Fibroblast Activation Protein-Targeted PET/CT with 18F-Fibroblast Activation Protein Inhibitor-74 for Evaluation of Gastrointestinal Cancer: Comparison with 18F-FDG PET/CT.
Fibroblast activation protein is overexpressed in the stroma of several cancer types. 18F-fibroblast activation protein inhibitor (FAPI)-74 is a PET tracer with high selectivity for fibroblast activation protein and has shown high accumulation in human tumors in clinical studies. However, the use of 18F-FAPI-74 for PET imaging of gastrointestinal cancer has not been systematically investigated. Herein, we investigated the diagnostic accuracy of 18F-FAPI-74 (18F-LNC1005) PET/CT in gastric, liver, and pancreatic cancers and compared the results with those of 18F-FDG PET/CT. Methods: This prospective study analyzed patients with confirmed gastric, liver, or pancreatic malignancies who underwent concurrent 18F-FDG and 18F-FAPI-74 PET/CT between June 2022 and December 2022. PET/CT findings were confirmed by histopathology or radiographic follow-up. 18F-FDG and 18F-FAPI-74 uptake and tumor-to-background ratios were compared using the Wilcoxon signed-rank test. The McNemar test was used to compare the diagnostic accuracy of the 2 scans. Results: Our cohort consisted of 112 patients: 49 with gastric cancer, 39 with liver cancer, and 24 with pancreatic cancer. Among them, 69 patients underwent PET/CT for initial staging and 43 for recurrence detection. Regarding lesion-based diagnostic accuracy, 18F-FAPI-74 PET/CT showed higher sensitivity than did 18F-FDG in the detection of primary tumors (gastric cancer, 88% [22/25] vs. 60% [15/25], P = 0.016; liver cancer, 100% [22/22] vs. 82% [18/22], P = 0.125; pancreatic cancer, 100% [22/22] vs. 86% [19/22], P = 0.250), local recurrence (92% [23/25] vs. 56% [14/25]; P = 0.021), involved lymph nodes (71% [41/58] vs. 40% [23/58]; P < 0.001), and bone and visceral metastases (98% [350/358] vs. 47% [168/358]; P < 0.001). Compared with 18F-FDG, 18F-FAPI-74 PET/CT upstaged 17 patients' TNM staging among all treatment-naïve patients (17/69, 25%) and changed the clinical management of 4 patients (4/43, 9%) in whom recurrence or metastases were detected. Conclusion: 18F-FAPI-74 PET/CT is superior to 18F-FDG PET/CT in detecting primary tumors, local recurrence, lymph node involvement, and bone and visceral metastases in gastric, pancreatic, and liver cancers, with higher uptake in most primary and metastatic lesions.


Expression of macrophage markers by a population of T cells obtained from synovial fluid of a subgroup of patients with juvenile rheumatoid arthritis.
To characterize distinctive lymphoid cell populations in the synovial fluid (SF) of patients with juvenile rheumatoid arthritis (JRA) that have the specific ability to display monocytic markers when cultured in vitro. Mononuclear cells obtained from SF of patients with JRA and depleted of adherent macrophages were cultured in vitro in RPMI 1640 medium supplemented with only fetal calf serum (FCS). Phenotypic evaluation of these cells was by flow cytometry and immunohistochemical analysis was by specific fluorochrome labeled antibodies. T cells from a JRA subgroup displayed some typical macrophage attributes, i.e., abundant cytoplasm, adherence to plastic, and phagocytosis of latex beads when cultured in vitro. These cells have the ability to survive in culture for several weeks in RPMI 1640 medium containing only 10% FCS. The macrophage-like T cells rosetted with sheep red blood cells and proliferated when stimulated with phytohemagglutinin or anti-CD3, indicating functional T cell responses. Our data indicate that a population of T cells obtained from the SF of a subgroup of patients with JRA exhibited characteristics of macrophages, yet retained their CD3 and T cell receptor expression. Whether this promiscuous behavior is caused by malignant transformation of lymphoid precursor cells or is induced by the concerted effect of a myriad of cytokines and growth factors present in the SF remains unknown. The presence of these cells in the SF of 2 patients with JRA with different onset types raises the question of their function and significance in an autoimmune disorder such as JRA.


Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia.
We have previously shown that low-dose ionizing radiation (LDIR) induces angiogenesis but there is no evidence that it induces neovascularization in the setting of peripheral arterial disease. Here, we investigated the use of LDIR as an innovative and non-invasive strategy to stimulate therapeutic neovascularization using a model of experimentally induced hindlimb ischemia (HLI). After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.3 Gy, in consecutive days and allowed to recover. We demonstrate that LDIR, significantly improved blood perfusion in the murine ischemic limb by stimulating neovascularization, as assessed by laser Doppler flow, capillary density, and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF, and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs) mediating their incorporation to ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Importantly, LDIR induced a durable and simultaneous up-regulation of a repertoire of pro-angiogenic factors and their receptors in endothelial cells (ECs), as evident in ECs isolated from the irradiated gastrocnemius muscles by laser capture microdissection. This specific mechanism was mediated via vascular endothelial growth factor (VEGF) receptor signaling, since VEGF receptor inhibition abrogated the LDIR-mediated gene up-regulation and impeded the increase in capillary density. Finally, the vasculature in an irradiated non-ischemic bed was not affected and after 52 week of LDIR exposure no differences in the incidence of morbidity and mortality were seen. These findings disclose an innovative, non-invasive strategy to induce therapeutic neovascularization in a mouse model of HLI, emerging as a novel approach in the treatment of critical limb ischemia patients.


Stable organic field-effect transistors for continuous and nondestructive sensing of chemical and biologically relevant molecules in aqueous environment.
The use of organic field-effect transistors (OFETs) as sensors in aqueous media has gained increased attention for environmental monitoring and medical diagnostics. However, stable operation of OFETs in aqueous media is particularly challenging because of electrolytic hydrolysis of water, high ionic conduction through the analyte, and irreversible damage of organic semiconductors when exposed to water. To date, OFET sensors have shown the capability of label-free sensing of various chemical/biological species, but they could only be used once because their operational stability and lifetime while operating in aqueous environments has been poor, and their response times typically slow. Here, we report on OFETs with unprecedented water stability. These OFETs are suitable for the implementation of reusable chemical/biological sensors because they primarily respond to charged species diluted in an aqueous media by rapidly shifting their threshold voltage. These OFET sensors present stable current baselines and saturated signals which are ideal for detection of low concentration of small or large molecules that alter the pH of an aqueous environment. The overall response of these OFET sensors paves the way for the development of continuous chemical/biological nondestructive sensor applications in aqueous media.


Do bending, twisting, and diurnal fluid changes in the disc affect the propensity to prolapse? A viscoelastic finite element model.
A finite element model of a lumbar motion segment was constructed. The model was directed toward understanding the effect of compression, bending and twisting, and diurnal fluid changes in the disc on the propensity to disc prolapse. Tensile stresses in the anulus fibers were computed and used to determine the successive steps required to create a fissure in the disc. Disc prolapse is more likely under combined loading involving compression and bending and twisting. Changes in fluid content in the disc also affect the mechanical behavior of the disc. The three-dimensional model accounted for the viscoelastic material properties of the anulus fibers and ligaments. Diurnal fluid exchange was simulated by changing the fluid content in the nucleus of the disc. Combined with bending and twisting, a compressive load was applied at different loading rates. The maximum tensile stress in the anulus fibers always occurred in the fibers at the inner posterior anulus at the junction of the disc and the endplate. Of the three models tested, the "weakest" (or the first to fail) was the saturated disc subjected to compression and bending and twisting. As the loading rate increased, anulus fiber failure was initiated at a lower value of compressive load. An increasing compressive load applied to a flexed, twisted, and saturated disc resulted in progressive failure, or fissure propagation, starting at the posterior inner anulus at the junction of the disc and the endplate. The results from this study suggest that there are several key factors involved in the initiation and propagation of anulus failure: axial compressive load, bending and twisting, and disc saturation. If one of these is lacking, anulus failure is harder to achieve.


Multi UAV Coverage Path Planning in Urban Environments.
Coverage path planning (CPP) is a field of study which objective is to find a path that covers every point of a certain area of interest. Recently, the use of Unmanned Aerial Vehicles (UAVs) has become more proficient in various applications such as surveillance, terrain coverage, mapping, natural disaster tracking, transport, and others. The aim of this paper is to design efficient coverage path planning collision-avoidance capable algorithms for single or multi UAV systems in cluttered urban environments. Two algorithms are developed and explored: one of them plans paths to cover a target zone delimited by a given perimeter with predefined coverage height and bandwidth, using a boustrophedon flight pattern, while the other proposed algorithm follows a set of predefined viewpoints, calculating a smooth path that ensures that the UAVs pass over the objectives. Both algorithms have been developed for a scalable number of UAVs, which fly in a triangular deformable leader-follower formation with the leader at its front. In the case of an even number of UAVs, there is no leader at the front of the formation and a virtual leader is used to plan the paths of the followers. The presented algorithms also have collision avoidance capabilities, powered by the Fast Marching Square algorithm. These algorithms are tested in various simulated urban and cluttered environments, and they prove capable of providing safe and smooth paths for the UAV formation in urban environments.


Investigating reference genes for quantitative real-time PCR analysis across four chicken tissues.
Accurate normalization of data is required to correct for different efficiencies and errors during the processing of samples in reverse transcription PCR analysis. The chicken is one of the main livestock species and its genome was one of the first reported and used in large scale transcriptomic analysis. Despite this, the chicken has not been investigated regarding the identification of reference genes suitable for the quantitative PCR analysis of growth and fattening genes. In this study, five candidate reference genes (B2M, RPL32, SDHA, TBP and YWHAZ) were evaluated to determine the most stable internal reference for quantitative PCR normalization in the two main commercial muscles (pectoralis major (breast) and biceps femoris (thigh)), liver and abdominal fat. Four statistical methods (geNorm, NormFinder, CV and BestKeeper) were used in the evaluation of the most suitable combination of reference genes. Additionally, a comprehensive ranking was established with the RefFinder tool. This analysis identified YWHAZ and TBP as the recommended combination for the analysis of biceps femoris and liver, YWHAZ and RPL32 for pectoralis major and RPL32 and B2M for abdominal fat and across-tissue studies. The final ranking for each tool changed slightly but overall the results, and most particularly the ability to discard the least robust candidates, were consistent between tools. The selection and number of reference genes were validated using SCD, a target gene related to fat metabolism. Overall, the results can be directly used to quantitate target gene expression in different tissues or in validation studies from larger transcriptomic experiments.


High-density microprojection array delivery to rat skin of low doses of trivalent inactivated poliovirus vaccine elicits potent neutralising antibody responses.
To secure a polio-free world, the live attenuated oral poliovirus vaccine (OPV) will eventually need to be replaced with inactivated poliovirus vaccines (IPV). However, current IPV delivery is less suitable for campaign use than OPV, and more expensive. We are progressing a microarray patch delivery platform, the Nanopatch, as an easy-to-use device to administer vaccines, including IPV. The Nanopatch contains an ultra-high density array (10,000/cm2) of short (~230 μm) microprojections that delivers dry coated vaccine into the skin. Here, we compare the relative immunogenicity of Nanopatch immunisation versus intramuscular injection in rats, using monovalent and trivalent formulations of IPV. Nanopatch delivery elicits faster antibody response kinetics, with high titres of neutralising antibody after just one (IPV2) or two (IPV1 and IPV3) immunisations, while IM injection requires two (IPV2) or three (IPV1 and IPV3) immunisations to induce similar responses. Seroconversion to each poliovirus type was seen in 100% of rats that received ~1/40th of a human dose of IPV delivered by Nanopatch, but not in rats given ~1/8th or ~1/40th dose by IM injection. Ease of administration coupled with dose reduction observed in this study suggests the Nanopatch could facilitate inexpensive IPV vaccination in campaign settings.


High-power Femtosecond Optical Parametric Amplification at 1 kHz in BiB(3)O(6) pumped at 800 nm.
Substantial power scaling of a travelling-wave femtosecond optical parametric amplifier, pumped near 800 nm by a 1 kHz Ti:sapphire laser amplifier, is demonstrated using monoclinic BiB(3)O(6) in a two stage scheme with continuum seeding. Total energy output (signal plus idler) exceeding 1 mJ is achieved, corresponding to an intrinsic conversion efficiency of approximately 32% for the second stage. The tunability extends from 1.1 to 2.9 microm. The high parametric gain and broad amplification bandwidth of this crystal allowed the maintenance of the pump pulse duration, leading to pulse lengths less than 140 fs, both for the signal and idler pulses, even at such high output levels.


A comparison between cetirizine and ondansetron in preventing postoperative nausea and vomiting in adults.
Postoperative nausea and vomiting are some of the important and common side effects of anesthesia after surgery occurring in almost 20-30% of patients and is the second factor of a patient's complaint and inconvenience after pain. This study compares the effect of oral cetirizine and ondansetron in the prevention of postoperative nausea and vomiting in adults. In a blind and prospective study in fall 2010, 300 patients aged 18-65 years who were among ASA I-II in Chamran Orthopedic Hospital were randomly divided into three equal groups receiving cetirizine, ondansetron, and placebo, respectively. General anesthesia was identical. After operation (after 1-2 h in the recovery room, after 2-12 and 12-24 h in the ward), the presence or absence and any nausea or vomiting was recorded. The postoperative nausea and vomiting (PONV) rate after 1-2 h in the recovery room, after 2-12 and 12-24 h in the ward in placebo, and both groups of cetirizine and ondansetron were 50%, 21%, and 11%, respectively while the difference was significant (P value < 0.05). Regarding the number of vomiting, the least was related to ondansetron (especially in the first 2-12 h) but the difference was not significant (P > 0.05). The PONV rate in cetirizine and ondansetron groups was less than the placebo group.


Hepatic microsomal adenosine triphosphatase and mitochondrial function. Response to cold and warm ischemia.
We investigated the response of mitochondrial function and microsomal adenosine triphosphatase (ATPase) activity in rat liver tissue subjected to in vitro ischemia at either 0 degree C to 4 degrees C or 37 degrees C for 30 to 60 minutes. Mitochondrial coupling, expressed as respiratory control index, was preserved at up to 60 minutes' cold ischemia. However, respiratory control index was decreased significantly from control by 30 minutes of warm ischemia. Both microsomal magnesium-activated ATPase and sodium-potassium ATPase activity were significantly increased by 60 minutes of warm ischemia yet were unaltered by 60 minutes of ischemia at 0 degree C to 4 degrees C. Warm ischemia produces deleterious effects on energy-generating (mitochondria) and energy-utilizing (ATPase) activity. Hypothermia provides a significant prolongation of cellular viability in ischemic tissue in terms of bioenergetic status. In addition to organ procurement and transplantation, hypothermic cytoprotection may prove valuable in areas such as shock, ischemia, and other clinical conditions of compromised visceral perfusion.


Meta-analysis of prevalence: I2 statistic and how to deal with heterogeneity.
Over the last decade, there has been a 10-fold increase in the number of published systematic reviews of prevalence. In meta-analyses of prevalence, the summary estimate represents an average prevalence from included studies. This estimate is truly informative only if there is no substantial heterogeneity among the different contexts being pooled. In systematic reviews, heterogeneity is usually explored with I-squared statistic (I2 ), but this statistic does not directly inform us about the distribution of effects and frequently systematic reviewers and readers misinterpret this result. In a sample of 134 meta-analyses of prevalence, the median I2 was 96.9% (IQR 90.5-98.7). We observed larger I2 in meta-analysis with higher number of studies and extreme pooled estimates (defined as <10% or >90%). Studies with high I2 values were more likely to have conducted a sensitivity analysis, including subgroup analysis but only three (2%) systematic reviews reported prediction intervals. We observed that meta-analyses of prevalence often present high I2 values. However, the number of studies included in the meta-analysis and the point estimate can be associated with the I2 value, and a high I2 value is not always synonymous with high heterogeneity. In meta-analyses of prevalence, I2 statistics may not be discriminative and should be interpreted with caution, avoiding arbitrary thresholds. To discuss heterogeneity, reviewers should focus on the description of the expected range of estimates, which can be done using prediction intervals and planned sensitivity analysis.


Gender sensitivity among general practitioners: results of a training programme.
Gender differences contribute to patients' health and illness. However in current healthcare practices attention to gender differences is still underdeveloped. Recognizing these differences and taking them into account can improve the quality of care. In this study we aimed to investigate whether GPs' gender sensitivity can be stimulated by a training programme. The focus was on three diseases: angina pectoris, depression and urinary incontinence. This study had a quantitative, explorative and descriptive design. By means of a training programme 18 GPs were trained to focus on gender-sensitive recommendations for the three diseases. With standardised registration forms, data were collected during a 6-month period. During the registration period, the GPs were visited by the study team to discuss the process of data collection. The GPs filled in registration forms for 100 patients: 39 with angina pectoris (31 women and 8 men), 40 with depression (26 women and 14 men), and 21 with urinary incontinence (20 women and 1 man). The results show that gender sensitivity can be stimulated among trained professionals. The combination of the training programme, clear and practical recommendations, daily discussion of relevant cases between the GP couples, feedback and support during registration by the study team probably contributed to the outcome. GPs' gender sensitivity was stimulated by the training programme and the supporting visits. Ideally, structural attention could be realised by embedding gender issues in existing organisational structures of general practices.


Characterization of drug release from diltiazem-loaded polylactide microspheres prepared using sodium caseinate and whey protein as emulsifying agents.
The influence of milk protein emulsifying agents on the characteristics, particularly drug release, of polylactide microspheres was investigated. Diltiazem loaded polylactide (PL) microspheres were successfully prepared using the dairy proteins, sodium casinate (SC) and whey protein isolate (WPI) as the emulsifying agents. Microspheres were characerized in terms of microsphere yield, electron microscopy, particle size, drug loading, DSC and XRD analysis and drug release. The yields of microspheres obtained were 53-63% and were independent of the emulsifying agent used. SEM revealed that, regardless of the emulsifying agent employed, the microspheres were of good sphericity, but the surface appearance of the microspheres was not the same in all cases. The milk proteins resulted in microspheres approximately half the size of those obtained with methylcellulose (MC). Significant differences in drug loading were observed between the three emulgents, the MC systems giving the highest values. Release profiles were sigmoidal in shape and were well fitted to the equation ln (x/1 - x) = k x t - k x tmax, reflecting degradation controlled drug release. The parameter k increased with drug loading, while tmax decreased. The relationships between the release parameters [P(k and tmax)] and loading (L) could be quantified by equations of the form P = a x L(N), N being negative in the case of tmax. Apart from the effect on loading efficiency, neither SC nor WPI appeared to significantly alter drug release. The quantitative relationships observed in this study may have more general application in quantifying drug release from drug-polymer composites at low loadings where polymer degradation controls drug release.


New pituitary peptide relationships.
A glycoprotein molecule discovered in pituitary glands of experimental animals is thought to be the precursor molecule for the pituitary peptides ACTH and beta-lipotropin, molecules themselves known to contain the amino acid sequences of several smaller peptides subsequently isolated. Evidence now exists to suggest the enzymatic cleavage of ACTH to alpha-MSH and corticotropic-like intermediate lobe peptide (CLIP), pituitary peptides with effects upon the fetal pituitary gland. Beta-lipotropin is probable the prohormone for the peptides beta-MSH, gamma-lipotropin, methionine-enkephalin, and beta-endorphin. Beta-MSH may enchance the known physiologic effects of mammalian central nervous system transmitters, while the enkephalins and beta-endorphin have been shown to exhibit opioid analgesic properties as well as effects upon behavior, temperature regulation, and the release of growth hormone and prolactin. Homologies among their amino acid sequences and evidence for prohormone activity in ACTH, beta-lipotropin, and the putative ACTH-beta lipotropin precursor suggest the possibility of the presence of a previously unsuspected interrelationship in the synthesis and release of these various pituitary peptides.


Optimal perioperative anesthesia management for gynecologic interstitial brachytherapy.
To propose an optimal perioperative pain management clinical care pathway for interstitial brachytherapy for gynecologic cancer based on our interdepartmental experience. We conducted a retrospective review of 23 women who underwent 32 interstitial brachytherapy procedures for gynecological cancers, analyzing patient demographics, type of anesthetic, medications, postoperative pain scores, adverse events, and delays in discharge. We measured the association of postoperative nausea and/or vomiting (PONV) with hydromorphone use, and postoperative pain scores and total narcotic administration with type of anesthesia. In 91% of patients postoperative pain was managed with an epidural infusion plus, as needed (PRN), IV or patient controlled analgesia (PCA) narcotics. The most common postoperative adverse event was PONV (53%), followed by delirium (22%). Hospital discharge was delayed, at least by one night, in 26% of patients. Use of a basal rate on the PCA was associated with all cases of delayed discharge from over-sedation and PONV. The use of 5 mg or more of intravenous (IV) hydromorphone during the first 24-hours postoperatively was associated with PONV (p = 0.01). Use of a basal PCA was associated with delirium (p = 0.03). Postoperative pain scores were not significantly associated with the type of anesthesia. Interstitial gynecologic brachytherapy requires a multidisciplinary effort for optimal perioperative management. Our study outlines the appropriate preoperative, intraoperative, and postoperative anesthesia clinical care pathway. Decreased narcotic use during hospitalization and utilization of a patient-directed infusion may decrease side effects and allow for a more efficient hospital discharge.


Nonsteroidal antiinflammatory drugs and bladder cancer: a pooled analysis.
Case-control studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk, but few cohort studies have evaluated this association. The authors investigated NSAID use and bladder cancer in 3 large prospective studies (NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists Study). Frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using self-administered questionnaires. Study-specific hazard ratios and 95% confidence intervals were estimated using Cox regression models and were combined using a fixed-effects meta-analytic model. Data from all studies were aggregated, and aggregated hazard ratios were estimated. The analysis included 508,842 individuals, with 2,489 incident cases of bladder cancer. A reduction in risk was observed for individuals who reported regular use (>2 times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). The risk reduction was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83) (P(trend) = 0.008) (P(interaction) = 0.02). No association was observed between regular aspirin use and bladder cancer risk (HR = 1.04, 95% CI: 0.94, 1.15). Results suggest that nonaspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers.


Levocetirizine ameliorates high fructose diet-induced insulin resistance, vascular dysfunction and hepatic steatosis in rats.
This study investigates the possible protective effects of levocetirizine against fructose-induced insulin resistance, hepatic steatosis and vascular dysfunction, in comparison to pioglitazone, a standard insulin sensitizer. Male Sprague Dawley rats (150-200 g) were divided into 4 groups. Three groups were fed on high fructose diets (HFD) containing 60% w/w fructose, while the fourth control group was fed on standard laboratory food for 8 weeks. AUCOGTT, AUCITT, fasting glucose, HOMA-IR, hepatic glutathione (GSH) and malondialdehyde (MDA) levels, serum total cholesterol, LDL-C, C-reactive protein (CRP) level and lactate dehydrogenase (LDH) activity and liver steatosis scores were significantly higher in HFD group compared to control group. Moreover, body weight gain, food intake, feeding efficiency, HOMA-β, Emax and pEC50 of acetylcholine-induced relaxations of aortic rings and hepatic superoxide dismutase (SOD) activity were significantly lower in HFD group than in control group. Treatment with levocetirizine caused significant decreases in AUCOGTT, AUCITT, HOMA-IR, hepatic GSH and MDA levels and serum CRP level and LDH activity and significant increases in hepatic SOD activity and HOMA-β when compared with the HFD group. Although levocetirizine failed to alter TC and LDL-C levels, it produced a significant increase in HDL-C level relative to control group. Levocetirizine was also able to improve acetylcholine-induced relaxations of aortic rings, indicating a protective effect against insulin resistance-induced endothelial damage comparable to that offered by pioglitazone. Moreover, levocetirizine substantially attenuated insulin resistance-associated liver macrovesicular steatosis. These findings demonstrate that levocetirizine ameliorates insulin resistance, improves glucose tolerance and attenuates insulin resistance-linked hepatic steatosis and vascular damage.


Educational and health outcomes of schoolchildren in local authority care in Scotland: A retrospective record linkage study.
Looked after children are defined as children who are in the care of their local authority. Previous studies have reported that looked after children have poorer mental and physical health, increased behavioural problems, and increased self-harm and mortality compared to peers. They also experience poorer educational outcomes, yet population-wide research into the latter is lacking, particularly in the United Kingdom. Education and health share a bidirectional relationship; therefore, it is important to dually investigate both outcomes. Our study aimed to compare educational and health outcomes for looked after children with peers, adjusting for sociodemographic, maternity, and comorbidity confounders. Linkage of 9 Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, examinations, school absences/exclusions, unemployment, and looked after children provided retrospective data on 715,111 children attending Scottish schools between 2009 and 2012 (13,898 [1.9%] looked after). Compared to peers, 13,898 (1.9%) looked after children were more likely to be absent (adjusted incidence rate ratio [AIRR] 1.27, 95% confidence interval [CI] 1.24 to 1.30) and excluded (AIRR 4.09, 95% CI 3.86 to 4.33) from school, have special educational need (SEN; adjusted odds ratio [AOR] 3.48, 95% CI 3.35 to 3.62) and neurodevelopmental multimorbidity (AOR 2.45, 95% CI 2.34 to 2.57), achieve the lowest level of academic attainment (AOR 5.92, 95% CI 5.17 to 6.78), and be unemployed after leaving school (AOR 2.12, 95% CI 1.96 to 2.29). They were more likely to require treatment for epilepsy (AOR 1.50, 95% CI 1.27 to 1.78), attention deficit hyperactivity disorder (ADHD; AOR 3.01, 95% CI 2.76 to 3.27), and depression (AOR 1.90, 95% CI 1.62 to 2.22), be hospitalised overall (adjusted hazard ratio [AHR] 1.23, 95% CI 1.19 to 1.28) for injury (AHR 1.80, 95% CI 1.69 to 1.91) and self-harm (AHR 5.19, 95% CI 4.66 to 5.78), and die prematurely (AHR 3.21, 95% CI 2.16 to 4.77). Compared to children looked after at home, children looked after away from home had less absenteeism (AIRR 0.35, 95% CI 0.33 to 0.36), less exclusion (AIRR 0.63, 95% CI 0.56 to 0.71), less unemployment (AOR 0.53, 95% CI 0.46 to 0.62), and better attainment (AIRR 0.31, 95% CI 0.23 to 0.40). Therefore, among those in care, being cared for away from home appeared to be a protective factor resulting in better educational outcomes. The main limitations of this study were lack of data on local authority care preschool or before 2009, total time spent in care, and age of first contact with social care. Looked after children had poorer health and educational outcomes than peers independent of increased neurodevelopmental conditions and SEN. Further work is required to understand whether poorer outcomes relate to reasons for entering care, including maltreatment and adverse childhood events, neurodevelopmental vulnerabilities, or characteristics of the care system.


Cardiac arrhythmia and hypoglycaemia in patients receiving haemodialysis with and without diabetes (the CADDY study): protocol for a Danish multicentre cohort study.
Patients receiving haemodialysis are at increased risk of arrhythmias and sudden cardiac death, but data on arrhythmia burden and the pathophysiology remain limited. Among potential risk factors, hypoglycaemia is proposed as a possible trigger of lethal arrhythmias. The development of implantable loop recorders (ILR) and continuous glucose monitoring (CGM) enables long-term continuous ECG and glycaemic monitoring. The current article presents the protocol of a study aiming to increase the understanding of arrhythmias and risk factors in patients receiving haemodialysis. The findings will provide a detailed exploration of the burden and nature of arrhythmias in these patients including the potential association between hypoglycaemia and arrhythmias. The study is an investigator-initiated, prospective, multicentre cohort study recruiting 70 patients receiving haemodialysis: 35 with diabetes and 35 without diabetes. Participants are monitored with ILRs and CGM for 18 months follow-up. Data collection further includes a monthly collection of predialysis blood samples and dialysis parameters. The primary outcome is the presence of clinically significant arrhythmias defined as a composite of bradycardia, ventricular tachycardia, or ventricular fibrillation. Secondary outcomes include the characterisation of clinically significant arrhythmias and other arrhythmias, glycaemic characteristics, and mortality. The data analyses include an assessment of the association between arrhythmias and hypoglycaemia and hyperglycaemia, baseline clinical variables, and parameters related to kidney failure and the haemodialysis procedure. The study has been approved by the Ethics Committee of the Capital Region of Denmark (H-20069767). The findings will be presented at national and international congresses as well as in international peer-reviewed scientific journals. NCT04841304.


Critical role of electrostatic interactions of amino acids at the cytoplasmic region of helices 3 and 6 in rhodopsin conformational properties and activation.
The cytoplasmic sides of transmembrane helices 3 and 6 of G-protein-coupled receptors are connected by a network of ionic interactions that play an important role in maintaining its inactive conformation. To investigate the role of such a network in rhodopsin structure and function, we have constructed single mutants at position 134 in helix 3 and at positions 247 and 251 in helix 6, as well as combinations of these to obtain double mutants involving the two helices. These mutants have been expressed in COS-1 cells, immunopurified using the rho-1D4 antibody, and studied by UV-visible spectrophotometry. Most of the single mutations did not affect chromophore formation, but double mutants, especially those involving the T251K mutant, resulted in low yield of protein and impaired 11-cis-retinal binding. Single mutants E134Q, E247Q, and E247A showed the ability to activate transducin in the dark, and E134Q and E247A enhanced activation upon illumination, with regard to wild-type rhodopsin. Mutations E247A and T251A (in E134Q/E247A and E134Q/T251A double mutants) resulted in enhanced activation compared with the single E134Q mutant in the dark. A role for Thr(251) in this network is proposed for the first time in rhodopsin. As a result of these mutations, alterations in the hydrogen bond interactions between the amino acid side chains at the cytoplasmic region of transmembrane helices 3 and 6 have been observed using molecular dynamics simulations. Our combined experimental and modeling results provide new insights into the details of the structural determinants of the conformational change ensuing photoactivation of rhodopsin.


Epidemiological and pathological aspects of skin cancer in North East of Romania.
In the last years skin cancer has become the most frequent cancer in humans, with the majority made up of two tumors: malignant melanoma (MM) and non-melanoma skin cancer (NMSC). To provide for the first time in the North East region of Romania, descriptive epidemiological data of melanoma and non-melanoma skin cancers. We undertook a retrospective study over a five year period on the most frequent forms of skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and MM, which included a total number of 1231 patients, hospitalized and treated in the Plastic Surgery Department of "St. Spiridon" Emergency Clinical Hospital, Iaşi from 2008 until 2012. Results: BCC was diagnosed in a total of 675 patients, representing 54.9%. SCC was found in 217 patients, representing 17.6% and melanoma was diagnosed in 119 cases, a percent of 9.7% of the total number. The predominance of cutaneous malignancies waried with age, major site distribution was face and neck for BCC and SCC and the trunk for MM. This article describes the most common forms of skin cancer in our region, BCC (almost 55%), SCC (17.6%), and less in number MM (near to 10%); these results are similar to those published abroad in the last years. Future more elaborate interventional studies are necessary to identify the main risk factors in order to design the best preventive methods and, according to the skin cancer trend to specify the needs for dermatology network in our country.


Polyoxometalate-loaded hyper-crosslinked nanoparticles as a Pickering interfacial catalyst for solvent-free epoxidation of allyl chloride under static conditions.
Epoxidation of allyl chloride and hydrogen peroxide (H2O2) carried out in heterogeneous catalytic systems suffer from poor reaction efficiency due to their heavy mass transfer resistance present at the liquid-liquid interface. Pickering interfacial catalysis (PIC) provides an elegant solution by involving the design of amphiphilic heterogeneous catalysts, which can act as emulsifiers simultaneously. In this study, interface-active polyoxometalate-loaded hyper-crosslinked nanoparticles (HCNPs) were designed. The structural properties of materials were characterized in detail by elemental analysis, Zeta potential, ICP-OES, SEM, TEM, BET, FT-IR, TGA, and XPS. The prepared nanoparticles can build efficient W/O PIC systems with allyl chloride and H2O2. Systematic experiments indicate that catalysts' surface properties, catalyst dosage, and water/oil volume ratio significantly affect the PIC system's catalytic activity and emulsion properties. Moreover, this PIC system maintains high stability after the reaction and can be reused for at least 8 cycles. Excitingly, these interface-active HCNPs can also efficiently promote allyl chloride epoxidation in the absence of solvent and external stirring, illustrating that this approach holds great potential for developing catalytic systems suitable for multiphase reactions.


Vitamin D, ultraviolet exposure, and skin cancer in the elderly.
Ultraviolet (UV) radiation has both beneficial and harmful effects on the human body. Its most important beneficial effect may be vitamin D production in the skin, also known as vitamin D photosynthesis. This is of particular interest for the elderly who often show vitamin D-deficiency. Intentional UV exposure has been recommended by different institutions in order to increase vitamin D levels. Nevertheless, UV radiation directly causes DNA damage and is verifiably responsible for carcinogenesis, potentially resulting in lethal skin cancers. Unfortunately, skin cancer incidence is rising worldwide, and there is still a lack of appropriate treatment for metastasized types. The only proven and avoidable risk factor is UV radiation. It has been shown that the earlier UV protection is started, the greater the benefit in terms of skin cancer prevention. Nevertheless, even if UV protection is started at older ages, individuals will benefit measurably. Because UV radiation is neither a reliable nor a safe method of achieving healthy vitamin D levels, intentional UV radiation is not recommended to increase vitamin D levels. In order to prevent skin cancer, UV protection is to be conducted as commonly recommended, by minimizing sun exposure, and especially sunburn, with appropriate sun protective behaviors, e.g. usage of sunscreen and clothing (hat, sunglasses, long sleeves, and pants). Infants must be protected with extra care. Tanning beds must be avoided.


Acute Liver Failure: Outcome and Value of Pediatric End-Stage Liver Disease Score in Pediatric Cases.
The aims of this study were to analyze the characteristics of patients with acute liver failure (ALF) in our center and evaluate the prognostic value of the Pediatric End-Stage Liver Disease (PELD) score calculated at admission. A retrospective analysis of patients with ALF younger than 15 years between 2005 and 2013 was performed. Information collected included age, sex, etiology of ALF, laboratory tests, PELD score, stage of encephalopathy, and need for liver support devices such as MARS and/or liver transplant (LT) and survival. A poor prognosis was defined as the need for LT or death. Twenty patients (10 male patients, 50%) with a median age of 2.6 years (3 days-14.5 y old) were included. Acute liver failure was of indeterminate cause in 5 cases (25%). Within the recognized causes, the most frequent were viral hepatitis (herpes simplex virus, adenovirus, influenza B, Epstein-Barr virus), autoimmune hepatitis, and metabolopathies. Sixty percent presented with encephalopathy at diagnosis. Four patients were aided by a MARS liver support device. Six patients received a total of 7 transplants, all from deceased donors. The rate of spontaneous recovery was 45%. Currently 13 patients (65%) are living, 4 of them with an LT. Six patients died because of ALF. The mean PELD score of patients with spontaneous recovery was 15.31 (5.3-27.6) compared with a mean of 29.5 (17.2-39.4) in LT patients and 31.55 (15.8-52.4) for nonsurvivors (P = 0.013). High PELD scores at diagnosis were accurate predictors of a poor prognosis in our patients with ALF. This model may help in the clinical management of this entity, although prospective validation is needed.


Morphological priming in the German mental lexicon.
We present results from cross-modal priming experiments on German participles and noun plurals. The experiments produced parallel results for both inflectional systems. Regular inflection exhibits full priming whereas irregularly inflected word forms show only partial priming: after hearing regularly inflected words (-t participles and -s plurals), lexical decision times on morphologically related word forms (presented visually) were similar to reaction times for a base-line condition in which prime and target were identical, but significantly shorter than in a control condition where prime and target were unrelated. In contrast, prior presentation of irregular words (-n participles and -er plurals) led to significantly longer response times on morphologically related word forms than the prior presentation of the target itself. Hence, there are clear priming differences between regularly and irregularly inflected German words. We compare the findings on German with experimental results on regular and irregular inflection in English and Italian, and discuss theoretical implications for single versus dual-mechanism models of inflection.


The effects of native and synthetic estrogenic compounds as well as vitamin D less-calcemic analogs on adipocytes content in rat bone marrow.
We demonstrated previously that phytoestrogens and vitamin D analogs like estradiol-17β (E2) modulate bone morphology in rat female model. We now analyze the effects of phytoestrogens, E2, selective E2 re ceptor modulators, and the less-calcemic analogs of vitamin D: JKF1624F2-2 (JKF) or QW1624F2-2 (QW) on fat content in bone marrow (BM) from long bones in ovariectomized female rats (OVX). OVX rats were injected with treatments known to affect bone formation, 5 days per week for 2.5 month for analysis of fat content in BM. In OVX young adults there is a decreased bone formation and a 10-fold increase in fat cells content in BM. Treatment with E2, raloxifene (Ral) or DT56a resulted in almost completely abolishment of fat cells content. Daidzein (D) decreased fat cells content by 80%, genistein (G) or biochainin A (BA) did not change fat cells content and carboxy BA (cBA) had a small but significant effect. JKF or QW did not affect fat cells content, whereas combined treatment of JKF or QW with E2 resulted in complete abolishment of fat cells content. These changes in fat cells content are inversely correlated with changes in bone formation. Our results demonstrate that adipogenesis induced by OVX is a reversible process which can be corrected by hormonal treatments. The awareness of a relationship between fat and bone at the marrow level might provide a better understanding of the pathophysiology of bone loss as well as a novel approach to diagnosis and treatment of postmenopausal osteoporosis.


Suppressor genes for malignant and anchorage-independent phenotypes located on human chromosome 9 have no dosage effects.
We have previously shown that microcell-mediated transfer of a der(9)t(X;9) human chromosome (HSA), derived from human fibroblast strain GM0705, into the Syrian hamster cell line BHK-191-5C produced only near-tetraploid hybrids, although the recipient cell line contained a 1:1 ratio of near-diploid and near-tetraploid cells. However, the tumorigenicity and the anchorage independence could be suppressed in the near-tetraploid hybrids with one copy of the der(9)t(X;9) chromosome. The introduction of an HSA X chromosome did not suppress either of these phenotypes. We concluded that in addition to two suppressor genes, one for tumorigenicity and another for anchorage independence, HSA 9 might carry a third gene capable of inhibiting cellular growth in vitro, which had dosage effects. In the present study, keeping one copy of the der(9)t(X;9) chromosome, we have increased the hamster background chromosome number beyond hexaploid level by fusing two microcell-generated hybrid cell lines, where both malignant and anchorage-independent phenotypes were suppressed, with the parental malignant BHK-191-5C cell line. Tests with nude mice showed that hybrids containing one copy of the der(9)t(X;9) chromosome against the increased background of chromosomes of malignant parental origin were still suppressed for both phenotypes. These results suggest that the suppressor genes for malignancy and for anchorage independence have no dosage effects, in contrast to the suppressor gene(s) for cellular growth.


Transcriptional regulation in response to exercise.
Much progress has been made in recent years into understanding molecular mechanisms by which transcription is regulated following changes in physiological stimuli. This review has tried to focus on what is known about four specific physiological challenges--mechanical load, intracellular calcium, hypoxia, and redox state. Because of our biased interest in exercise, it was our goal to review these relatively well-studied systems so that we might provide insight into potential mechanisms that govern exercise-induced transcriptional changes. What becomes obvious, when reaching the end of this review, is that there are many common themes among the different physiological responses described. Some examples include the activation of IEGs, such as c-jun and c-fos, the phosphorylation of the transcription factor CREB, and the importance of the serum response element and the serum response factor. These commonalities across the different physiological systems suggest a certain redundancy or shared mechanism(s) for regulating transcription in response to physiological stimuli. While very little is known at this time about how exercise regulates transcription, it is an exciting time in this field of research. The recent growth in the molecular biological research literature of more physiologically-based studies provides exciting new molecular and cellular tools for those researchers willing to take on the challenge of understanding the complex mechanisms of exercise-induced adaptations.


Phytoplankton Temporal Strategies Increase Entropy Production in a Marine Food Web Model.
We develop a trait-based model founded on the hypothesis that biological systems evolve and organize to maximize entropy production by dissipating chemical and electromagnetic free energy over longer time scales than abiotic processes by implementing temporal strategies. A marine food web consisting of phytoplankton, bacteria, and consumer functional groups is used to explore how temporal strategies, or the lack thereof, change entropy production in a shallow pond that receives a continuous flow of reduced organic carbon plus inorganic nitrogen and illumination from solar radiation with diel and seasonal dynamics. Results show that a temporal strategy that employs an explicit circadian clock produces more entropy than a passive strategy that uses internal carbon storage or a balanced growth strategy that requires phytoplankton to grow with fixed stoichiometry. When the community is forced to operate at high specific growth rates near 2 d-1, the optimization-guided model selects for phytoplankton ecotypes that exhibit complementary for winter versus summer environmental conditions to increase entropy production. We also present a new type of trait-based modeling where trait values are determined by maximizing entropy production rather than by random selection.


[Peroxisome proliferator activated receptors and cardiovascular disorders].
Peroxisome proliferator activated receptors (PPARs) are transcription factors only recently discovered. Nevertheless, the interest surrounding their study has involved and involves a continuously growing number of researchers. This is due to the role that PPARs play in the understanding of the pathophysiology of clinical conditions such as obesity, diabetes, atherosclerosis, and angiogenesis. Lipid and glucidic metabolism, synthesis of cytokines, adhesion molecules, coagulation factors, fibrinolysis, are only few of the several processes controlled by PPARs. In this review the more recent acquisitions on PPAR mechanisms of action will be described. The clinical implications that their activation/deactivation induce will be also evaluate. Particular emphasis will be placed on their role in the control of the physiology of lipid and glucidic metabolism, as well as in the pathophysiology of inflammatory and atherosclerotic processes.


Tumours in white suckers from Lake Michigan tributaries: pathology and prevalence.
The prevalence and histopathology of neoplastic lesions were assessed in white sucker Catostomus commersonii captured at two Lake Michigan Areas of Concern (AOCs), the Sheboygan River and Milwaukee Estuary. Findings were compared to those observed at two non-AOC sites, the Root and Kewaunee rivers. At each site, approximately 200 adult suckers were collected during their spawning migration. Raised skin lesions were observed at all sites and included discrete white spots, mucoid plaques on the body surface and fins and large papillomatous lesions on lips and body. Microscopically, hyperplasia, papilloma and squamous cell carcinoma were documented. Liver neoplasms were also observed at all sites and included both hepatocellular and biliary tumours. Based on land use, the Kewaunee River was the site least impacted by human activities previously associated with fish tumours and had significantly fewer liver neoplasms when compared to the other sites. The proportion of white suckers with liver tumours followed the same patterns as the proportion of urban land use in the watershed: the Milwaukee Estuary had the highest prevalence, followed by the Root, Sheboygan and Kewaunee rivers. The overall skin neoplasm (papilloma and carcinoma) prevalence did not follow the same pattern, although the percentage of white suckers with squamous cell carcinoma exhibited a similar relationship to land use. Testicular tumours (seminoma) were observed at both AOC sites but not at the non-AOC sites. Both skin and liver tumours were significantly and positively associated with age but not sex.


Obesity, Disability and Self-Perceived Health Outcomes in Australian Adults: A Longitudinal Analysis Using 14 Annual Waves of the HILDA Cohort.
Both obesity and disability have been widely recognised as major public health challenges because they play significant roles in determining self-perceived general and mental health. Longitudinal studies of the relationship between obesity and disability with self-reported health outcomes are scarce. Therefore, the objective of the present study is to examine the relationship between obesity and disability with self-perceived general and mental health among Australian adults aged 15 years and above. Data were extracted from the most recent 14 waves (waves 6 through 19) of the annual individual person dataset of the Household, Income and Labour Dynamics in Australia (HILDA) survey. The longitudinal random-effects logistic regression model was adopted to investigate the relationships between obesity and disability with self-reported health outcomes. The results revealed that obese individuals and adults with some form of disability are more likely to report poor or fair general and mental health. The odds of self-reporting poor or fair general health were 2.40 and 6.07 times higher among obese (aOR: 2.40, 95% CI: 2.22-2.58) and adults with some form of disability (aOR: 6.07, 95% CI: 5.77-6.39), respectively, relative to adults with healthy weight and those without disability . The results also showed that self-rated poor or fair mental health were 1.22 and 2.40 times higher among obese adults (aOR: 1.22, 95% CI: 1.15-1.30) and adults with disability (aOR: 2.40, 95% CI: 2.30-2.51), respectively, compared to their healthy weight peers and peers without disability. As governmental and non-governmental organisations seek to improve the community's physical and mental well-being, these organisations need to pay particular attention to routine health care prevention, specific interventions, and treatment practices, especially for obese and/or people with disabilities.


Fair trade international surrogacy.
Since the development of assisted reproductive technologies, infertile individuals have crossed borders to obtain treatments unavailable or unaffordable in their own country. Recent media coverage has focused on the outsourcing of surrogacy to developing countries, where the cost for surrogacy is significantly less than the equivalent cost in a more developed country. This paper discusses the ethical arguments against international surrogacy. The major opposition viewpoints can be broadly divided into arguments about welfare, commodification and exploitation. It is argued that the only valid objection to international surrogacy is that surrogate mothers may be exploited by being given too little compensation. However, the possibility of exploitation is a weak argument for prohibition, as employment alternatives for potential surrogate mothers may be more exploitative or more harmful than surrogacy. It is concluded that international surrogacy must be regulated, and the proposed regulatory mechanism is termed Fair Trade Surrogacy. The guidelines of Fair Trade Surrogacy focus on minimizing potential harms to all parties and ensuring fair compensation for surrogate mothers.


Lesions of an avian forebrain nucleus that disrupt song development alter synaptic connectivity and transmission in the vocal premotor pathway.
The avian forebrain nucleus, the lateral magnocellular nucleus of the anterior neostriatum (LMAN), is necessary for normal song development because LMAN lesions made in juvenile birds disrupt song production but do not disrupt song when made in adults. Although these age-limited behavioral effects implicate LMAN in song learning, a potential confound is that LMAN lesions could disrupt normal vocal motor function independent of any learning role by altering LMAN's premotor target, the song nucleus, the robust nucleus of the archistriatum (RA). To date, however, no studies have examined directly the effects of LMAN lesions on the circuitry of the RA. We report here that juvenile LMAN lesions rapidly and profoundly affect RA, altering synaptic connectivity within this nucleus, including descending inputs from the song nucleus HVc. Specifically, morphological assays of the dendritic spines of RA projection neurons and axon terminal boutons arising from HVc show a numerical decline in the density of connections in RA in LMAN-lesioned juveniles compared with controls. Concurrently, LMAN lesions alter excitatory transmission within the juvenile RA: after LMAN lesions, the stimulus-response relationship between HVc fibers and RA neurons steepens, and the amplitude of spontaneous monophasic EPSCs increases. Rather than arresting RA in a juvenile state, LMAN lesions transform the structure and function of RA and its connections, such that it is distinct from that of the normal juvenile. In many ways, RA circuitry in LMAN-lesioned juveniles resembles that of normal adults, suggesting that LMAN lesions induce a premature maturation of the vocal motor pathway, which may lead to a loss of behavioral plasticity and abnormal song development.


Trends in educational differences in adolescent daily smoking across Europe, 2002-10.
Across Europe, tobacco use is more prevalent among secondary school students attending vocational tracks compared with students attending academic tracks. The purpose of the present study is to describe trends in social inequality in daily smoking among adolescents between 2002 and 2010 by addressing both absolute social inequality (prevalence difference between vocational and academic tracks) and relative social inequality (prevalence ratio) in seven European countries. Analyses were based on data from 15-year-olds who participated in the Health Behaviour in School-aged Children study in 2002, 2006 and 2010 in Belgium, Croatia, France, Germany, Hungary, Italy and The Netherlands (total N = 32 867). Overall, daily smoking decreased between 2002 and 2010 in Belgium, France, Germany and The Netherlands, increased in Croatia and remained stable in Hungary and Italy. Considerable differences in daily smoking according to educational track existed in all countries. Absolute educational inequalities increased dramatically in Croatia and Italy, while relative inequalities showed a tendency to increase in all countries (significant in Belgium and The Netherlands). Conclusions on social inequality in adolescent smoking may appear differently when described by absolute and relative measures. Especially the large increase in absolute educational inequalities in daily smoking in Croatia and Italy are worrisome and warrant attention from the public health domain. The findings underline the need for appropriate smoking policies and interventions in vocational schools across Europe.


Nickel deficiency alters liver lipid metabolism in rats.
The present investigation was designed to examine the effect of nickel deficiency on lipid metabolism in liver and serum lipoproteins of rats. Therefore, a study over two generations was conducted feeding a nickel-deficient diet containing 13 microg/kg nickel or a nickel-adequate diet supplemented with 1 mg/kg nickel. Male 7-wk-old pups from the second offspring were studied. Pups fed a diet poor in nickel tended to have lower weight gains (P < 0.15), nickel concentrations in liver (P < or = 0.1) and iron levels in serum (P < 0.1) than nickel-adequate rats. They were classified as nickel-deficient on the basis of significantly lower erythrocyte counts, hemoglobin concentrations, hematocrits and nickel concentrations in kidney compared with nickel-adequate rats. Nickel deficiency caused a significant triacylglycerol accumulation in liver, with greater concentrations of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids than nickel-adequate rats. Nickel deficiency had slight but significant effects on the fatty acid composition of liver total lipids and phosphatidylcholine and phosphatidylethanolamine. Moreover, nickel-deficient rats had significantly lower activities of the lipogenic enzymes glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme and fatty acid synthase than nickel-adequate rats. Nickel-depleted pups had significantly higher concentrations of triacylglycerols and phospholipids in serum VLDL, and cholesterol in serum LDL than nickel-adequate pups. Most of these alterations in lipid metabolism are similar to those obtained in several iron-deficiency studies. Because nickel deficiency also slightly compromised iron status, it is possible that at least some of the observed alterations are due to the moderate iron deficiency.


Optimization of wedelolactone accumulation in shoot cultures of Eclipta alba.
Influence of different environmental factors on accumulation of wedelolactone, a potential anti-hepatotoxic principle of E. alba in shoot cultures was investigated. A significant increase in the content of wedelolactone due to kinetin treatment, temperature change and photoperiod alteration in shoot cultures was observed. Incorporation of phenylalanine in the medium also increased content of wedelolactone significantly in a dose-dependent manner.


Testing the consistency of wildlife data types before combining them: the case of camera traps and telemetry.
Wildlife data gathered by different monitoring techniques are often combined to estimate animal density. However, methods to check whether different types of data provide consistent information (i.e., can information from one data type be used to predict responses in the other?) before combining them are lacking. We used generalized linear models and generalized linear mixed-effects models to relate camera trap probabilities for marked animals to independent space use from telemetry relocations using 2 years of data for fishers (Pekania pennanti) as a case study. We evaluated (1) camera trap efficacy by estimating how camera detection probabilities are related to nearby telemetry relocations and (2) whether home range utilization density estimated from telemetry data adequately predicts camera detection probabilities, which would indicate consistency of the two data types. The number of telemetry relocations within 250 and 500 m from camera traps predicted detection probability well. For the same number of relocations, females were more likely to be detected during the first year. During the second year, all fishers were more likely to be detected during the fall/winter season. Models predicting camera detection probability and photo counts solely from telemetry utilization density had the best or nearly best Akaike Information Criterion (AIC), suggesting that telemetry and camera traps provide consistent information on space use. Given the same utilization density, males were more likely to be photo-captured due to larger home ranges and higher movement rates. Although methods that combine data types (spatially explicit capture-recapture) make simple assumptions about home range shapes, it is reasonable to conclude that in our case, camera trap data do reflect space use in a manner consistent with telemetry data. However, differences between the 2 years of data suggest that camera efficacy is not fully consistent across ecological conditions and make the case for integrating other sources of space-use data.


Identification of aluminium-regulated genes by cDNA-AFLP in rice (Oryza sativa L.): aluminium-regulated genes for the metabolism of cell wall components.
Aluminium (Al) toxicity is the major factor limiting crop productivity in acid soils. To investigate the molecular mechanisms of Al toxicity and Al tolerance of rice, cDNA-amplified fragment length polymorphism (cDNA-AFLP) was used for identifying Al-regulated genes in roots of an Al-tolerant tropical upland rice, Azucena, and an Al-sensitive lowland rice, IR1552. Nineteen function-known genes were found among 34 transcript-derived fragments (TDFs) regulated by Al stress. The results indicate that Al stress could induce the biosynthesis of lignin and other cell wall components in roots. Temporal expression patterns of 14 genes were identified between the two varieties. In silico mapping was performed for all the 33 unique genes. Two genes for a function-unknown protein and for a ubiquitin-like protein, respectively, were mapped on the interval with the common QTL (quantitative trait loci) for Al tolerance in rice on chromosome 1.


Conformational Compatibility Is Essential for Heterologous Aggregation of α-Synuclein.
Under aggregation-prone conditions, soluble amyloidogenic protein monomers can self-assemble into fibrils or they can fibrillize on preformed fibrillar seeds (seeded aggregation). Seeded aggregations are known to propagate the morphology of the seeds in the event of cross-seeding. However, not all proteins are known to cross-seed aggregation. Cross-seeding has been proposed to be restricted either because of differences in the protein sequences or because of conformations between the seeds and the soluble monomers. Here, we examine cross-seeding efficiency between three α-synuclein sequences, wild-type, A30P, and A53T, each varying in only one or two amino acids but forming morphologically distinct fibrils. Results from bulk Thioflavin-T measurements, monomer incorporation quantification, single fibril fluorescence microscopy, and atomic force microscopy show that under the given solution conditions conformity between the conformation of seeds and monomers is essential for seed elongation. Moreover, elongation characteristics of the seeds are defined by the type of seed.


Thiazide diuretics, endothelial function, and vascular oxidative stress.
Increased endothelial production of reactive oxygen species and decreased nitric oxide bioactivity, associated with the upregulation of monocyte chemoattractant protein (MCP)-1 and lectin-like oxidized low-density lipoprotein receptor (LOX)-1, link hypertension with atherogenesis. We investigated whether the beneficial effects of thiazide diuretics are exclusively related to a reduction in the biomechanical stress of hypertension or are also endowed with pleiotropic vasculoprotective effects that are independent of their effect upon blood pressure. Dahl salt-sensitive (DSS) rats, a paradigm of human salt-sensitive hypertension, were given a diet with normal salt (0.5% NaCl), high salt (4% NaCl), or a high salt diet plus either hydrochlorothiazide 75 mg/l, chlorthalidone 37 or 75 mg/l in their drinking water for 6 weeks. We determined systolic blood pressure (SBP), left ventricular hypertrophy (LVH), proteinuria, aortic superoxide anion (O2(-)) production, endothelium-dependent relaxation (EDR) to acetylcholine, and aortic angiotensin II type 1 (AT1) receptor, LOX-1, and MCP-1 messenger RNA expression (by real-time polymerase chain reaction). DSS rats on a high salt diet developed hypertension, LVH, proteinuria, increased production of aortic O2(-) (106%), impaired EDR, and aortic upregulation of AT1 receptor (198%), LOX-1 (135%), and MCP-1 (145%). Hydrochlorothiazide as well as the high and low dose of chlorthalidone reduced SBP, LVH, and proteinuria, but did not reduce O2(-) production, AT1 receptor, LOX-1, or MCP-1 expression, or improved EDR. This study demonstrates that thiazide diuretics do not reduce oxidative stress, improve endothelial function, or prevent the expression of pro-atherogenic molecules. We conclude that thiazide diuretics may not fully provide long-term global cardiovascular protection beyond lowering blood pressure.


Speciation within genomic networks: a case study based on Steatocranus cichlids of the lower Congo rapids.
Hybridization in animals is a much more common phenomenon as previously thought and may have profound implications for speciation research. The cichlid genus Steatocranus (Teleostei: Cichlidae), a close relative to members of the East African cichlid radiations, radiated under riverine conditions in the lower Congo rapids and produced a small species flock. Previous phylogenetic analyses suggested that hybridization occurred and contributed to speciation in this genus. A re-analysis of an already published 2000 loci-AFLP data set explicitly testing for patterns of ancient gene flow provided strong evidence for a highly reticulate phylogenetic history of the genus. We provide, to our knowledge, the first example of a complex reticulate network in vertebrates, including multiple closely related species connected through ancient as well as recent gene flow. In this context, the limited validity of strictly bifurcating tree hypotheses as a phylogenetic basis for hypothesis testing in evolutionary biology is discussed.


Expansion and Divergence of Argonaute Genes in the Oomycete Genus Phytophthora.
Modulation of gene expression through RNA interference is well conserved in eukaryotes and is involved in many cellular processes. In the oomycete Phytophthora, research on the small RNA machinery and function has started to reveal potential roles in the pathogen, but much is still unknown. We examined Argonaute (AGO) homologs within oomycete genome sequences, especially among Phytophthora species, to gain a clearer understanding of the evolution of this well-conserved protein family. We identified AGO homologs across many representative oomycete and stramenopile species, and annotated representative homologs in P. sojae. Furthermore, we demonstrate variable transcript levels of all identified AGO homologs in comparison to previously identified Dicer-like (DCL) and RNA-dependent RNA polymerase (RDR) homologs. Our phylogenetic analysis further refines the relationship of the AGO homologs in oomycetes and identifies a conserved tandem duplication of AGO homologs in a subset of Phytophthora species.


Metastatic Gallbladder Carcinoma in Meningioma: A Case Report.
Metastases from tumors to systemic cancers are rare. The most common intracranial recipient tumor is meningioma. Metastasis from gallbladder cancer has been previously reported from only one patient during autopsy. We present a case of a 72-year-old woman who underwent surgery for right frontal skull base meningioma. The tumor was completely removed. Histological specimens showed gallbladder carcinomatous metastasis with diffuse neuroendocrine differentiation in meningothelial meningioma. The Ki-67 proliferation index of the meningioma was 3%. Further, 60% positive immunoreactivity with the progesterone receptor was observed in meningioma cells. In carcinoma cells, diffuse positive immunoreactivity with chromogranin, CDX2, CEA, panCK, cytokeratin 7, and synaptophysin was observed. A combination of molecular, metabolic, immunological, and/or hormonal factors may contribute to the pathogenesis of this lesion. It cannot be ruled out that it is more common than expected.


Ischemia-induced translocation of protein kinase C-epsilon mediates cardioprotection in the streptozotocin-induced diabetic rat.
The present study investigated the role of translocation of protein kinase C (PKC) during ischemia/reperfusion in cardioprotection in the streptozotocin (STZ)-induced diabetic rat. Twelve weeks after injection of STZ or vehicle, male Wister-King rat hearts were isolated and perfused in the presence or absence of 50 nmol/L staurosporine or 2 mumol/L chelerythrine using a Langendorff apparatus. Thirty minutes of global ischemia was followed by the same period of reperfusion. The time to onset of contracture was determined during ischemia. The recovery of left ventricular function, incidence of ventricular tachycardia/fibrillation (VT/VF), and amount of released creatine kinase (CK) were determined during the reperfusion period. Translocation of the PKC-alpha, -beta, -delta and -epsilon isoforms was determined by immunoblotting. Development of contracture was delayed, the recovery of left ventricular function was greater, and the incidence of VT/VF and amount of released CK were lower in diabetic than in control hearts. Ischemia caused an increase in the particulate/cytosolic fraction ratio of the PKC- epsilon isoform in the diabetic and control hearts. However, this translocation of PKC-epsilon during ischemia was transient in the control heart, but was persistent in the diabetic heart. The ischemia-induced translocation of PKC-epsilon was abolished by chelerythrine perfusion. These results suggest that persistent translocation of PKC-epsilon during ischemia plays a major role in cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats.


Tuning the reaction pathways of phenanthroline-Schiff bases: routes to novel phenanthroline ligands.
Pyrido-phenanthrolin-7-one compounds are structural analogues of the cytotoxic alkaloid, ascididemin, and would be expected to have interesting biological activities. Synthetic strategies are reported for a novel simple route to form this class of ligand. 1,10-Phenanthrolin-5,6-dione reacts with l-phenylalanine alkyl esters and their para-substituted analogues to form both a phenanthroline-oxazine and a pyrido-phenanthrolin-7-one product. The nature of the major product is dependent on the electronic properties of the para substituent. Successful metal coordination to the pyrido-phenanthrolin-7-one ligand is also presented.


Lateral Ridge Augmentation with Autogenous Bone Harvested Using Trephine Drills: A Noninvasive Technique.
The aim of this pilot study was to evaluate the success rate of a chairside ridge augmentation procedure using bone autografts harvested with trephine drills and placed without the use of screws. Thirty patients were recruited for the study. After the surgical site was anesthetized and a crestal incision was made, an envelope flap was retracted using blunt dissection limited to the graft site, and the periosteum was raised intact and undamaged from the bone. The flap was extended laterally to obtain sufficient space for the bone graft. At the donor site, bone was obtained from the external oblique ridge area. A #5 or #6 trephine drill was used to harvest one or two pieces of bone. The bone blocks were placed inside the envelope flap at the recipient site, which was then sutured and covered with periodontal dressing. Antibiotics, analgesics, and mouthwash were prescribed. Measurements of ridge width were performed using CBCT before and 3 months after surgery. The pre- and post operative results were compared using paired t test. Pre- and post-operative mean ridge widths were 2.23 ± 0.79 and 5.16 ± 0.68 mm, respectively. The mean increase in width was 2.92 ± 0.89 mm(P < 0.001). This non-invasive and simple technique provided an acceptable increase in ridge width. As the sample was small, we recommend further clinical investigation with larger samples to confirm that this technique may be used successfully as an alternative to current invasive augmentation methods.


T regulatory cell phenotypes in peripheral blood and bronchoalveolar lavage from non-asthmatic and asthmatic subjects.
An unresolved issue in T regulatory cells' cell biology is the lack of consensus on phenotypic markers that accurately define the natural Treg (nTreg) population. To examine nTreg frequency and functional capacity in healthy controls and their frequency in asthmatic subjects using three different phenotypic strategies. We hypothesized that phenotypically different nTreg are quantitatively and functionally different. Thirty-four healthy, non-asthmatic and 17 asthmatic subjects were studied. Three nTreg phenotypes were defined as follows: nTreg1 (CD4(+) CD25(+) Foxp3(+) ), nTreg2 (CD4(+) CD25(+) CD127(low) Foxp3(+) ), and nTreg3 (CD4(+) CD25(high) Foxp3(+) ). The flow cytometric determination of nTreg frequency in peripheral blood (PB) and bronchoalveolar lavage (BAL) was performed using fluorescently labelled antibodies. Peripheral blood nTreg functional capacity was assessed using a CFSE-based suppression assay. There was a significantly lower frequency of PB nTreg3 compared to nTreg2 and nTreg1 (P < 0.05). Both nTreg2 and nTreg3 had a significantly greater suppressive capacity than nTreg1 at T responder (Tresp) to nTreg ratios of 16 : 1 up to 1 : 1 (P < 0.01). Asthmatics exhibited a significantly lower PB nTreg3 and nTreg1 frequency than healthy controls (P < 0.05). There were no differences between healthy controls and asthmatic subjects when comparing BAL nTreg frequency. Phenotypically different nTreg subsets are quantitatively and functionally different and are variably observed in asthma. The CD4(+) CD25(high) Foxp3(+) phenotype was the least frequent, but demonstrated the greatest suppression, and was significantly lower in PB of asthmatic subjects. Consequently, it is imperative that nTreg phenotypes be clearly defined and that the interpretation of their frequency and function be phenotype specific.


Estimating contributions of pelagic and benthic pathways to consumer production in coupled marine food webs.
Pelagic and benthic systems usually interact, but their dynamics and production rates differ. Such differences influence the distribution, reproductive cycles, growth rates, stability and productivity of the consumers they support. Consumer preferences for, and dependence on, pelagic or benthic production are governed by the availability of these sources of production and consumer life history, distribution, habitat, behavioural ecology, ontogenetic stage and morphology. Diet studies may demonstrate the extent to which consumers feed on prey in pelagic or benthic environments. But they do not discriminate benthic production directly supported by phytoplankton from benthic production recycled through detrital pathways. The former will track the dynamics of phytoplankton production more closely than the latter. We develop and apply a new analytical method that uses carbon (C) and sulphur (S) natural abundance stable isotope data to assess the relative contribution of pelagic and benthic pathways to fish consumer production. For 13 species of fish that dominate community biomass in the northern North Sea (estimated >90% of total biomass), relative modal use of pelagic pathways ranged from <25% to >85%. Use of both C and S isotopes as opposed to just C reduced uncertainty in relative modal use estimates. Temporal comparisons of relative modal use of pelagic and benthic pathways revealed similar ranking of species dependency over 4 years, but annual variation in relative modal use within species was typically 10%-40%. For the total fish consumer biomass in the study region, the C and S method linked approximately 70% and 30% of biomass to pelagic and benthic pathways, respectively. As well as providing a new method to define consumers' links to pelagic and benthic pathways, our results demonstrate that a substantial proportion of fish biomass, and by inference production, in the northern North Sea is supported by production that has passed through transformations on the seabed.


A review of non-invasive imaging methods and applications in contaminant hydrogeology research.
Contaminant hydrogeological processes occurring in porous media are typically not amenable to direct observation. As a result, indirect measurements (e.g., contaminant breakthrough at a fixed location) are often used to infer processes occurring at different scales, locations, or times. To overcome this limitation, non-invasive imaging methods are increasingly being used in contaminant hydrogeology research. Four of the most common methods, and the subjects of this review, are optical imaging using UV or visible light, dual-energy gamma radiation, X-ray microtomography, and magnetic resonance imaging (MRI). Non-invasive imaging techniques have provided valuable insights into a variety of complex systems and processes, including porous media characterization, multiphase fluid distribution, fluid flow, solute transport and mixing, colloidal transport and deposition, and reactions. In this paper we review the theory underlying these methods, applications of these methods to contaminant hydrogeology research, and methods' advantages and disadvantages. As expected, there is no perfect method or tool for non-invasive imaging. However, optical methods generally present the least expensive and easiest options for imaging fluid distribution, solute and fluid flow, colloid transport, and reactions in artificial two-dimensional (2D) porous media. Gamma radiation methods present the best opportunity for characterization of fluid distributions in 2D at the Darcy scale. X-ray methods present the highest resolution and flexibility for three-dimensional (3D) natural porous media characterization, and 3D characterization of fluid distributions in natural porous media. And MRI presents the best option for 3D characterization of fluid distribution, fluid flow, colloid transport, and reaction in artificial porous media. Obvious deficiencies ripe for method development are the ability to image transient processes such as fluid flow and colloid transport in natural porous media in three dimensions, the ability to image many reactions of environmental interest in artificial and natural porous media, and the ability to image selected processes over a range of scales in artificial and natural porous media.


Effects of intraabdominally insufflated carbon dioxide and elevated intraabdominal pressure on postoperative gastrointestinal transit: an experimental study in mice.
Postoperative ileus after abdominal operations is thought to be related to the degree of surgical trauma, and it has been shown that the simple act of opening the peritoneum can decrease gastrointestinal motility. Accordingly, some investigators have shown a reduction in the duration of postoperative ileus after laparoscopic procedures. It is not clear, however, if this reduction is secondary to less manipulation of the viscera or to the lack of an abdominal incision. The aim of this study was to determine the effect of intraabdominal insufflation with CO2 on postoperative gastrointestinal transit. Twenty-eight male mice weighing between 25 and 30 g were divided randomly into 4 groups: Control (unoperated), Incision (conventional laparotomy), Cecal (laparotomy plus cecal manipulation), and Insufflation (abdominal insufflation with CO2). Postoperative gastrointestinal motility was assessed by weighing total fecal output over the first 15 postoperative hours. Fecal pellet output over 15 hours in the untreated control group was 1.20 +/- 0.12 g. In mice subjected to peritoneal incision alone, fecal pellet output was significantly decreased to 0.82 +/- 0.11 g (P < .05). However, in mice subjected to abdominal insufflation with CO2, fecal pellet output was not significantly different from untreated controls (1.2 +/- 0.05 g; not significant). Fecal pellet output was markedly reduced by incision combined with cecal manipulation (0.24 +/- 0.02 g, P < .01). The current study findings show that abdominal insufflation, in a procedure similar to that used during laparoscopic surgery, had no measurable effect on gastrointestinal transit in awake mice. This suggests that the lack of an abdominal incision can contribute to a reduced postoperative ileus after abdominal surgery.


CT findings in biliary and pancreatic ascariasis.
In a child with biliary and pancreatic ascariasis CT demonstrated liver abscesses and a pancreatic pseudocyst, in addition to air in the biliary tree and main pancreatic duct.


Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics.
Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power-law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.


Long-term outcome of kidney transplant by using restored kidney grafts after tumour ex vivo excision - a prospective study.
The aim of this study is to report long-term outcomes of kidney transplantation by using the kidney graft after a small tumour ex vivo excision. A structured programme was established to use the restored kidney graft from urological referral after radical nephrectomy. The criteria were defined as tumour size ≤3 cm, margin clear on frozen section and recipients aged ≥60 years or those on the urgent list for transplantation as a result of imminent lack of dialysis access. The recipients were followed up regularly for surveillance of tumour recurrence. Between February 2007 and February 2018, 28 recipients had kidney transplantation by using the restored kidney grafts. The tumour size was 2.6 ± 0.7 cm. The follow-up was median 7 years without evidence of tumour recurrence. The patient and graft survival was satisfactory. Kidney transplantation by using restored kidneys after a small tumour excision is a novel source for selected recipients. The long-term patient and graft survival is satisfactory. Although there is a risk of tumour recurrence, it is rare event. Together with literature review, we would support use of kidney graft after a small tumour excision for selected recipients.


The influence of tetrad shape and intersporal callose wall formation on pollen aperture pattern ontogeny in two eudicot species.
In flowering plants, microsporogenesis is accompanied by various types of cytoplasmic partitioning (cytokinesis). Patterns of male cytokinesis are suspected to play a role in the diversity of aperture patterns found in pollen grains of angiosperms. The relationships between intersporal wall formation, tetrad shape and pollen aperture pattern ontogeny are studied. A comparative analysis of meiosis and aperture distribution was performed within tetrads in two triporate eudicot species with contrasting aperture arrangements within their tetrads [Epilobium roseum (Onagraceae) and Paranomus reflexus (Proteaceae)]. Intersporal wall formation is a two-step process in both species. Cytokinesis is first achieved by the formation of naked centripetal cell plates. These naked cell plates are then covered by additional thick, localized callose deposits that differ in location between the two species. Apertures are finally formed in areas in which additional callose is deposited on the cell plates. The recorded variation in tetrad shape is correlated with variations in aperture pattern, demonstrating the role of cell partitioning in aperture pattern ontogeny.


Human papillomavirus type 16 E5 protein induces expression of beta interferon through interferon regulatory factor 1 in human keratinocytes.
Crucial steps in high-risk human papillomavirus (HR-HPV)-related carcinogenesis are the integration of HR-HPV into the host genome and loss of viral episomes. The mechanisms that promote cervical neoplastic progression are, however, not clearly understood. During HR-HPV infection, the HPV E5 protein is expressed in precancerous stages but not after viral integration. Given that it has been reported that loss of HPV16 episomes and cervical tumor progression are associated with increased expression of antiviral genes that are inducible by type I interferon (IFN), we asked whether E5, expressed in early phases of cervical carcinogenesis, affects IFN-β signaling. We show that the HPV type 16 (HPV16) E5 protein expression per se stimulates IFN-β expression. This stimulation is specifically mediated by the induction of interferon regulatory factor 1 (IRF-1) which, in turn, induces transcriptional activation of IRF-1-targeted interferon-stimulated genes (ISGs) as double-stranded RNA-dependent protein kinase R (PKR) and caspase 8. Our data show a new and unexpected role for HR-HPV E5 protein and indicate that HPV16 E5 may contribute to the mechanisms responsible for cervical carcinogenesis in part via stimulation of IFN-β and an IFN signature, with IRF-1 playing a pivotal role. HPV16 E5 and IRF-1 may thus serve as potential therapeutic targets in HPV-associated premalignant lesions.


Mucosal secretory IgA and secretory piece in adult coeliac disease.
Immunofluorescence studies with specific antisera to secretory IgA (11S IgA) and secretory piece were carried out on the jejunal mucosa of nine patients with adult coeliac disease (treated and untreated). The results were compared with those obtained in four normal patients and in four patients with local and systemic IgA (7S) deficiency. 11S IgA and secretory piece were localized to the upper third of the epithelial cells of both surface and glandular epithelium in all groups of patients. However, in the untreated coeliac patients fluorescence was also demonstrated in the basement membrane and connective tissue of the mucosa (returning to normal on treatment). On the basis of our findings, a revised pathway for the normal production of 11S IgA is proposed as well as an additional pathway involving a ;backflow' of 11S IgA into the lamina propria in pathological states such as coeliac disease. This backflow is reversed by an adequate gluten-free diet. It is suggested that 7S IgA and 11S IgA may be involved in immune reactions in the mucosa with antigens such as gluten.


Eye movements reveal fast, voice-specific priming.
In spoken word perception, voice specificity effects are well-documented: When people hear repeated words in some task, performance is generally better when repeated items are presented in their originally heard voices, relative to changed voices. A key theoretical question about voice specificity effects concerns their time-course: Some studies suggest that episodic traces exert their influence late in lexical processing (the time-course hypothesis; McLennan & Luce, 2005), whereas others suggest that episodic traces influence immediate, online processing. We report 2 eye-tracking studies investigating the time-course of voice-specific priming within and across cognitive tasks. In Experiment 1, participants performed modified lexical decision or semantic classification to words spoken by 4 speakers. The tasks required participants to click a red "x" or a blue "+" located randomly within separate visual half-fields, necessitating trial-by-trial visual search with consistent half-field response mapping. After a break, participants completed a second block with new and repeated items, half spoken in changed voices. Voice effects were robust very early, appearing in saccade initiation times. Experiment 2 replicated this pattern while changing tasks across blocks, ruling out a response priming account. In the General Discussion, we address the time-course hypothesis, focusing on the challenge it presents for empirical disconfirmation, and highlighting the broad importance of indexical effects, beyond studies of priming.


Patient Preferences for Diagnostic Imaging: CTA vs MRA When Diagnosing Pulmonary Embolism.
To identify preferences regarding choice of diagnostic imaging (computed tomographic angiography [CTA] vs magnetic resonance angiography [MRA]) for the evaluation of pulmonary embolism. We conducted 4 focus group discussions with residents of 2 Wisconsin cities. Community members ≥18 years old were recruited via telephone using a commercially available telephone database. The discussions were audio recorded and professionally transcribed. Three investigators (a research specialist, emergency physician, and qualitative methodologist) independently analyzed these transcripts using inductive thematic coding to identify the overarching themes and underlying concepts. Intercoder discrepancies were resolved through consensus discussion by the reviewers. Focus groups were held over a 3-month period and included 29 participants (16 female). Ages were well represented: 18-30 (n = 7), 31-40 (n = 8), 41-55 (n = 6), and 56+ (n = 8) years old. Analysis revealed 3 central themes: time, risk, and experience. Participants who preferred CTA commonly cited the need for immediate results in the emergency department. When nonemergent scenarios were discussed, the option to undergo MRA was considered more strongly; participants weighed additional details like radiation and diagnostic accuracy. Regarding risks, discussants expressed concerns from multiple sources, including radiation and intravenous contrast. However, understanding of this risk varied across the groups. Prior experience with medical imaging-both personal and indirect experiences-carried considerable weight. Preferences regarding imaging choice in the diagnosis of pulmonary embolism were mixed, often reliant on vicarious experiences and an exaggerated notion of the difference in timing of imaging results. Participants frequently used incomplete or even incorrect information as the basis for decision-making.


Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease.
Follicular helper CD4+ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7+CD4+ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4+ T (Th), particularly Tfh, cells and SLAMF7+ CD4+ T cells in IgG4-RD. The patients with IgG4-RD enrolled in this study were aged 66 ± 12 years and their titers of serum IgG4 were 372 ± 336 mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7+ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7+ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7+ cTfh1 cells, but not SLAMF7+ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7+ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7+ cTfh1 cells. In addition to CD4+ T cells, the frequency of SLAMF7+ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-γ, most significantly induced SLAMF7 expression in memory B cells. Together, these results suggest that circulating SLAMF7+ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.


Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons.
In low-density, serum-free cultures of neurons from embryonic rat dorsal root ganglia, interleukin-6 supports the survival of less than one third of the neurons yet virtually all of them bear interleukin-6 alpha-receptors. A finding that might explain this selectivity is that interleukin-6 acts on sensory neurons in culture through a mechanism requiring endogenous brain-derived neurotrophic factor. Antibodies or a trkB fusion protein that block the biological activity of brain-derived neurotrophic factor synthesized by dorsal root ganglion neurons also block the survival-promoting actions of interleukin-6 on these neurons. Two results indicate that interleukin-6 influences synthesis of brain-derived neurotrophic factor in adult dorsal root ganglion neurons. Intrathecal infusion of interleukin-6 in rats increases the concentration of brain-derived neurotrophic factor mRNA in rat lumbar dorsal root ganglia. The induction of brain-derived neurotrophic factor in dorsal root ganglion neurons that is seen after nerve injury in rats or wild-type mice is severely attenuated in mice with null mutation of the interleukin-6 gene. In brief, the ability of interleukin-6 to support the survival of embryonic sensory neurons in vitro depends upon the presence of endogenous brain-derived neurotrophic factor and the induction of brain-derived neurotrophic factor in injured adult sensory neurons depends upon the presence of endogenous interleukin-6.


Factor XII Contact Activation.
Contact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation-associated disease states.