Repetition suppression of face-selective evoked and induced EEG recorded from human cortex.
In functional MRI studies, repetition suppression refers to the reduction of hemodynamic activation to repeated stimulus presentation. For example, the repeated presentation of a face reduces the hemodynamic response evoked by faces in the fusiform gyrus. The neural events that underlie repetition suppression are not well understood. Indeed, in contrast to the hemodynamic response, the face-specific N200 recorded from subdural electrodes on the ventral occipitotemporal cortex, primarily along the fusiform gyrus, has been reported to be insensitive to face-identity repetition. We have previously described a face-specific broadband gamma (30-100 Hz) response at ventral face-specific N200 sites that is functionally dissociable from the N200. In this study, we investigate whether gamma and other components of the electroencephalogram spectrum are affected by face-identity repetition independently of the N200. Participants viewed sequentially presented identical faces. At sites on and around the fusiform gyrus, we found that face repetition modulated alpha (8-12 Hz), low-gamma (30-60 Hz), and high-gamma (60-100 Hz) synchrony, but not the N200. These findings provide evidence of a spatially co-localized progression of face processing. Whereas the N200 reflects an initial obligatory response that is less sensitive to face-identity repetition, the subsequent spectral fluctuations reflect more elaborative face processing and are thus sensitive to face novelty. It is notable that the observed modulations were different for different frequency bands. We observed repetition suppression of broadband gamma, but repetition enhancement of alpha synchrony. This difference is discussed with regard to an existing model of repetition suppression and behavioral repetition priming.


Design of a robotic zebra finch for experimental studies on developmental song learning.
Birdsong learning has been consolidated as the model system of choice for exploring the biological substrates of vocal learning. In the zebra finch (Taeniopygia guttata), only males sing and they develop their song during a sensitive period in early life. Different experimental procedures have been used in the laboratory to train a young finch to learn a song. So far, the best method to achieve a faithful imitation is to keep a young bird singly with an adult male. Here, we present the different characteristics of a robotic zebra finch that was developed with the goal to be used as a song tutor. The robot is morphologically similar to a life-sized finch: it can produce movements and sounds contingently to the behaviours of a live bird. We present preliminary results on song imitation, and other possible applications beyond the scope of developmental song learning.


Plasma matrix metalloproteinases 7 and 9 in patients with metastatic breast cancer treated with marimastat or placebo: Eastern Cooperative Oncology Group trial E2196.
The purpose of this study was to evaluate the prognostic and predictive utility of measuring plasma levels of matrix metalloproteinase (MMP)-7 and MMP-9 in patients with metastatic breast cancer (MBC) treated with the oral MMP inhibitor (MMPI) marimastat or a placebo. We measured plasma levels of MMP-7 and MMP-9 using an enzyme-linked immunoassay method in 140 evaluable patients with MBC enrolled on a multicenter clinical trial that compared the MMPI marimastat with placebo. Specimens were collected after completion of first-line chemotherapy in patients who had responding or stable disease and 3, 6, and 12 months after initiation of marimastat (10 mg orally twice daily) or placebo. Baseline plasma MMP-7 and MMP-9 levels did not correlate with each other or with progression-free or overall survival. In addition, serial evaluation of plasma MMP-7 and MMP-9 levels revealed no significant changes over time in the marimastat or placebo groups or any correlation with trough plasma marimastat level. We conclude that measurement of plasma MMP-7 or MMP-9 levels, as performed in our trial, was not a useful prognostic or predictive factor in patients with MBC or in patients treated with an MMPI.


Application of CCME Water Quality Index to monitor water quality: a case study of the Mackenzie River Basin, Canada.
All six ecosystem initiatives evolved from many years of federal, provincial, First Nation, local government and community attention to the stresses on sensitive habitats and species, air and water quality, and the consequent threats to community livability. This paper assesses water quality aspect for the ecosystem initiatives and employs newly developed Canadian Council of Ministers of the Environment Water Quality Index (CCME WQI) which provides a convenient mean of summarizing complex water quality data that can be easily understood by the public, water distributors, planners, managers and policy makers. The CCME WQI incorporates three elements: Scope - the number of water quality parameters (variables) not meeting water quality objectives (F(1)); Frequency - the number of times the objectives are not met (F(2)); and Amplitude. the extent to which the objectives are not met (F(3)). The index produces a number between 0 (worst) to 100 (best) to reflect the water quality. This study evaluates water quality of the Mackenzie - Great Bear sub-basin by employing two modes of objective functions (threshold values): one based on the CCME water quality guidelines and the other based on site-specific values that were determined by the statistical analysis of the historical data base. Results suggest that the water quality of the Mackenzie-Great Bear sub-basin is impacted by high turbidity and total (mostly particulate) trace metals due to high suspended sediment loads during the open water season. Comments are also provided on water quality and human health issues in the Mackenzie basin based on the findings and the usefulness of CCME water quality guidelines and site specific values.


Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years.
Seventy-eight patients (109 eyes) with progressive glaucoma had argon laser trabeculoplasty as a substitute for filtration surgery and were then followed up for a minimum of 5 years. One hundred spots were placed at the anterior margin of the posterior trabecular meshwork over 360 degrees. Consecutive cases between 1980 and 1985 were reviewed, 95% of treated cases being included in the final analysis. Eighty-two eyes had primary open angle glaucoma. If only the group with primary open angle glaucoma is considered, the failure rate the first year was 19%. After that, the failure rate was approximately eight per year. At the end of 5 years, 65% of all eyes had failed. At the end of 10 years, data were available on 84 of the original 109 treated eyes; in 80 treatment had failed, and four were still receiving medical therapy.


Surface lattice dynamics and electron-phonon interaction in cesium ultra-thin films.
The phonon dispersion curves of ultrathin films of Cs(110) on Pt(111) measured with inelastic helium atom scattering (HAS) are reported and compared with density-functional perturbation theory (DFPT) calculations. The combined HAS and DFPT analysis also sheds light on the bulk phonon dynamics of bcc-Cs, on which very little is known from neutron scattering due to its large neutron capture cross-section. Moreover the temperature dependence of the elastic HAS Debye-Waller exponent of Cs(110)/Cu(111) ultrathin films allows for an estimation of the electron-phonon coupling strength λ as a function of the film thickness.


Correcting for Intra-Individual Variability in Sodium Excretion in Spot Urine Samples Does Not Improve the Ability to Predict 24 h Urinary Sodium Excretion.
Given a global focus on salt reduction efforts to reduce cardiovascular risk, it is important to obtain accurate measures of salt intake on a population level. This study determined firstly whether adjustment for intra-individual variation in urinary sodium (Na) excretion using three repeated 24 h collections affects daily estimates and whether the use of repeated spot urine samples results in better prediction of 24 h Na compared to a single collection. Twenty three community-dwelling men and women from South Africa (mean age 59.7 years (SD = 15.6)) participating in the World Health Organization Study on global AGEing and adult health (WHO-SAGE) Wave 3 study collected 24 h and spot early morning urine samples over three consecutive days to assess urinary Na excretion. INTERSALT, Tanaka, and Kawasaki prediction equations, with either average or adjusted spot Na values, were used to estimate 24 h Na and compared these against measured 24 h urinary Na. Adjustment was performed by using the ratio of between-person (sb) and total (sobs) variability obtained from repeated measures analysis of variance. Sensitivity of the equations to predict daily urinary Na values below 5 g salt equivalent was calculated. The sb/sobs for urinary Na using three repeated samples for spot and 24 h samples were 0.706 and 0.798, respectively. Correction using analysis of variance for 3 × 24 h collections resulted in contraction of the upper end of the distribution curve (90th centile: 157 to 136 mmoL/day; 95th centile: 220 to 178 mmoL/day). All three prediction equations grossly over-estimated 24 h urinary Na excretion, regardless of whether a single spot urine or repeated collections corrected for intra-individual variation were used. Sensitivity of equations to detect salt intake equivalent values of ≤5 g/day was 13% for INTERSALT, while the other two equations had zero sensitivity. Correcting for intra-individual variability in Na excretion using three 24 h urine collections contracted the distribution curve for high intakes. Repeated collection of spot samples for urinary Na analysis does not improve the accuracy of predicting 24 h Na excretion. Spot urine samples are not appropriate to detect participants with salt intakes below the recommended 5 g/day.


[Helmet use by motorcyclists injured in traffic accidents in Londrina, southern Brazil].
To describe helmet use among motorcyclists injured in traffic accidents in Londrina, a medium-sized city in Paraná, a state in southern Brazil, and to identify factors associated with not wearing a helmet at the time of the accident. We analyzed data concerning motorcycle users (drivers and passengers) who received care in 1998 from the only pre-hospitalization trauma and emergency care ambulance service in Londrina. The following variables were assessed: helmet use at the time of the accident; age; sex; seating position (driver or passenger); smell of alcohol on the breath; time of the day, day of the week, and month when the accident happened; and location of the accident (in the downtown area or outside of it). The average rate of helmet use was 63.2%. Factors independently associated with not using a helmet were (according to strength of association): being younger than 18 years of age (odds ratio (OR) = 6.61), having alcohol on the breath (OR = 3.93), accident occurring at night (OR = 2.51), accident happening outside the city's downtown area (OR = 2.27), and accident taking placing during the weekend (OR = 2.25). It is imperative to implement public policies aimed at promoting safety for motorcyclists, ongoing education in defensive driving, and the use of helmets and other safety equipment. Interventions should take into account that driving behaviors depend not just on individuals but also on the overall social and historical context.


Matrix analysis and risk management to avert depression and suicide among workers.
Suicide is among the most tragic outcomes of all mental disorders, and the prevalence of suicide has risen dramatically during the last decade, particularly among workers. This paper reviews and proposes strategies to avert suicide and depression with regard to the mind body medicine equation hypothesis, metrics analysis of mental health problems from a public health and clinical medicine view.In occupational fields, the mind body medicine hypothesis has to deal with working environment, working condition, and workers' health. These three factors chosen in this paper were based on the concept of risk control, called San-kanri, which has traditionally been used in Japanese companies, and the causation concepts of host, agent, and environment. Working environment and working condition were given special focus with regard to tackling suicide problems. Matrix analysis was conducted by dividing the problem of working conditions into nine cells: three prevention levels (primary, secondary, and tertiary) were proposed for each of the three factors of the mind body medicine hypothesis (working environment, working condition, and workers' health). After using these main strategies (mind body medicine analysis and matrix analysis) to tackle suicide problems, the paper talks about the versatility of case-method teaching, "Hiyari-Hat activity," routine inspections by professionals, risk assessment analysis, and mandatory health check-up focusing on sleep and depression. In the risk assessment analysis, an exact assessment model was suggested using a formula based on multiplication of the following three factors: (1) severity, (2) frequency, and (3) possibility.Mental health problems, including suicide, are rather tricky to deal with because they involve evaluation of individual cases. The mind body medicine hypothesis and matrix analysis would be appropriate tactics for suicide prevention because they would help the evaluation of this issue as a tangible problem.


Highly delayed systemic translocation of aluminum-based adjuvant in CD1 mice following intramuscular injections.
Concerns regarding vaccine safety have emerged following reports of potential adverse events in both humans and animals. In the present study, alum, alum-containing vaccine and alum adjuvant tagged with fluorescent nanodiamonds were used to evaluate i) the persistence time at the injection site, ii) the translocation of alum from the injection site to lymphoid organs, and iii) the behavior of adult CD1 mice following intramuscular injection of alum (400 μg Al/kg). Results showed for the first time a strikingly delayed systemic translocation of adjuvant particles. Alum-induced granuloma remained for a very long time in the injected muscle despite progressive shrinkage from day 45 to day 270. Concomitantly, a markedly delayed translocation of alum to the draining lymph nodes, major at day 270 endpoint, was observed. Translocation to the spleen was similarly delayed (highest number of particles at day 270). In contrast to C57BL/6J mice, no brain translocation of alum was observed by day 270 in CD1 mice. Consistently neither increase of Al cerebral content, nor behavioral changes were observed. On the basis of previous reports showing alum neurotoxic effects in CD1 mice, an additional experiment was done, and showed early brain translocation at day 45 of alum injected subcutaneously at 200 μg Al/kg. This study confirms the striking biopersistence of alum. It points out an unexpectedly delayed diffusion of the adjuvant in lymph nodes and spleen of CD1 mice, and suggests the importance of mouse strain, route of administration, and doses, for future studies focusing on the potential toxic effects of aluminum-based adjuvants.


From homoligand- to mixed-ligand- monolayer-protected metal nanoparticles: a scanning tunneling microscopy investigation.
The ligand shell that coats, protects, and imparts a large number of properties to gold nanoparticles is a 2-D self-assembled monolayer wrapped around a 3-D metallic core. Here we present a study of the molecular packing of ligand shells on gold nanoparticles based on the analysis of scanning tunneling microscopy (STM) images. We discuss methods for optimal nanoparticle sample preparation in relation to STM imaging conditions. We show that the packing of a self-assembled monolayer composed solely of octanethiols on gold nanoparticles depends on the particle's diameter with an average headgroup spacing of 5.4 A, which is different from that of similar monolayers formed on flat Au(111) surfaces (5.0 A). In the case of nanoparticles coated with mixtures of ligands-known to phase separate into randomly shaped and ordered domains on flat surfaces-we find that phase separation leads to the formation of concentric, ribbonlike domains of alternating composition. The spacing of these domains depends on the ligand shell composition. We find that, for a given composition, the spacing increases with diameter in a manner characterized by discontinuous transitions at "critical" particle sizes. We discuss possible interpretations for the observed trends in our data.


Tuberculosis and diabetes mellitus: merging epidemics.
The link between tuberculosis (TB) and diabetes mellitus (DM) has occupied the center stage of discussion. Experts have raised concern about the merging epidemics of tuberculosis and diabetes particularly in the low to medium income countries like India and China that have the highest burden of TB in the world, and are experiencing the fastest increase in the prevalence of DM. There is good evidence that DM makes a substantial contribution to TB incidence. The huge prevalence of DM in India, may be contributing to the increasing prevalence of TB. This review looks at the link between these two merging epidemics. We discuss the epidemiology, clinical features, microbiology and radiology, and management and treatment outcomes of patients with tuberculosis and diabetes mellitus.


A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding.
The optimal dosage of proton pump inhibitor in bleeding peptic ulcers remains controversial. The aim was to compare the clinical effectiveness of two doses of infusional pantoprazole in peptic ulcer bleeding. Peptic ulcer patients (n= 120) with bleeding stigmata were enrolled after successful endoscopic therapy. After an initial bolus injection of 80 mg pantoprazole, patients were randomized to receive continuously infused pantoprazole at either 192 mg day(-1) or 40 mg every 6 h (i.e. 160 mg day(-1)) for 3 days. Clinical outcomes between the two groups within 14 days were compared, with 14-day recurrent bleeding regarded as the primary end-point. Both groups (n= 60 each) were well matched in demographic and clinical factors upon entry. Bleeding totally recurred in 11 (9.2%) patients, with six (10%) in the 192 mg day(-1) group and five (8.3%) in the 160 mg day(-1) group (relative risk of bleeding recurrence between two treatments 1.2; 95% CI 0.39, 3.72). All secondary outcomes between the two groups were similar, including the amount of blood transfusion (mean 1179 ml vs. 1203 ml, P > 0.1), hospital stay (mean 9.5 days vs. 9.9 days, P > 0.1), need for surgery (n= 1 vs. n= 0, P > 0.1), and mortality (n= 1 vs. n= 0, P > 0.1). Following endoscopic haemostasis, infusional pantoprazole at either 192 mg day(-1) or 40 mg every 6 h appear similar.


Concordance between health administrative data and survey-derived diagnoses for mood and anxiety disorders.
To assess whether estimates of survey structured interview diagnoses of mood and anxiety disorders were concordant with diagnoses of these disorders obtained from health administrative data. All Ontario respondents to the 2012 Canadian Community Health Survey-Mental Health (CCHS-MH) were linked to health administrative databases at ICES (formerly known as the Institute for Clinical Evaluative Sciences). Survey structured interview diagnoses were compared with health administrative data diagnoses obtained using a standardized algorithm. We used modified Poisson regression analyses to assess whether socio-demographic factors were associated with concordance between the two measures. Of the 4157 Ontarians included in our sample, 20.4% had either a structured interview diagnosis (13.9%) or health administrative diagnosis (10.4%) of a mood or anxiety disorder. There was high discordance between measures, with only 19.4% agreement. Migrant status, age, employment, and income were associated with discordance between measures. Our findings indicate that previous estimates of the 12-month prevalence of mood and anxiety disorders in Ontario may be underestimating the true prevalence, and that population-based surveys and health administrative data may be capturing different groups of people. Understanding the limitations of data commonly used in epidemiologic studies is a key foundation for improving population-based estimates of mental disorders.


Maturity onset diabetes of the young: clinical characteristics, diagnosis and management.
Maturity Onset Diabetes of the Young (MODY), represents a rare cause of diabetes (1% of all cases), commonly misdiagnosed as Type 1 Diabetes (T1D) or Type 2 Diabetes (T2D). Clinical characteristics of MODY include age of onset before 45 years, absence of beta-cell autoimmunity and features of metabolic syndrome, sustained endogenous insulin production and strong family history. Common reasons for misdiagnosis are limitations in physicians' awareness and restrictions in performing genetic testing. In an attempt to improve diagnosis rates, recent research efforts have focused on the discovery of non-genetic biomarkers for prioritising individuals for genetic testing, with some promising progress (identification of high-sensitivity CRP, plasma glycan profile as HNF1A-MODY). The information provided is relevant to physicians dealing with young adults but details on pediatric populations are also included. Raising awareness about MODY and making the diagnosis more accessible will improve prognostication and management of these patients and their relatives.


Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.
Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.


The Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN): Design and Methods for Recruitment and Psychological Measures.
Although studies show that genomics and environmental stressors affect blood pressure, few studies have examined their combined effects, especially in African Americans. We present the recruitment methods and psychological measures of the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) study, which seeks to investigate the individual and combined effects of genetic (G) and environmental (E) (psychological) stressors on blood pressure in African American mother-child dyads. Genetic methods are presented elsewhere, but here we present the recruitment methods, psychological measures, and analysis plan for these environmental stressors. This longitudinal study will enroll 250 mother-child dyads (N = 500). Study participation is restricted to women who (a) are ≤21 years of age, (b) self-identify as African American or Black, (c) speak English, (d) do not have an identified mental illness or cognitive impairment, and (e) have a biological child between 3 and 5 years old. The primary environmental stressors assessed are parenting stress, perceived racism and discrimination, and maternal mental health. Covariates include age, cigarette smoking (for mothers), and gender (for children). The study outcome variables are systolic and diastolic blood pressure. The main analytic outcome is genetic-by-environment interaction analyses (G × E); however, main effects (G) and (E) will be individually assessed first. Genetic (G) and interaction analyses (G × E) are described in a companion paper and will include laboratory procedures. Statistical modeling of environmental stressors on blood pressure will be done using descriptive statistics and generalized estimating equation models. The methodology presented here includes the study rationale, community engagement and recruitment protocol, psychological variable measurement, and analysis plan for assessing the association of environmental stressors and blood pressure. This study may provide the foundation for other studies and development of interventions to reduce the risk for hypertension and to propose targeted health promotion programs for this high-risk population.


Concomitant detection of HER2 protein and gene alterations by immunohistochemistry (IHC) and silver enhanced in situ hybridization (SISH) identifies HER2 positive breast cancer with and without gene amplification.
HER2 status assessment became a mandatory test assay in breast cancer, giving prognostic and predictive information including eligibility for adjuvant anti-HER2 therapy. Precise and reliable assessment of HER2 status is therefore of utmost importance. In this study we analyzed breast cancer samples by a novel technology for concomitant detection of the HER2 protein and gene copy number. Tissue microarrays containing 589 invasive breast cancer samples were analyzed with a double immunohistochemistry (IHC) and silver labeled in situ hybridization (SISH) assay simultaneously detecting HER2 protein and gene copy number in the same tumor cells. This bright-field assay was analyzed using scores according to the modified ASCO guidelines and the results were correlated with patient prognosis. Overall concordance rate between protein expression and the presence of gene amplification was 98%. Fifty-seven of 60 tumors (95%) with IHC score 3+, 6 of 10 tumors with IHC score 2+ (60%) and only 3 of 519 tumors (0.6%) with IHC score 0/1+ were amplified by SISH. Patients with gene amplification despite IHC score 0/1+ had a tendency for worse overall survival (p = 0.088, reaching nearly statistical significance) compared to IHC score 0/1+ without amplification. In contrast, there was no difference in overall survival in IHC score 3+/2+ tumors with and without gene amplification. The novel double IHC and SISH assay for HER2 is efficient in the identification of breast cancer with discordant HER2 protein and HER2 gene status, especially for the prognostically relevant groups of HER2 protein negative tumors with HER2 amplification and HER2 protein positive tumors without HER2 amplification. Breast cancer without HER2 amplification among IHC score 2+/3+ tumors (10% in our cohort) suggests that other mechanisms than gene amplification contribute to protein overexpression in these cells.


A two-step O- to C-glycosidic bond rearrangement using complementary glycosyltransferase activities.
An efficient 2'-O- to 3'-C-β-d-glucosidic bond rearrangement on the dihydrochalcone phloretin to convert phlorizin into nothofagin was achieved by combining complementary O-glycosyltransferase (OGT) and C-glycosyltransferase (CGT) activities in a one-pot transformation containing catalytic amounts of uridine 5'-diphosphate (UDP). Two separate enzymes or a single engineered dual-specific O/CGT were applied. Overall (quantitative) conversion occurred in two steps via intermediary UDP-glucose and phloretin.


Common community-acquired infections and subsequent risk of multiple myeloma: a population-based study.
The role of bacteria and viruses as aetiological agents in the pathogenesis of cancer has been well established for several sites, including a number of haematological malignancies. Less clear is the impact of such exposures on the subsequent development of multiple myeloma (MM). Using the population-based U.S. Surveillance Epidemiology and End Results-Medicare dataset, 15,318 elderly MM and 200,000 controls were identified to investigate the impact of 14 common community-acquired infections and risk of MM. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were adjusted for sex, age and calendar year of selection. The 13-month period prior to diagnosis/selection was excluded. Risk of MM was increased by 5-39% following Medicare claims for eight of the investigated infections. Positive associations were observed for several infections including bronchitis (adjusted OR 1.14, 95% CI 1.09-1.18), sinusitis (OR 1.15, 95% CI 1.10-1.20) pneumonia (OR 1.27, 95% CI 1.21-1.33), herpes zoster (OR 1.39, 95% CI 1.29-1.49) and cystitis (OR 1.09, 95% CI 1.05-1.14). Each of these infections remained significantly elevated following the exclusion of more than 6 years of claims data. Exposure to infectious antigens may therefore play a role in the development of MM. Alternatively, the observed associations may be a manifestation of an underlying immune disturbance present several years prior to MM diagnosis and thereby part of the natural history of disease progression.


Observation of Complex Time Structures in the Cosmic-Ray Electron and Positron Fluxes with the Alpha Magnetic Spectrometer on the International Space Station.
We present high-statistics, precision measurements of the detailed time and energy dependence of the primary cosmic-ray electron flux and positron flux over 79 Bartels rotations from May 2011 to May 2017 in the energy range from 1 to 50 GeV. For the first time, the charge-sign dependent modulation during solar maximum has been investigated in detail by leptons alone. Based on 23.5×10^{6} events, we report the observation of short-term structures on the timescale of months coincident in both the electron flux and the positron flux. These structures are not visible in the e^{+}/e^{-} flux ratio. The precision measurements across the solar polarity reversal show that the ratio exhibits a smooth transition over 830±30 days from one value to another. The midpoint of the transition shows an energy dependent delay relative to the reversal and changes by 260±30 days from 1 to 6 GeV.


Functionalization of diazotetronic acid and application in a stereoselective modular synthesis of pulvinone, aspulvinones A-E, G, Q and their analogues.
A modular synthesis of aspulvinones A, B, C, D, E, G and the recently isolated aspulvinone Q was developed. The methodology features a highly stereoselective aldol condensation of diazotetronic acid with aldehydes to provide 5-arylidene diazotetronates. Subsequent catalytic intermolecular C-H insertion reactions of the arylidene tetronates with arenes provide a series of naturally occurring aspulvinones including aspulvinones C, D and Q which have not been synthesized before. Variation of the aldehyde and the arene components furnishes synthetic analogues of the aspulvinones.


Effects of venue-specific state clean indoor air laws on smoking-related outcomes.
A large literature has documented relationships between state clean indoor air laws (SCIALs) and smoking-related outcomes in the United States. These laws vary within states over time and across venues such as schools, government buildings, and bars. Few studies, however, have evaluated whether the effects of SCIALs are plausibly concentrated among workers who should have been directly affected because they worked at locations covered by the venue-specific restrictions. We fill this gap in the literature using data on private sector workers, government employees, school workers, eating and drinking place workers, and bartenders from the 1992-2007 Tobacco Use Supplements to the Current Population Survey. Our quasi-experimental models indicate robust effects of SCIALs restricting smoking in bars: these laws significantly increased the presence of workplace smoking restrictions as reported by bartenders and reduced the fraction of bartenders who smoke. We do not, however, find that SCIALs in private workplaces, government workplaces, schools, or restaurants increased the presence of workplace smoking restrictions among groups of workers working in venues covered by these laws. This suggests that the smoking reductions associated with SCIALs in previous research are unlikely to have been directly caused by effects of workplace smoking restrictions on workers.


Clinical and pathologic characteristics of biopsy-proven iris melanoma: a multicenter international study.
To collaborate with multiple centers to identify representative epidemiological, clinical, and pathologic characteristics of melanoma of the iris. This international, multicenter, Internet-assisted study in ophthalmic oncology demonstrates the collaboration among eye cancer specialists to stage and describe the clinical and pathologic characteristics of biopsy-proven melanoma of the iris. A computer program was created to allow for Internet-assisted multicenter, privacy-protected, online data entry. Eight eye cancer centers in 6 countries performed retrospective chart reviews. Statistical analysis included patient and tumor characteristics, ocular and angle abnormalities, management, histopathology, and outcomes. A total of 131 patients with iris melanoma (mean age, 64 years [range, 20-100 years]) were found to have blue-gray (62.2%), green-hazel (29.1%), or brown (8.7%) irides. Iris melanoma color was brown (65.6%), amelanotic (9.9%), and multicolored (6.9%). A mean of 2.5 clock hours of iris was visibly involved with melanoma, typically centered at the 6-o'clock meridian. Presentations included iritis, glaucoma, hyphema, and sector cataract. High-frequency ultrasonography revealed a largest mean tumor diameter of 4.9 mm, a mean maximum tumor thickness of 1.9 mm, angle blunting (52%), iris root disinsertion (9%), and posterior iris pigment epithelium displacement (9%). Using the American Joint Commission on Cancer-International Union Against Cancer classification, we identified 56% of tumors as T1, 34% of tumors as T2, 2% of tumors as T3, and 1% of tumors as T4. Histopathologic grades were G1-spindle (54%), G2-mixed (28%), G3-epithelioid (5%), and undetermined (13%) cell types. Primary treatment involved radiation (26%) and surgery (64%). Kaplan-Meier analysis found a 10.7% risk of metastatic melanoma at 5 years. Iris melanomas were most likely to be brown and found in the inferior quadrants of patients with light irides. Typically small and unifocal, melanomas are commonly associated with angle blunting and spindle cell histopathology. This multicenter, Internet-based, international study successfully pooled data and extracted information on biopsy-proven melanoma of the iris.


[The effect of heparin induced increase of free plasma thyroxine on cardiac rhythm after myocardial infarction].
It is well known that an acute myocardial infarction is accompanied by a rise in levels of plasma free fatty acids (FFA), which may lead to a subsequent increase in cardiac arrhythmias. Administration of heparin to patients after an acute myocardial infarction gives rise to an increase both in plasma FFA levels and plasma free thyroxine levels. If administered without a fatty meal the rise in FFA is not accompanied by an increase in arrhythmias. The effect of the heparin-induced rise in plasma free thyroxine on cardiac rhythm has never been investigated. The aim of the present study was to investigate a possible arrhythmic effect of a heparin induced increase in plasma free thyroxine in a group of patients with acute myocardial infarction. We were able to confirm a significant heparin-induced rise in plasma free thyroxine levels, as measured by the effective thyroxine ratio. Although a slightly significant increase in ventricular premature beats could be demonstrated after heparin administration when using the Wilcoxon rank sum test for statistical analysis (but not when the paired t-test was utilized), no significant correlation with free thyroxine levels could be found. Heparin administration to patients suffering from myocardial infarction seems to be safe in terms of a possible arrhythmic effect.


Recent trends in childhood attention-deficit/hyperactivity disorder.
OBJECTIVE To examine trends in attention-deficit/hyperactivity disorder (ADHD) by race/ethnicity, age, sex, and median household income. DESIGN An ecologic study of trends in the diagnosis of ADHD using the Kaiser Permanente Southern California (KPSC) health plan medical records. Rates of ADHD diagnosis were derived using Poisson regression analyses after adjustments for potential confounders. SETTING Kaiser Permanente Southern California, Pasadena. PARTICIPANTS All children who received care at the KPSC from January 1, 2001, through December 31, 2010 (n = 842 830). MAIN EXPOSURE Period of ADHD diagnosis (in years). MAIN OUTCOME MEASURES Incidence of physician-diagnosed ADHD in children aged 5 to 11 years. RESULTS Rates of ADHD diagnosis were 2.5% in 2001 and 3.1% in 2010, a relative increase of 24%. From 2001 to 2010, the rate increased among whites (4.7%-5.6%; relative risk [RR] = 1.3; 95% CI, 1.2-1.4), blacks (2.6%- 4.1%; RR = 1.7; 95% CI, 1.5-1.9), and Hispanics (1.7%-2.5%; RR = 1.6; 95% CI, 1.5-1.7). Rates for Asian/Pacific Islander and other racial groups remained unchanged over time. The increase in ADHD diagnosis among blacks was largely driven by an increase in females (RR = 1.9; 95% CI, 1.5-2.3). Although boys were more likely to be diagnosed as having ADHD than girls, results suggest the sex gap for blacks may be closing over time. Children living in high-income households were at increased risk of diagnosis. CONCLUSIONS The findings suggest that the rate of ADHD diagnosis among children in the health plan notably has increased over time. We observed disproportionately high ADHD diagnosis rates among white children and notable increases among black girls.


Indicating spinal joint mobilisations or manipulations in patients with neck or low-back pain: protocol of an inter-examiner reliability study among manual therapists.
Manual spinal joint mobilisations and manipulations are widely used treatments in patients with neck and low-back pain. Inter-examiner reliability of passive intervertebral motion assessment of the cervical and lumbar spine, perceived as important for indicating these interventions, is poor within a univariable approach. The diagnostic process as a whole in daily practice in manual therapy has a multivariable character, however, in which the use and interpretation of passive intervertebral motion assessment depend on earlier results from the diagnostic process. To date, the inter-examiner reliability among manual therapists of a multivariable diagnostic decision-making process in patients with neck or low-back pain is unknown. This study will be conducted as a repeated-measures design in which 14 pairs of manual therapists independently examine a consecutive series of a planned total of 165 patients with neck or low-back pain presenting in primary care physiotherapy. Primary outcome measure is therapists' decision about whether or not manual spinal joint mobilisations or manipulations, or both, are indicated in each patient, alone or as part of a multimodal treatment. Therapists will largely be free to conduct the full diagnostic process based on their formulated examination objectives. For each pair of therapists, 2×2 tables will be constructed and reliability for the dichotomous decision will be expressed using Cohen's kappa. In addition, observed agreement, prevalence of positive decisions, prevalence index, bias index, and specific agreement in positive and negative decisions will be calculated. Univariable logistic regression analysis of concordant decisions will be performed to explore which demographic, professional, or clinical factors contributed to reliability. This study will provide an estimate of the inter-examiner reliability among manual therapists of indicating spinal joint mobilisations or manipulations in patients with neck or low-back pain based on a multivariable diagnostic reasoning and decision-making process, as opposed to reliability of individual tests. As such, it is proposed as an initial step toward the development of an alternative approach to current classification systems and prediction rules for identifying those patients with spinal disorders that may show a better response to manual therapy which can be incorporated in randomised clinical trials. Potential methodological limitations of this study are discussed.


Measurements of three-dimensional glenoid erosion when planning the prosthetic replacement of osteoarthritic shoulders.
The three-dimensional (3D) correction of glenoid erosion is critical to the long-term success of total shoulder replacement (TSR). In order to characterise the 3D morphology of eroded glenoid surfaces, we looked for a set of morphological parameters useful for TSR planning. We defined a scapular coordinates system based on non-eroded bony landmarks. The maximum glenoid version was measured and specified in 3D by its orientation angle. Medialisation was considered relative to the spino-glenoid notch. We analysed regular CT scans of 19 normal (N) and 86 osteoarthritic (OA) scapulae. When the maximum version of OA shoulders was higher than 10°, the orientation was not only posterior, but extended in postero-superior (35%), postero-inferior (6%) and anterior sectors (4%). The medialisation of the glenoid was higher in OA than normal shoulders. The orientation angle of maximum version appeared as a critical parameter to specify the glenoid shape in 3D. It will be very useful in planning the best position for the glenoid in TSR.


Anti-Apoptotic Signature in Thymic Squamous Cell Carcinomas - Functional Relevance of Anti-Apoptotic BIRC3 Expression in the Thymic Carcinoma Cell Line 1889c.
The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.


In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation.
Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Here we demonstrate that caffeine (10 mM) released Ca2+ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase was present, caffeine induced larger Ca2+ spikes in as many as 60% of the cells. Forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone did not release Ca2+ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, released Ca2+ from ER, giving rise to a slow and small increase in [Ca2+]i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively altered Ca2+ release by 4-CEP, giving rise to Ca2+ spikes. In glucose-stimulated beta cells forskolin induced Ca2+ spikes that were enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting betaTC-3-cells by RNase protection assay, using type-specific RY probes, revealed low-level expression of mRNA for the type 2 isoform of the receptor (RY2). We conclude that in situ activation of RY2 in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form.


Multiple adverse outcomes following first discharge from inpatient psychiatric care: a national cohort study.
Discharged psychiatric inpatients are at elevated risk of serious adverse outcomes, but no previous study has comprehensively examined an array of multiple risks in a single cohort. We used data from the Danish Civil Registration System to delineate a cohort of all individuals born in Denmark in 1967-2000, who were alive and residing in Denmark on their 15th birthday, and who had been discharged from their first inpatient psychiatric episode at age 15 years or older. Each individual in the discharged cohort was matched on age and sex with 25 comparators without a history of psychiatric admission. Data linked to each individual were also obtained from the Psychiatric Central Research Register, Register of Causes of Death, National Patient Register, and the National Crime Register. We used survival analysis techniques to estimate absolute and relative risks of all-cause mortality, suicide, accidental death, homicide victimisation, homicide perpetration, non-fatal self-harm, violent criminality, and hospitalisation following violence, until Dec 31, 2015. We included 62 922 individuals in the discharged cohort, and 1 573 050 matched comparators. Risks for each of all eight outcomes examined were markedly elevated in the discharged cohort relative to the comparators. Within 10 years of first discharge, the cumulative incidence of death, self-harm, committing a violent crime, or hospitalisation due to interpersonal violence was 32·0% (95% CI 31·6-32·5) in the discharged cohort (37·1% [36·5-37·8] in men and 27·2% [26·7-27·8] in women). Absolute risk of at least one adverse outcome occurring within this timeframe were highest in people diagnosed with a psychoactive substance use disorder at first discharge (cumulative incidence 49·4% [48·4-50·4]), and lowest in those diagnosed with a mood disorder (24·4% [23·6-25·2]). For suicide and non-fatal self-harm, risks were especially high during the first 3 months post-discharge, whereas risks for accidental death, violent criminality, and hospitalisation due to violence were more constant throughout the 10-year follow-up. People discharged from inpatient psychiatric care are at higher risk than the rest of the population for a range of serious fatal and non-fatal adverse outcomes. Improved inter-agency liaison, intensive follow-up immediately after discharge, and longer-term social support are indicated. Medical Research Council, European Research Council, and Wellcome Trust.


A topological approach to simplification of three-dimensional scalar functions.
This paper describes an efficient combinatorial method for simplification of topological features in a 3D scalar function. The Morse-Smale complex, which provides a succinct representation of a function's associated gradient flow field, is used to identify topological features and their significance. The simplification process, guided by the Morse-Smale complex, proceeds by repeatedly applying two atomic operations that each remove a pair of critical points from the complex. Efficient storage of the complex results in execution of these atomic operations at interactive rates. Visualization of the simplified complex shows that the simplification preserves significant topological features while removing small features and noise.


Phosphorylation and localization of protein-zero related (PZR) in cultured endothelial cells.
Protein-zero related (PZR) is an immunoglobulin V (IgV)-type immunoreceptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). PZR interacts with Src homology 2 domain-containing tyrosine phosphatase (SHP-2) via its tyrosine-phosphorylated ITIMs, for which c-Src is a putative kinase. Towards elucidating PZR function in endothelial cells (ECs), the authors cloned PZR from bovine aortic endothelial cells (BAECs) and characterized it. Mature bovine PZR had 94.8% and 92.7% sequence identity with canine and human proteins, respectively, and the two ITIM sequences were conserved among higher vertebrates. PZR was expressed in many cell types and was localized to cell contacts and intracellular granules in BAECs and mesothelioma (REN) cells. Coimmunoprecipitation revealed that PZR, Grb-2-associated binder-1 (Gab1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) were three major SHP-2-binding proteins in BAECs. H(2)O(2) enhanced PZR tyrosine phosphorylation and PZR/SHP-2 interaction in ECs in a dose-and time-dependent manner. To see if tyrosine kinases other than Src are also capable of phosphorylating PZR, the authors cotransfected HEK293 cells with PZR and one of several tyrosine kinases and found that c-Src, c-Fyn, c-Lyn, Csk, and c-Abl, but not c-Fes, phosphorylated PZR and increased PZR/SHP-2 interaction. These results suggest that PZR is a cell adhesion protein that may be involved in SHP-2-dependent signaling at interendothelial cell contacts.


A new distribution-free approach to constructing the confidence region for multiple parameters.
Construction of confidence intervals or regions is an important part of statistical inference. The usual approach to constructing a confidence interval for a single parameter or confidence region for two or more parameters requires that the distribution of estimated parameters is known or can be assumed. In reality, the sampling distributions of parameters of biological importance are often unknown or difficult to be characterized. Distribution-free nonparametric resampling methods such as bootstrapping and permutation have been widely used to construct the confidence interval for a single parameter. There are also several parametric (ellipse) and nonparametric (convex hull peeling, bagplot and HPDregionplot) methods available for constructing confidence regions for two or more parameters. However, these methods have some key deficiencies including biased estimation of the true coverage rate, failure to account for the shape of the distribution inherent in the data and difficulty to implement. The purpose of this paper is to develop a new distribution-free method for constructing the confidence region that is based only on a few basic geometrical principles and accounts for the actual shape of the distribution inherent in the real data. The new method is implemented in an R package, distfree.cr/R. The statistical properties of the new method are evaluated and compared with those of the other methods through Monte Carlo simulation. Our new method outperforms the other methods regardless of whether the samples are taken from normal or non-normal bivariate distributions. In addition, the superiority of our method is consistent across different sample sizes and different levels of correlation between the two variables. We also analyze three biological data sets to illustrate the use of our new method for genomics and other biological researches.


Development of an unbiased statistical method for the analysis of unigenic evolution.
Unigenic evolution is a powerful genetic strategy involving random mutagenesis of a single gene product to delineate functionally important domains of a protein. This method involves selection of variants of the protein which retain function, followed by statistical analysis comparing expected and observed mutation frequencies of each residue. Resultant mutability indices for each residue are averaged across a specified window of codons to identify hypomutable regions of the protein. As originally described, the effect of changes to the length of this averaging window was not fully eludicated. In addition, it was unclear when sufficient functional variants had been examined to conclude that residues conserved in all variants have important functional roles. We demonstrate that the length of averaging window dramatically affects identification of individual hypomutable regions and delineation of region boundaries. Accordingly, we devised a region-independent chi-square analysis that eliminates loss of information incurred during window averaging and removes the arbitrary assignment of window length. We also present a method to estimate the probability that conserved residues have not been mutated simply by chance. In addition, we describe an improved estimation of the expected mutation frequency. Overall, these methods significantly extend the analysis of unigenic evolution data over existing methods to allow comprehensive, unbiased identification of domains and possibly even individual residues that are essential for protein function.


Impact of milk consumption and resistance training on body composition of female athletes.
Resistance exercise (RE) preceding the provision of high-quality dairy protein supports muscle anabolism. Milk contains bioactive components, including two high-quality protein fractions, calcium and vitamin D, each of which has been shown modulate body composition (increasing lean mass and decreasing fat mass) under energy balance and hypoenergetic conditions. These dairy nutrients are also essential for skeletal health. Acutely, no study of RE and milk/whey consumption has been undertaken exclusively in female athletes, let alone women, nevertheless, studies with both men and women show increased lean mass accretion following milk/whey compared to soy/placebo. Currently, no longer-term RE studies with milk supplementation have been done in female athletes. However, trials in young recreationally active women demonstrated augmented increases in lean mass and decreases in fat mass with RE and milk or whey protein consumption. The amount of protein consumed post-exercise is also important; two trials using yogurt (5 g protein/6 oz) failed to demonstrate a positive change in body composition compared to placebo. For bone health, RE plus dairy improved bone mineral density at clinically important sites and reduced bone resorption. With energy restriction, in one study, higher dairy plus higher protein resulted in greater fat loss, lean mass gain and improved bone health in overweight women. In another study, milk and calcium supplementation showed no greater benefit. Neither trial exclusively utilized RE. Overall, RE and milk/dairy consumption positively impact body composition in women by promoting losses in fat, gains or maintenance of lean mass and preservation of bone. Future studies in female athletes and under energy restriction with RE alone are warranted.


Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.
Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.


Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility.
Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5(+/-) leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development. These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease.


Changes in physiological parameters and feeding behaviour of Atlantic salmon Salmo salar infected with sea lice Lepeophtheirus salmonis.
Atlantic salmon Salmo salar L. artificially infected with salmon lice Lepeophtheirus salmonis (Krøyer 1837) recovered from detrimental physiological changes and skin damage induced by preadult lice as the parasites matured. Growth rates of Atlantic salmon remained unaffected by lice infection, but food consumption decreased with increasing feeding and movement of the lice prior to and post-mating, correlating with the appearance of head erosions and detrimental changes in physiological integrity. Food consumption of the fish increased as the lice moulted to the adult stage and gravid female lice settled in a posterior location on the fish, subsequently reducing the impact of infection and allowing recovery of the skin damage. However, the impact of preadults was limited, as the decrease in food consumption of fish at 21 d post-infection had no effect on either the specific growth rate or condition factor of the fish. Furthermore, the intensity of lice infections at each of the sample days was not correlated with food consumption, specific growth rate or any of the haematological or physiological parameters measured, either before or after infection, indicating that lice intensity was independent of social dominance/subordinance. This work has provided the first evidence that infected fish can recover from the detrimental changes caused by lice infection, even when they are still infected with lice. If fish can survive the preadult stage of lice, then the mortal impact of lice infections is greatly reduced.


Analysis of the (μ/μI,λ)-CSA-ES with Repair by Projection Applied to a Conically Constrained Problem.
Theoretical analyses of evolution strategies are indispensable for gaining a deep understanding of their inner workings. For constrained problems, rather simple problems are of interest in the current research. This work presents a theoretical analysis of a multi-recombinative evolution strategy with cumulative step size adaptation applied to a conically constrained linear optimization problem. The state of the strategy is modeled by random variables and a stochastic iterative mapping is introduced. For the analytical treatment, fluctuations are neglected and the mean value iterative system is considered. Nonlinear difference equations are derived based on one-generation progress rates. Based on that, expressions for the steady state of the mean value iterative system are derived. By comparison with real algorithm runs, it is shown that for the considered assumptions, the theoretical derivations are able to predict the dynamics and the steady state values of the real runs.


Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial.
Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH. We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915. Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism). In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA. Octapharma.


Amyloid imaging in cognitively normal older adults: comparison between (18)F-flutemetamol and (11)C-Pittsburgh compound B.
Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.


Engaging Young Black Males in Sexual and Reproductive Health Care: A Review of the Literature.
Young Black males (YBM) ages 18 to 24 years are more at risk of contracting sexually transmitted infections (STIs) and have a substantially greater need for sexual reproductive health (SRH) services than other groups. Despite this significant need, the extant literature does not provide a comprehensive picture of how YBM seek preventive care services (e.g., STI testing). Therefore, the purpose of this review is to address YBM's SRH access and use of STI/HIV testing and screening in this population, with a specific emphasis on young heterosexual Black males, by identifying barriers and facilitators of engaging with SRH care. An electronic search was performed using Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, PubMed, and Scopus online databases. Keywords were adapted to each database and included variations of "Black males," "sexual reproductive healthcare services," "youth (18-24 years old)," and "healthcare access and utilization." Studies from the review reported that barriers to engaging in SRH care included lack of health insurance, ideas of masculinity that conflict with SRH care, stigma related to accessing services, and lack of knowledge regarding available services and care options. The top facilitators for utilizing SRH care were engagement on behalf of health clinics, confidence gained from social support, access to quality health care in one's community, and trust in the health care system and providers. This review contributes to the current state of the science and is important to the improvement of high-quality services for this population, including respect, choice in care, confidentially, and compassion.


Soft drink and juice consumption and risk of pancreatic cancer: the Singapore Chinese Health Study.
Sugar-sweetened carbonated beverages (called soft drinks) and juices, which have a high glycemic load relative to other foods and beverages, have been hypothesized as pancreatic cancer risk factors. However, data thus far are scarce, especially from non-European descent populations. We investigated whether higher consumption of soft drinks and juice increases the risk of pancreatic cancer in Chinese men and women. A prospective cohort analysis was done to examine the association between soft drink and juice consumption and the risk of pancreatic cancer in 60,524 participants of the Singapore Chinese Health Study with up to 14 years of follow-up. Information on consumption of soft drinks, juice, and other dietary items, as well as lifestyle and environmental exposures, was collected through in-person interviews at recruitment. Pancreatic cancer cases and deaths were ascertained by record linkage of the cohort database with records of population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths. The first 14 years for the cohort resulted in cumulative 648,387 person-years and 140 incident pancreatic cancer cases. Individuals consuming > or = 2 soft drinks/wk experienced a statistically significant increased risk of pancreatic cancer (hazard ratio, 1.87; 95% confidence interval, 1.10-3.15) compared with individuals who did not consume soft drinks after adjustment for potential confounders. There was no statistically significant association between juice consumption and risk of pancreatic cancer. Regular consumption of soft drinks may play an independent role in the development of pancreatic cancer.


Analysis of proteoglycan gene messages in human nasal mucosa and nasal polyp using dot blot hybridization.
It has been suggested that the formation and growth of nasal polyp require the remodeling of extracellular matrix. Proteoglycans (PGs) are major components of the extracellular matrix that maintain the integrity of structural tissue. The leucine-rich repeat PGs include lumican, decorin and biglycan and have many important biologic activities in various pathologic conditions, including the remodeling of the extracellular matrix. Therefore, these small-PG families may be involved in the formation and growth of nasal polyp. In the present study, surgical specimens of nasal polyps and nasal mucosa were assessed for expression of mRNA coding for lumican, decorin and biglycan using reverse transcriptase-polymerase chain reaction followed by dot blot hybridization. Lumican, decorin and biglycan mRNA were expressed in all tissue samples examined. Semiquantitative dot blot hybridization revealed that the levels of the lumican and biglycan messages are lower in nasal polyp tissues than in nasal mucosa. The decorin messages in nasal polyp were expressed at levels similar to those in nasal mucosa. These results suggest that lumican, decorin and biglycan may be important components of the extracellular matrix in nasal mucosa. Considering the function of these PGs, normal levels of decorin associated with low levels of biglycan and lumican may play a role in the pathogenesis of nasal polyposis.


Seasonal microbial and nutrient responses during a 5-year reduction in the daily temperature range of soil in a Chihuahuan Desert ecosystem.
High daily temperature range of soil (DTRsoil) negatively affects soil microbial biomass and activity, but its interaction with seasonal soil moisture in regulating ecosystem function remains unclear. For our 5-year field study in the Chihuahuan Desert, we suspended shade cloth 15 cm above the soil surface to reduce daytime temperature and increase nighttime soil temperature compared to unshaded plots, thereby reducing DTRsoil (by 5 ºC at 0.2 cm depth) without altering mean temperatures. Microbial biomass production was primarily regulated by seasonal precipitation with the magnitude of the response dependent on DTRsoil. Reduced DTRsoil more consistently increased microbial biomass nitrogen (MBN; +38%) than microbial biomass carbon (MBC) with treatment responses being similar in spring and summer. Soil respiration depended primarily on soil moisture with responses to reduced DTRsoil evident only in wetter summer soils (+53%) and not in dry spring soils. Reduced DTRsoil had no effect on concentrations of dissolved organic C, soil organic matter (SOM), nor soil inorganic N (extractable NO3 (-)-N + NH4 (+)-N). Higher MBN without changes in soil inorganic N suggests faster N cycling rates or alternate sources of N. If N cycling rates increased without a change to external N inputs (atmospheric N deposition or N fixation), then productivity in this desert system, which is N-poor and low in SOM, could be negatively impacted with continued decreases in daily temperature range. Thus, the future N balance in arid ecosystems, under conditions of lower DTR, seems linked to future precipitation regimes through N deposition and regulation of soil heat load dynamics.


Comparison of four peak spinal loading exposure measurement methods and their association with low-back pain.
This paper examines the performance of 4 different methods of estimating peak spinal loading and their relationship with the reporting of low-back pain. The data used for this comparison was a subset of subjects from a case-referent study of low-back-pain reporting in the automotive industry, in which 130 random referents and 105 cases (or job-matched proxies) were studied. The peak load on the lumbar spine was determined using a biomechanical model with model inputs coming from a detailed self-report questionnaire, a task-based check list, a video digitization method, and a posture and load sampling technique. The methods were directly comparable through a common metric of newtons or newton meters of spinal loading in compression, shear, or moment modes. All the methods showed significant and substantial associations with low-back pain in all modes (odds ratios 1.6-2.3). The intraclass correlation coefficients (ICC) showed strong similarities between the checklist and video digitized techniques (ICC 0.84-0.91), moderate similarities between these techniques and the work sampling method (ICC 0.49-0.52), and poor correlations (ICC 0.16-0.40) between the self-report questionnaire and the observer recorded measures. While all the methods detected significant odds ratios, they cannot all be used interchangeably for risk assessment at the individual level. Peak spinal compression, moment, and shear are important risk factors for low-back pain reporting, no matter which measurement method is used. Questionnaires can be used for large-scale studies. At the individual level a task-based checklist provides biomechanical model inputs at lower cost and equal performance compared with the criterion video digitization system.


Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis.
The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes. We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33). Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.


Anisotropic Redox Conductivity within a Metal-Organic Framework Material.
Engendering electrical conductivity in otherwise insulating metal-organic framework (MOF) materials is key to rendering these materials fully functional for a range of potential applications, including electrochemical and photo-electrochemical catalysis. Here we report that the platform MOF, NU-1000, can be made electrically conductive via reversible electrochemical oxidation of a fraction of the framework's tetraphenylpyrene linkers, where the basis for conduction is redox hopping. At a microscopic level, redox hopping is akin to electron self-exchange and is describable by Marcus' well-known theory of electron transfer. At a macroscopic level, the hopping behavior leads to diffusive charge transport and is quantifiable as an apparent diffusion coefficient, Dhopping. Theory suggests that the csq topology of NU-1000, together with its characteristic one-dimensional mesopores, will result in direction-dependent, that is, anisotropic, electrical conductivity. Detailed computations suggest that the governing factor is the strength of electronic coupling between pairs of linkers sited in the a,b plane of the MOF versus the mesopore-aligned c axis of the crystal. The notion has been put to the test experimentally by configuring the MOF as an array of selectively oriented, electrode-supported crystallites, where the rodlike crystallites are either oriented largely normal to the electrode (requiring redox hopping along the c direction) or mainly parallel (requiring redox hopping mainly through the a,b plane). The orientations are preselected by preparing MOF films either via interfacial solvothermal synthesis or via electrophoretic deposition. In semiquantitative accord with computational predictions, Dhopping is up to ∼3500 times larger in the c direction than through the a,b plane. In addition to their fundamental significance, the findings have clear implications for the design and optimization of MOFs for electrocatalysis and for other applications that rely upon electrical conductivity.


Dewetting near the glass transition: transition from a capillary force dominated to a dissipation dominated regime.
Dynamics and corresponding morphology of dewetting of thin polystyrene films at temperatures close to the glass transition were investigated by measuring simultaneously dewetted distance and width of the rim. Comparing the opening of cylindrical holes with the retraction of a straight contact line revealed (i). a drastic influence of the geometry (planar or radial symmetry) on the dynamics at early stages, (ii). a new logarithmic dewetting regime, and (iii). transitions between four dewetting regimes clearly indicated by changes in the shape of the rim. The complete dewetting scenario can be understood as an initial dominance of capillary driving forces, which is progressively overtaken by dissipation related to the increasing size of the rim.


Diabetes-induced alterations in atrial natriuretic peptide gene expression in Wistar-Kyoto and spontaneously hypertensive rats.
We investigated the effects of streptozotocin-induced diabetes on atrial natriuretic peptide (ANP) synthesis, hemodynamic parameters, blood volume, and histopathology, as well as the reversibility of such effects with insulin therapy in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The biatrial ANP messenger RNA (mRNA) levels in the diabetic WKY rats increased by 16-17% compared with those in the age-matched WKY rats at 12 weeks after the onset of diabetes, whereas their ventricular ANP mRNA levels showed increases of 190% in left ventricles and 160% in right ventricles at 8 weeks. In the diabetic SHRs, the left atrial ANP mRNA levels increased by 36% compared with those in the age-matched SHRs, as early as 4 weeks after diabetes onset. Their ventricular ANP mRNA levels also showed 80-82% increases in left and right ventricles at 4 weeks. In proportion to changes in cardiac ANP synthesis, the biventricular end-diastolic pressures were significantly elevated at 8 weeks in the diabetic WKY rats and at 4 weeks in the diabetic SHRs. The blood volume significantly increased at 8 weeks in the diabetic WKY rats and remained higher thereafter, whereas it did not change in the diabetic SHRs throughout the experimental period. The left ventricular peak dP/dt was depressed in the 8-week diabetic SHRs, whereas in the diabetic WKY rats, its depression was observed at 12 weeks after diabetes onset. Histopathological studies showed that diabetic changes in ANP synthesis and hemodynamic parameters described above occurred before the cardiomyopathic histological changes. Cardiac ANP synthesis in the diabetic rats completely reverted to control levels after insulin therapy, accompanied by normalization of hemodynamic parameters. The present study indicates that 1) ANP synthesis is significantly augmented in the streptozotocin-induced diabetic rat compared with that in the normal rat, and the combination of diabetes and hypertension produces an earlier and greater effect in stimulating cardiac ANP synthesis than does either disease alone; 2) an elevation in the intraventricular filling pressure that occurs before observable cardiomyopathic histopathological alterations might be involved partially in the augmented ANP synthesis; and 3) the reversibility with insulin therapy suggests that the streptozotocin-induced alterations observed in cardiac ANP synthesis and hemodynamics result from insulin-deficient diabetes mellitus, not from cardiac toxicity of streptozotocin.


The effects of joint position and direction of joint motion on proprioceptive sensibility in anterior cruciate ligament-deficient athletes.
We studied a group of anterior cruciate ligament-deficient athletes to identify whether joint position and direction of joint motion have a significant effect on proprioception. Twenty-nine anterior cruciate ligament-deficient athletes were tested for their threshold to detect passive motion at both 15 degrees and 45 degrees moving into the directions of both flexion and extension. The single-legged hop test was used to identify function in the deficient limb. Results demonstrated statistically significant deficits in threshold to detect passive motion for the deficient limb at 15 degrees moving into extension. For the deficient limb, threshold to detect passive motion was significantly more sensitive moving into extension than flexion at a starting angle of 15 degrees; at a starting angle of 15 degrees moving into extension threshold was significantly more sensitive than at a starting angle of 45 degrees moving into extension. We conclude that in deficient limbs proprioception is significantly more sensitive in the end ranges of knee extension (15 degrees) and is significantly more sensitive moving into the direction of extension. To effectively restore reflex stabilization of the lower limb we recommend a rehabilitation program emphasizing performance-based, weightbearing, closed kinetic chain exercise for the muscle groups that act on the knee joint.


Validity and reliability of the St. George's Respiratory Questionnaire in assessing health status in patients with chronic pulmonary aspergillosis.
Chronic pulmonary aspergillosis (CPA) markedly reduces lung function through progressive lung destruction. To date, however, health status in patients with CPA has not been studied. This is due, in part, to a lack of adequately validated scales. The St. George's Respiratory Questionnaire (SGRQ) is widely used for several chronic respiratory diseases, but not for CPA. We examined the reliability and validity of SGRQ in CPA. Eighty-eight patients with CPA completed the SGRQ, the Short Form-36 Health Survey (SF-36), and the Medical Research Council (MRC) dyspnea scale. Lung function and BMI were also measured. Pearson correlation, t test, analysis of variance, and their equivalents for nonparametric data and multivariate linear and binary analyses were used. The SGRQ components (symptoms, activity, and impact) and total scores achieved high internal consistency (Cronbach α = 0.77, 0.91, 0.86, and 0.94), and SGRQ components had good intercorrelation (r ≥ 0.41; P < .001) and correlated well with the total score (r ≥ 0.63; P < .001). There were high, intraclass, correlation coefficients for the total SGRQ and its dimensions (≥ 0.92). The SGRQ scores showed significant correlation with the MRC dyspnea scale and SF-36 components and differentiated between all grades of shortness of breath and different bands of disease severity (P < .05). In addition, patients with greater clinician-rated disease severity had more impairment of health status (P < .006). CPA severity was independently associated with impairment in health status, and COPD comorbidity significantly affected the health status in patients with CPA. SGRQ demonstrated a significant level of reliability and validity in measuring health status in CPA.


Error analysis of CCD-based point source centroid computation under the background light.
The CCD-based point source centroid computation (PSCC) error under the background light is analyzed integrally in theory, numerical simulation and experiment. Furthermore, a comprehensive formula of the PSCC error caused by the diversified error sources is put forward. The optimum threshold to reduce the effects of all the error sources to a minimum is selected. The best threshold level is N(B) +3sigma(B), where N(B) is the average value of the error sources and sigma(B) is the mean-square value of the fluctuation of the error sources. The simulation and experiment results are in great accordance with the theoretical analysis.


Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis.
In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp0] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp0 strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp0 strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp0 strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond.


Assessment of deep tissue hyperalgesia in the groin - a method comparison of electrical vs. pressure stimulation.
Deep pain complaints are more frequent than cutaneous in post-surgical patients, and a prevalent finding in quantitative sensory testing studies. However, the preferred assessment method - pressure algometry - is indirect and tissue unspecific, hindering advances in treatment and preventive strategies. Thus, there is a need for development of methods with direct stimulation of suspected hyperalgesic tissues to identify the peripheral origin of nociceptive input. We compared the reliability of an ultrasound-guided needle stimulation protocol of electrical detection and pain thresholds to pressure algometry, by performing identical test-retest sequences 10 days apart, in deep tissues in the groin region. Electrical stimulation was performed by five up-and-down staircase series of single impulses of 0.04 ms duration, starting from 0 mA in increments of 0.2 mA until a threshold was reached and descending until sensation was lost. Method reliability was assessed by Bland-Altman plots, descriptive statistics, coefficients of variance and intraclass correlation coefficients. The electrical stimulation method was comparable to pressure algometry regarding 10 days test-retest repeatability, but with superior same-day reliability for electrical stimulation (P < 0.05). Between-subject variance rather than within-subject variance was the main source for test variation. There were no systematic differences in electrical thresholds across tissues and locations (P > 0.05). The presented tissue-specific direct deep tissue electrical stimulation technique has equal or superior reliability compared with the indirect tissue-unspecific stimulation by pressure algometry. This method may facilitate advances in mechanism based preventive and treatment strategies in acute and chronic post-surgical pain states.


Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas.
Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.


Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes.
Idd9.3, a locus that determines susceptibility to the autoimmune disease type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, has been mapped to the distal region of chromosome 4. In the current report we reduce the size of the Idd9.3 interval to 1.2Mb containing 15 genes, including one encoding the immune signaling molecule, 4-1BB, which shows amino acid variation between diabetes sensitive and resistant strains. 4-1BB, a member of the TNF receptor superfamily expressed by a variety of immune cells, mediates growth and survival signals for T cells. Functional analyses demonstrate that purified T cells from NOD congenic mice with the C57BL/10 (B10) allele at Idd9.3 produce more IL-2 and proliferate more vigorously in response to anti-CD3 plus immobilized 4-1BB ligand than T cells from NOD mice with the NOD allele at Idd9.3. In contrast, the response to anti-CD3 plus anti-CD28 costimulation was indistinguishable between the congenic strains, pinpointing the differences in NOD versus NOD.B10 Idd9.3 T cell responses to the 4-1BB costimulatory pathway. These data provide evidence in support of Idd9.3 as the locus encoding 4-1BB and suggest that the 4-1BB signaling pathway could have a primary function in the etiology of autoimmune disease.


Factors associated with depressive symptoms and use of antidepressant medications among participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies.
Depressive symptoms are correlated with poor health outcomes in adults with chronic kidney disease (CKD). The prevalence, severity, and treatment of depressive symptoms and potential risk factors, including level of kidney function, in diverse populations with CKD have not been well studied. Cross-sectional analysis. Participants at enrollment into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies. CRIC enrolled Hispanics and non-Hispanics at 7 centers in 2003-2007, and H-CRIC enrolled Hispanics at the University of Illinois in 2005-2008. Depressive symptoms measured by Beck Depression Inventory (BDI). Demographic and clinical factors. Elevated depressive symptoms (BDI score ≥11) and antidepressant medication use. Of 3,853 participants, 27.4% had evidence of elevated depressive symptoms and 18.2% were using antidepressant medications; 31.0% of persons with elevated depressive symptoms were using antidepressants. The prevalence of elevated depressive symptoms varied by level of kidney function: 23.6% for participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) and 33.8% of those with eGFR <30 mL/min/1.73 m(2). Lower eGFR (OR per 10-mL/min/1.73 m(2) decrease, 1.10; 95% CI, 1.04-1.17), and non-Hispanic black race (OR, 1.42; 95% CI, 1.16-1.74) were each associated with increased odds of elevated depressive symptoms after controlling for other factors. In regression analyses incorporating BDI score, whereas female sex was associated with greater odds of antidepressant use, Hispanic ethnicity, non-Hispanic black race, and higher urine albumin levels were associated with decreased odds of antidepressant use (P < 0.05 for each). Absence of clinical diagnosis of depression and use of nonpharmacologic treatments. Although elevated depressive symptoms were common in individuals with CKD, use of antidepressant medications is low. Individuals of racial and ethnic minority background and with more advanced CKD had a greater burden of elevated depressive symptoms and lower use of antidepressant medications.


Trajectories of Risk for Specific Readmission Diagnoses after Hospitalization for Heart Failure, Acute Myocardial Infarction, or Pneumonia.
The risk of rehospitalization is elevated in the immediate post-discharge period and declines over time. It is not known if the extent and timing of risk vary across readmission diagnoses, suggesting that recovery and vulnerability after discharge differ by physiologic system. We compared risk trajectories for major readmission diagnoses in the year after discharge among all Medicare fee-for-service beneficiaries hospitalized with heart failure (HF), acute myocardial infarction (AMI), or pneumonia from 2008-2010. We estimated the daily risk of rehospitalization for 12 major readmission diagnostic categories after accounting for the competing risk of death after discharge. For each diagnostic category, we identified (1) the time required for readmission risk to peak and then decline 50% from maximum values after discharge; (2) the time required for readmission risk to approach plateau periods of minimal day-to-day change; and (3) the extent to which hospitalization risks are higher among patients recently discharged from the hospital compared with the general elderly population. Among >3,000,000 hospitalizations, the yearly rate of rehospitalization was 67.0%, 49.5%, and 55.3% after hospitalization for HF, AMI, and pneumonia, respectively. The extent and timing of risk varied by readmission diagnosis and initial admitting condition. Risk of readmission for gastrointestinal bleeding/anemia peaked particularly late after hospital discharge, occurring 10, 6, and 7 days after hospitalization for HF, AMI, and pneumonia, respectively. Risk of readmission for trauma/injury declined particularly slowly, requiring 38, 20, and 38 days to decline by 50% after hospitalization for HF, AMI, and pneumonia, respectively. Patterns of vulnerability to different conditions that cause rehospitalization vary by time after hospital discharge. This finding suggests that recovery of various physiologic systems occurs at different rates and that post-discharge interventions to minimize vulnerability to specific conditions should be tailored to their underlying risks.