and 400 p.p.m.) only equivocally increased foci development in the highest dose group and rather was associated with decrease in the lower dose groups. DNA adduct formation assessed by 32P-postlabeling demonstrated a dose-dependent increase with both chemicals, the levels being much higher with MeA alpha C. Thus, two highly mutagenic heterocyclic amines that are produced in broiled foodstuffs exerted different influence on GST-P+ foci development and DNA adduct formation; these findings are consistent with liver carcinogenicity in rats and/or mice.


Suppression of HIV replication in vitro by CD8+ T-cells from HIV-infected and HIV-seronegative individuals.
The inhibitory effect of CD8+ T-cells from HIV-infected or HIV-seronegative individuals on HIV replication in the naturally-infected CD4+ T-cells in vitro was examined. Not only autologous CD8+ T-cells from HIV-infected individuals but also allogeneic CD8+ T-cells from HIV-seronegative individuals prevented or delayed HIV replication, even in transwell cocultures using a semi-permeable 0.45 micron filter. The level of the inhibitory effect of allogeneic CD8+ T-cells from the HIV-seronegative individuals on the HIV replication was varied among CD4+ T-cells obtained from HIV-infected individuals used. The results suggested that CD8+ T-cells from HIV-seronegative individuals as well as HIV-infected individuals could produce some cytokine(s) which suppress HIV replication in vitro. The sensitivity to the cytokine(s) might be variable among HIV strains, depending on differences in the nucleotide sequence of different HIV-1 strains. Further studies of control of HIV replication by CD8+ anti-HIV cytokine(s) should provide new strategies for the therapy of HIV infection.


Exploring interactions between pathogens and the Drosophila gut.
Gastrointestinal infection can provoke substantial disturbance at both a local as well as at a systemic level and may evolve into a chronic disease state. Our growing knowledge of gut-pathogen interactions has been based to a large extent on the use of genetically tractable model hosts such as the fruit fly Drosophila melanogaster. In this review we will summarise the growing literature and critically address the advantages and disadvantages of using this model to extrapolate results from studying pathogen virulence and intestinal responses to humans.


Effects of immunomanipulations on resistance induced by irradiated Schistosoma mansoni cercarial sensitization of C57BL/6 and CBA/J mice.
Mice sensitized with radiation-attenuated Schistosoma mansoni cercariae were treated by a variety of procedures known to interrupt immunoregulatory circuitries in attempts to alter the resistance induced by irradiated cercarial sensitization. Both highly resistant C57BL/6 and the often poorly resistant CBA/J strains were examined. Immunomanipulations included adult thymectomy, or administration of different drugs in relation to the time of challenge infection (day 0). Adult thymectomy was performed 3 weeks prior to sensitization or 3 weeks prior to challenge. Drug treatment included cyclophosphamide given at a dose of 20 mg/kg on alternate days, day -11 through day +11, cimetidine at 50 mg/kg/day, day -7 through day +21, or indomethacin at 2.5 mg/kg/day, day 0 through day +10. In most experiments, irradiated cercarial sensitized C57BL/6 mice developed significant resistance which was not altered by the immunomanipulative regimens used. If however, as fortuitously occurred in two adult thymectomy experiments, irradiated cercarial sensitization did not induce significant resistance, immunomanipulation by adult thymectomy allowed the development of a significant protected state. Similarly, adult thymectomy or cimetidine treatment in concert with immunization of CBA/J mice conferred moderate, statistically significant levels of stable resistance in this normally "less resistant" strain.


Statement of the Declaration of Istanbul Custodian Group Regarding Payments to Families of Deceased Organ Donors.
Governmental and private programs that pay next of kin who give permission for the removal of their deceased relative's organs for transplantation exist in a number of countries. Such payments, which may be given to the relatives or paid directly for funeral expenses or hospital bills unrelated to being a donor, aim to increase the rate of donation. The Declaration of Istanbul Custodian Group-in alignment with the World Health Organization Guiding Principles and the Council of Europe Convention Against Trafficking in Human Organs-has adopted a new policy statement opposing such practices. Payment programs are unwise because they produce a lower rate of donations than in countries with voluntary, unpaid programs; associate deceased donation with being poor and marginal in society; undermine public trust in the determination of death; and raise doubts about fair allocation of organs. Most important, allowing families to receive money for donation from a deceased person, who is at no risk of harm, will make it impossible to sustain prohibitions on paying living donors, who are at risk. Payment programs are also unethical. Tying coverage for funeral expenses or healthcare costs to a family allowing organs to be procured is exploitative, not "charitable." Using payment to overcome reluctance to donate based on cultural or religious beliefs especially offends principles of liberty and dignity. Finally, while it is appropriate to make donation "financially neutral"-by reimbursing the added medical costs of evaluating and maintaining a patient as a potential donor-such reimbursement may never be conditioned on a family agreeing to donate.


Establishment and characterization of two cell lines from bluefin trevally Caranx melampygus.
Bluefin trevally Caranx melampygus Cuvier is a popular game fish and highly valued sea food with potential importance for aquaculture. To help establish this marine animal as an important aquacultural species in Hawaii and the Pacific and develop in vitro cell culture systems for long-term management and control of potential viral diseases 2 cell lines were established from body muscle (bluefin trevally muscles, BTMS) and fins (bluefin trevally fins, BTF). Primary culture of these cells was conducted at 25 degrees C using L-15 medium supplemented with 20% fetal bovine serum and various antibiotics. These cells have been serially subcultured 37 to 41 times since their initiation in June 2002. Growth of the bluefin trevally cells was serum-dependent at the time of the experiments and their plating efficiencies ranged from 11 to 28.2%. Comparative analysis showed that these bluefin trevally cells grew equally well in the media L-15 (Leibovitz medium), RPMI 1640, M199 and MEM (minimum essential medium), which are commonly used for cell cultures derived from aquatic animals and mammalian species. Examination of the early passage cells stored at -196 degrees C revealed a large percent (nearly 98%) of cell viability following a 6 mo storage in liquid nitrogen. Karyotyping analysis indicated that these bluefin trevally derived cell lines remained diploid with a chromosome count of 48 at passage 7 and 12. These 2 cell lines shared a same pattern of viral susceptibility and they were sensitive to infectious hematopoietic necrosis virus (IHNV), infectious pancreatic necrosis (IPN), spring viremia carp virus (SVCV), viral hemorrhagic septicemia virus (VHSV), and snakehead rhabdovirus (SHRV) but refractory to channel catfish virus (CCV) infection. These newly established cell lines are currently being used to facilitate the diagnosis of viral disease affecting marine fish aquaculture in Hawaii, and will be available for future isolation and study of bluefin trevally fish viruses.


An Appraisal of Narcissistic Rage Through Path Modeling.
Pathological narcissism and borderline traits have been consistently associated with interpersonal aggression. Shame has been identified as an important trigger of aggressive behaviors in individuals with pathological personality traits, especially for narcissistic vulnerability and borderline traits. This is in line with Kohut's theory on narcissistic rage, that is, aggression, anger, and destruction that act as a protection for a grandiose self. The present study aims to investigate the interrelations between pathological narcissism, borderline traits, shame, and trait aggression, concepts that are parts of the narcissistic rage phenomenon introduced by Kohut, using path models. A total of 399 participants completed self-report questionnaires assessing personality traits (narcissistic grandiosity and vulnerability, and borderline traits), shame, and aggression. Three path models including these variables were tested and compared to one another on fit indices. Results show that shame acts as a mediator between pathological traits (narcissistic vulnerability and borderline traits) and trait aggression, whereas the relationship between narcissistic grandiosity and aggression was direct (i.e., shame was not involved). Results expand the narcissistic rage theory by suggesting that it might represent an internalizing type of aggression that manifests in the context of narcissistic vulnerability and borderline traits, which is not the case for narcissistic grandiosity that exerts a direct effect on trait aggression.


Towards high resolution optical imaging of beta cells in vivo.
Endocrine beta cells produce and release insulin in order to tightly regulate glucose homeostasis and prevent metabolic pathologies such as Diabetes Mellitus. Optical imaging has contributed greatly to our current understanding of beta cell structure and function. In vitro microscopy of beta cell lines has revealed the localization of molecular components in the cell and more recently their dynamic behavior. In cultured islets, interactions of beta cells with other islet cells and the matrix as well as paracrine and autocrine signaling or reaction to nutrients have been studied. Lastly, microscopy has been performed on tissue sections, visualizing the islets in an environment closer to their natural surroundings. In most efforts to date, the samples have been isolated for investigation and hence have by definition been divorced from their natural environments and deprived of vascularization and innervations. In such a setting the beta cells lack the metabolic information that is primordial to their basic function of maintaining glucose homeostasis. We review optical microscopy; its general principles, its impact in decoding beta cell function and its recent developments towards the more physiologically relevant assessment of beta cell function within the environment of the whole organism. This requires both large imaging depth and fast acquisition times. Only few methods can achieve an adequate compromise. We present extended focus Optical Coherence Microscopy (xfOCM) as a valuable alternative to both confocal microscopy and two photon microscopy (2PM), and discuss its potential in interpreting the mechanisms underlying glucose homeostasis and monitoring impaired islet function.


Prioritizing patient-centered care implementation and research for patients with kidney disease.
Patient-centered care is upheld as one of the fundamental components of high quality health care. Although a deceptively easy concept, patient-centered care is an elusive goal in clinical practice. A core objective for patient-centered care is a collaboration between health care providers and patients that aligns therapy with patients' values and preferences through shared decision making. Advances in communication training that are tailored to the specific requirements of nephrology care are promising methods for enhancing the skill-set of our providers. However, patient-centered care extends beyond shared decision-making and also involves attention to patients' physical and emotional symptoms, care coordination, and the inclusion of family members. Research about patient-centered care processes, interventions and outcomes among patients with kidney disease is sparse. Recent discussions among nephrology experts name patient-centered care as a priority for research and quality improvement in care. Given recent advances in methods for quantifying patient-centered care as well as patient reported outcomes, now is the time to prioritize our resources to evolve our health system and meet the needs of all patients with kidney disease.


Two proteases defining a melanization cascade in the immune system of Drosophila.
The melanization reaction is used as an immune mechanism in arthropods to encapsulate and kill microbial pathogens. In Drosophila, the serpin Spn27A regulates melanization apparently by inhibiting the protease that activates phenoloxidase, the key enzyme in melanin synthesis. Here, we have described the genetic characterization of two immune inducible serine proteases, MP1 and MP2, which act in a melanization cascade regulated by Spn27A. MP1 is required to activate melanization in response to both bacterial and fungal infection, whereas MP2 is mainly involved during fungal infection. Pathogenic bacteria and fungi may therefore trigger two different melanization cascades that use MP1 as a common downstream protease to activate phenoloxidase. We have also shown that the melanization reaction activated by MP1 and MP2 plays an important role in augmenting the effectiveness of other immune reactions, thereby promoting resistance of Drosophila to microbial infection.


Social positioning by people with Alzheimer's disease in a support group.
People with Alzheimer's disease (AD) are often negatively positioned by others, resulting in difficulties upholding a positive sense of self. This might cause them to withdraw socially and apparently 'lose their minds'. Conversely, the sense of self can be strengthened with the support from others. This study aimed to describe, in accordance with positioning theory, how people with moderate AD positioned themselves and each other in a support group for people with AD. We describe five first-order positions; the project manager, the storyteller, the moral agent, the person burdened with AD, and the coping person. In the interactions that followed among the support group participants, those positions were mainly affirmed. This enabled participants to construct strong and agentic personae, and to have the severity of their illness acknowledged. Despite their language impairment participants managed to position and reposition themselves and others by assistance of the trained facilitator.


Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates.
Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)- and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4(+) and CD8(+) T cells.


The mismeasure of morals: antisocial personality traits predict utilitarian responses to moral dilemmas.
Researchers have recently argued that utilitarianism is the appropriate framework by which to evaluate moral judgment, and that individuals who endorse non-utilitarian solutions to moral dilemmas (involving active vs. passive harm) are committing an error. We report a study in which participants responded to a battery of personality assessments and a set of dilemmas that pit utilitarian and non-utilitarian options against each other. Participants who indicated greater endorsement of utilitarian solutions had higher scores on measures of Psychopathy, machiavellianism, and life meaninglessness. These results question the widely-used methods by which lay moral judgments are evaluated, as these approaches lead to the counterintuitive conclusion that those individuals who are least prone to moral errors also possess a set of psychological characteristics that many would consider prototypically immoral.


Capacity of the golgi apparatus for biogenesis from the endoplasmic reticulum.
It is unclear whether the mammalian Golgi apparatus can form de novo from the ER or whether it requires a preassembled Golgi matrix. As a test, we assayed Golgi reassembly after forced redistribution of Golgi matrix proteins into the ER. Two conditions were used. In one, ER redistribution was achieved using a combination of brefeldin A (BFA) to cause Golgi collapse and H89 to block ER export. Unlike brefeldin A alone, which leaves matrix proteins in relatively large remnant structures outside the ER, the addition of H89 to BFA-treated cells caused ER accumulation of all Golgi markers tested. In the other, clofibrate treatment induced ER redistribution of matrix and nonmatrix proteins. Significantly, Golgi reassembly after either treatment was robust, implying that the Golgi has the capacity to form de novo from the ER. Furthermore, matrix proteins reemerged from the ER with faster ER exit rates. This, together with the sensitivity of BFA remnants to ER export blockade, suggests that presence of matrix proteins in BFA remnants is due to cycling via the ER and preferential ER export rather than their stable assembly in a matrix outside the ER. In summary, the Golgi apparatus appears capable of efficient self-assembly.


Suppressor of cytokine signaling-3 is affected in T-cells from tuberculosisTB patients.
T-cells and T-cell-derived cytokines are crucial mediators of protection against Mycobacterium tuberculosis infection, but these factors are insufficient as biomarkers for disease susceptibility. In order to define T-cell molecules involved in tuberculosis (TB), we compared gene expression profiles of T-cells from patients with active TB, healthy donors with latent M. tuberculosis infection (LTBIs) and non-infected healthy donors (NIDs) by microarray analysis. Pathway-focused analyses identified a prevalent subset of candidate genes involved in the Janus kinase (JAK)-signal transducer and activator of transcription signalling pathway, including those encoding suppressor of cytokine signalling (SOCS) molecules, in the subset of protection-associated genes. Differential expression was verified by quantitative PCR analysis for the cytokine-inducible SH2-containing protein (CISH), SOCS3, JAK3, interleukin-2 receptor α-chain (IL2RA), and the proto-oncogene serine/threonine protein kinase (PIM1). Classification analyses revealed that this set of molecules was able to discriminate efficiently between T-cells from TB patients and those from LTBIs, and, notably, to achieve optimal discrimination between LTBIs and NIDs. Further characterization by quantitative PCR revealed highly variable candidate gene expression in CD4(+) and CD8(+) T-cells from TB patients and only minor differences between CD4(+) and CD8(+) T-cell subpopulations. These results point to a role of cytokine receptor signalling regulation in T-cells in susceptibility to TB.


Tractography-based priors for dynamic causal models.
Functional integration in the brain rests on anatomical connectivity (the presence of axonal connections) and effective connectivity (the causal influences mediated by these connections). The deployment of anatomical connections provides important constraints on effective connectivity, but does not fully determine it, because synaptic connections can be expressed functionally in a dynamic and context-dependent fashion. Although it is generally assumed that anatomical connectivity data is important to guide the construction of neurobiologically realistic models of effective connectivity; the degree to which these models actually profit from anatomical constraints has not yet been formally investigated. Here, we use diffusion weighted imaging and probabilistic tractography to specify anatomically informed priors for dynamic causal models (DCMs) of fMRI data. We constructed 64 alternative DCMs, which embodied different mappings between the probability of an anatomical connection and the prior variance of the corresponding of effective connectivity, and fitted them to empirical fMRI data from 12 healthy subjects. Using Bayesian model selection, we show that the best model is one in which anatomical probability increases the prior variance of effective connectivity parameters in a nonlinear and monotonic (sigmoidal) fashion. This means that the higher the likelihood that a given connection exists anatomically, the larger one should set the prior variance of the corresponding coupling parameter; hence making it easier for the parameter to deviate from zero and represent a strong effective connection. To our knowledge, this study provides the first formal evidence that probabilistic knowledge of anatomical connectivity can improve models of functional integration.


Access to drinking water: time matters.
Despite the reported achievement of the Millennium Development Goals (MDGs) with respect to drinking water, lack of access to water remains widespread worldwide. The indicator used there to measure access to water in the MDGs refers to the use of an improved water source. However, the amount of time spent in collecting water is high in countries where access to drinking water supplies located on premises is not common. 26.3% of the world's population did not have such access in 2015. Thus the need to travel to a water point, possibly queue, fill water containers, and carry them home is prevalent. The amount of time and effort used in water collection can be considerable, and household surveys increasingly provide data on collection time. This study aims to demonstrate the effect of adding a 30-minute collection time component to monitor access to drinking water. This study draws on household surveys from 17 countries to highlight the widespread burden of fetching water and its significant impact on estimates of coverage. The proportion of the population with access decreased by 13% on average for these 17 countries when collection time was added as a consideration.


Investigating Variation in Island Effects: A Case Study of Norwegian Wh-Extraction.
We present a series of large-scale formal acceptability judgment studies that explored Norwegian island phenomena in order to follow up on previous observations that speakers of Mainland Scandinavian languages like Norwegian accept violations of certain island constraints that are unacceptable in most languages cross-linguistically. We tested the acceptability of wh-extraction from five island types: whether-, complex NP, subject, adjunct, and relative clause (RC) islands. We found clear evidence of subject and adjunct island effects on wh-extraction. We failed to find evidence that Norwegians accept wh-extraction out of complex NPs and RCs. Our participants judged wh-extraction from complex NPs and RCs to be just as unacceptable as subject and adjunct island violations. The pattern of effects in Norwegian paralleled island effects that recent experimental work has documented in other languages like English and Italian (Sprouse et al. 2012; Sprouse et al. 2016). Norwegian judgments consistently differed from prior findings for one island type: whether-islands. Our results reveal that Norwegians exhibit significant inter-individual variation in their sensitivity to whether-island effects, with many participants exhibiting no sensitivity to whether-island violations whatsoever. We discuss the implications of our findings for universalist approaches to island constraints. We also suggest ways of reconciling our results with previous observations, and offer a systematic experimental framework in which future research can investigate factors that govern apparent island insensitivity.


Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.
Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes. A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient's usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause-safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, NCT00377676). In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 [95% two-sided CI 0.35-0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group. The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point.


Identification and classification of chromosomal aberrations in human induced pluripotent stem cells.
Because of their somatic cell origin, human induced pluripotent stem cells (HiPSCs) are assumed to carry a normal diploid genome, and adaptive chromosomal aberrations have not been fully evaluated. Here, we analyzed the chromosomal integrity of 66 HiPSC and 38 human embryonic stem cell (HESC) samples from 18 different studies by global gene expression meta-analysis. We report identification of a substantial number of cell lines carrying full and partial chromosomal aberrations, half of which were validated at the DNA level. Several aberrations resulted from culture adaptation, and others are suspected to originate from the parent somatic cell. Our classification revealed a third type of aneuploidy already evident in early passage HiPSCs, suggesting considerable selective pressure during the reprogramming process. The analysis indicated high incidence of chromosome 12 duplications, resulting in significant enrichment for cell cycle-related genes. Such aneuploidy may limit the differentiation capacity and increase the tumorigenicity of HiPSCs.


Cryptococcus neoformans-reactive and total immunoglobulin profiles of human immunodeficiency virus-infected and uninfected Ugandans.
We determined total and Cryptococcus neoformans glucuronoxylomannan (GXM)-reactive antibody repertoires of human immunodeficiency virus (HIV)-infected and HIV-uninfected Ugandans in a retrospective, case-control study of participants in a randomized controlled trial of pneumococcal vaccination. The study included 192 adults: 48 who subsequently developed cryptococcal meningitis (CM); (HIV+ CM+); 2 individuals who matched them in CD4+ T-cell level, stage of HIV disease, and age but did not develop CM (HIV+ CM-); and 48 HIV-uninfected individuals. Total serum immunoglobulin concentrations and titers of immunoglobulin M (IgM), IgG, and IgA to GXM, pneumococcal polysaccharides, and antibodies expressing certain V(H)3 idiotypes were determined with banked sera obtained before the development of cryptococcosis for HIV+ CM+ subjects. The results showed that HIV-infected subjects had significantly lower levels of IgM to GXM but higher levels of total immunoglobulin and IgG and IgA to GXM than those of HIV-uninfected subjects. HIV-infected subjects with a history of pneumonia had higher levels, and those with a history of herpes zoster had lower levels of GXM-binding antibodies than subjects with no history of either disease. Minimal to no cross-reactivity was demonstrated between antibodies to GXM and polysaccharides in a pneumococcal vaccine. No significant differences between the antibody repertoires of HIV+ CM+ and HIV+ CM- subjects were identified, but among subjects without a history of pneumonia, there was a trend towards lower V(H)3-positive antibody levels among HIV+ CM+ than among HIV+ CM- subjects. Our findings demonstrate an association between previous infectious diseases and differences in the total and GXM-reactive antibody repertoires of HIV-infected subjects and suggest the question of whether certain microbes modulate subsequent antibody responses to GXM deserves further study.


Agreement between rapid onsite and final cytologic interpretations of EUS-guided FNA specimens: implications for the endosonographer and patient management.
The practice of onsite cytology interpretation varies across endoscopic ultrasound (EUS) programs in the United States and Europe. The value, reliability, and agreement of rapid onsite evaluation (ROSE) compared with final interpretation and its impact on patient management remain largely unknown. We compared agreement between ROSE of EUS-FNA (endoscopic ultrasound-guided fine needle aspiration) specimens with final cytology interpretation and their respective operating characteristics. We prospectively evaluated consecutive EUS-FNA specimens obtained by a single endosonographer in the presence of an attending cytopathologist (July 2000-November 2002). The "agreement" between ROSE and final cytology interpretation was assessed by the "kappa" statistic. The frequency and possible reasons for discrepancy between ROSE and final cytologic interpretation were determined. A total of 540 patients (median age 63 yr, 77% white) underwent EUS-FNAs of 656 lesions. These included lymph nodes (LNs, N = 248), solid pancreatic masses (SPMs, N = 229), cystic pancreatic masses (CPM, N = 57), mural lesions (41), bile duct/gallbladder (N = 28), liver (N = 17), mediastinum/lung (N = 17), adrenal (N = 15), spleen (N = 3), and kidney (N = 1). Data were available for onsite evaluation in 607 lesions. Initial cytology was benign (N = 243), atypical (N = 23), suspicious (24), malignant (300), and indeterminate (N = 17). Out of the 243 benign lesions interpreted by onsite evaluation, five lesions (2.1%) were upgraded to be malignant or suspicious for malignancy on final cytology report. Of the 300 lesions initially reported malignant on ROSE, 294 (98%) remained malignant on the final cytology. There was an excellent agreement between ROSE and final cytologic evaluation (kappa = 84.0%, 95% CI 80.2-87.7), Compared with the true final status, accuracy for final interpretation was slightly higher than for ROSE but was not statistically significant (95.8%vs 93.9%). Scant cellularity remained the most frequent reason for discrepancy, accounting for 21 of 51 discrepancies (41%). Other reasons for discrepancy included: cases requiring an intradepartmental consultation (22%), cases requiring ancillary studies (12%), intra-observer variability (10%), and challenging diagnosis (10%). In three cases, (6%) we were unable to determine the possible reason for discrepancy. ROSE of EUS-FNA specimens is highly accurate compared with final cytologic evaluation. Because the diagnosis of malignancy rarely changes, informing our patients and their families and our referring physicians of a cancer diagnosis significantly reduces physician work load and expedites patient management. The majority of discrepancies are related to the nature of the lesion either because it sheds few cells, has challenging morphology, and/or requires additional ancillary studies.


Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent.
Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell proliferation and angiogenesis. We observed that the proliferative index of nicotine is different in the lung cancer cell lines H1299 (p53-/-) and A549 (p53+/+) which indicates that the mode of up-regulation of survival signals by nicotine might be different in cells with and without p53. While low concentrations of nicotine induced activation of NF-κB, Akt, Bcl2, MAPKs, AP1 and IAPs in H1299, it failed to induce NF-κB in A549, and compared to H1299, almost 100 times higher concentration of nicotine was required to induce all other survival signals in A549. Transfection of WT-p53 and DN-p53 in H1299 and A549 respectively, reversed the mode of activation of survival signals. Curcumin down-regulated all the survival signals induced by nicotine in both the cells, irrespective of their p53 status. The hypothesis was confirmed when lower concentrations of nicotine induced NF-κB in two more lung cancer cells, Hop-92 and NCI-H522 with mutant p53 status. Silencing of p53 in A549 using siRNA made the cells susceptible to nicotine-induced NF-κB nuclear translocation as in A549 DN-p53 cells. The present study reveals a detrimental role of nicotine especially in lung cancer patients with impaired p53 status and identifies curcumin as a potential chemopreventive.