Mechanism of impairment of long-term potentiation by amyloid beta is independent of NMDA receptors or voltage-dependent calcium channels in hippocampal CA1 pyramidal neurons.
beta-Amyloid peptide (Abeta) is known to be involved in Alzheimer's disease (AD). Although the fibril form of Abeta is known to have neurotoxicity, it has been shown that not only the fibril form but also the oligomer form of Abeta may be related to the neuropathophysiology of AD, specifically to memory loss. Some studies have demonstrated that low concentrations of the Abeta oligomer impair long-term potentiation (LTP), a cellular model for learning and memory, after short exposure times in vivo and in vitro, although little is known about the mechanism involved in Abeta-mediated inhibition of LTP. In this study, we used the patch clamp whole-cell technique in rat hippocampal CA1 pyramidal neurons to study more precisely how the Abeta oligomer affects synaptic plasticity. The brief perfusion of slices with a low concentration (1microM) of Abeta(1-42) significantly impaired LTP induction of the excitatory input. The same concentration of Abeta did not affect basal transmission or paired-pulse facilitation. We also demonstrated that neither NMDAR-EPSCs nor the voltage-depended calcium channel (VDCC) currents were affected by the same concentration of Abeta(1-42) as used in the LTP experiments. These data suggest that Abeta mediated impairment of LTP induction is independent of NMDARs or VDCCs.


Changes in psychological variables and health behaviors by dieting status over a three-year period in a cohort of adolescent females.
Psychologic and behavioral changes associated with frequent dieting were examined. Compared to nondieters, frequent dieters were hypothesized to show more adverse psychologic changes and increased use of unhealthy weight control behaviors, but possibly healthier eating and exercise behavior changes, over the three-year period of observation. A prospective study of female students, in grades 7-10 at baseline completed a health behavior survey in school once a year for a total of three years. Restrained eating, body dissatisfaction and drive for thinness, self-induced vomiting, laxative use, diet pill use, and alcohol use, significantly increased, and physical appearance and self-concept significantly decreased among frequent dieters, compared to non-dieters. Changes in scores on five EDI subscales, eight self-esteem subscales, weight fluctuations, dietary intake, and physical activity patterns did not significantly differ over time by dieting status. Dieting may reflect a general pattern of unhealthy behaviors adopted in adolescence, rather than act as a causal factor in promoting psychologic distress.


Correction to: Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.
This article is published with the incorrect copyright holder name in the HTML article as "© Springer 2018". The correct copyright line should read "The Author(s) 2018" (as it appears in the article PDF).


Normative Cardiopulmonary Exercise Test Responses at the Ventilatory Threshold in Canadian Adults 40 to 80 Years of Age.
Physiologic and symptom responses at the ventilatory threshold (Tvent) during incremental cardiopulmonary exercise testing (CPET) can provide important prognostic information. This study aimed to develop an updated normative reference set for physiologic and symptom responses at Tvent during cycle CPET (primary aim) and to evaluate previously recommended reference equations from a 1985 study for predicting Tvent responses (secondary aim). Participants were adults 40 to 80 years of age who were free of clinically relevant disease from the Canadian Cohort Obstructive Lung Disease. Rate of oxygen consumption (V˙O2) at Tvent was identified by two independent raters; physiologic and symptom responses corresponding to V˙O2 at Tvent were identified by linear interpolation. Reference ranges (5th-95th percentiles) for responses at Tvent were calculated according to participant sex and age for 29 and eight variables, respectively. Prediction models were developed for nine variables (oxygen pulse, V˙O2, rate of CO2 production, minute ventilation, tidal volume, inspiratory capacity, end-inspiratory lung volume [in liters and as percentage of total lung capacity], and end-expiratory lung volume) using quantile regression, estimating the 5th (lower limit of normal), 50th (normal), and 95th (upper limit of normal) percentiles based on readily available participant characteristics. The two one-sided test of equivalence for paired samples evaluated the measured and 1985-predicted V˙O2 at Tvent for equivalence. Reference ranges and equations were developed based on 96 participants (49% men) with a mean ± SD age of 63 ± 9 years. Mean V˙O2 at Tvent was 50% of measured V˙O2 peak; the normal range was 33% to 66%. The 1985 reference equations overpredicted V˙O2 at Tvent: mean difference in men, -0.17 L/min (95% CI, -0.25 to -0.09 L/min); mean difference in women, -0.19 L/min (95% CI, -0.27 to -0.12 L/min). A contemporary reference set of CPET responses at Tvent from Canadian adults 40 to 80 years of age is presented that differs from the previously recommended and often used reference set from 1985. ClinicalTrials.gov; No.: NCT00920348; URL: www.clinicaltrials.gov.


Pharmacogenetics of nevirapine excretion into breast milk and infants' exposure through breast milk versus postexposure prophylaxis.
The influence of genetic factors on nevirapine (NVP) breast milk pharmacokinetics and breastfed infants' exposure were investigated. Associations between nine SNPs in NVP disposition genes in mothers and its plasma and breast milk concentrations were explored in nursing mother-infant pairs. NVP pharmacokinetics in maternal plasma, breast milk and infant exposure indices were influenced by CYP2B6 516G>T and 983T>C. The median (range) milk-to-plasma area under the curve (AUC0-12) ratio was 0.95 (0.56-1.5). Calculated as percentages of pediatric treatment, infant postexposure prophylaxis and maternal weight-adjusted doses, the maximum exposure indices were 3.64% (1.99-9.88), 26.0% (9.93-79.1) and 13.8% (5.77-27.7), respectively. Infant plasma concentration as a result of exposure through breast milk (n = 93), pre-exposure prophylaxis (n = 10) and both (n = 27) were 660 (104-3090), 1020 (401-3325) and 2720 ng/ml (1360-7290), respectively. The clinical significance of the observed differences between routes of infants' exposure warrants further investigation.


Impact of classroom-based MASK-ED™ (KRS simulation) on physiotherapy student clinical performance: a randomized cluster trial.
In physiotherapy there is a growing body of literature exploring the benefits simulation could have in the university-setting, prior to the commencement of work-integrated learning. MASK-ED™ simulation is one form of simulation that could be beneficial for student learning and improve performance in the clinical setting. MASK-ED™ simulation involves an educator donning a silicone mask and portraying a patient role that has been specifically developed to meet learning objectives. To evaluate the effectiveness of MASK-ED™ simulation compared to role-play with peers for training pre-clinical physiotherapy students. A single-centre, single-blind, cluster randomized trial with concealed allocation, between group post-measures, and intention-to-treat analysis was conducted at an Australian university between February 2018 - January 2021. Participants were 144 physiotherapy students, cluster randomized by tutorial groups (exp n = 70, con n = 74), undertaking their neurological curricula. The experimental group was exposed to MASK-ED™ simulation in five out of a potential thirty-two tutorials (16%) whilst the control continued with role-play with peers. The primary outcome measure was Assessment of Physiotherapy Practice scores from the students' rehabilitation work-integrated learning clinical placement. These were compared between the experimental and control groups using Mann-Whitney U tests. Secondary outcome measures include practical and written examination scores. These were compared between groups via independent t-tests. Participant satisfaction surveys were also administered to the experimental group. One hundred thirty-two participants' (exp n = 62, con n = 72) results were analyzed. There were no significant differences between the experimental and control groups for Assessment of Physiotherapy Practice scores (p = 0.699-0.995). There were no significant differences found between the groups, across the secondary outcome measures. Participants found MASK-ED™ simulation was somewhat helpful for preparing them for clinical practice, however felt that a group setting was not as effective as a one-on-one encounter would have been. MASK-ED™ simulation was no more effective than role-play with peers in preparing physiotherapy students for work-integrated learning. The influence of the design of simulation on effective learning and the number of classroom-based simulation encounters required to impact clinical performance requires further investigation.


Noninvasive blood glucose sensing by secondary speckle pattern artificial intelligence analyses.
Diabetes is a prevalent disease worldwide that can cause severe health problems. Accurate blood glucose detection is crucial for diabetes management, and noninvasive methods can be more convenient and less painful than traditional finger-prick methods. We aim to report a noncontact speckle-based blood glucose measurement system that utilizes artificial intelligence (AI) data processing to improve glucose detection accuracy. The study also explores the influence of an alternating current (AC) induced magnetic field on the sensitivity and selectivity of blood glucose detection. The proposed blood glucose sensor consists of a digital camera, an AC-generated magnetic field source, a laser illuminating the subject's finger, and a computer. A magnetic field is applied to the finger, and a camera records the speckle patterns generated by the laser light reflected from the finger. The acquired video data are preprocessed for machine learning (ML) and deep neural networks (DNNs) to classify blood plasma glucose levels. The standard finger-prick method is used as a reference for blood glucose level classification. The study found that the noncontact speckle-based blood glucose measurement system with AI data processing allows for the detection of blood plasma glucose levels with high accuracy. The ML approach gives better results than the tested DNNs as the proposed data preprocessing is highly selective and efficient. The proposed noncontact blood glucose sensing mechanism utilizing AI data processing and a magnetic field can potentially improve glucose detection accuracy, making it more convenient and less painful for patients. The system also allows for inexpensive blood glucose sensing mechanisms and fast blood glucose screening. The results suggest that noninvasive methods can improve blood glucose detection accuracy, which can have significant implications for diabetes management. Investigations involving representative sampling data, including subjects of different ages, gender, race, and health status, could allow for further improvement.


Giant Multinucleated Cells Are Associated with Mastocytic Inflammatory Signature Equine Asthma.
Equine asthma is currently diagnosed by the presence of increased neutrophil (>5%), mast cell (>2%), and/or eosinophil (>1%) differential cell count. Macrophages are normal resident cells within the alveoli. Their presence in BALF is considered normal, but the clinical implication of the presence of activated or fused macrophages (giant multinucleated cells, GMC) is currently overlooked. We aimed to assess the prevalence, cytological determinants, and clinical significance of increased GMC counts in BALF of 34 asthmatic horses compared to 10 controls. Counts were performed on 15 randomly selected high magnification fields per cytospin slide (40×), and expressed as GMC:single macrophage (GMC:M) ratio. Regression models were used for statistical analysis. GMC was frequently observed in both asthmatic and control horses, with an increased prevalence of equine asthma (p = 0.01). GMC:M ratio was significantly higher in severe vs. mild to moderate equine asthmatic and control horses. In asthmatic horses, an increased GMC:M ratio was significantly associated with BALF mastocytosis (p = 0.01), once adjusting for age and the presence and severity of clinical signs of the horses. Tachypnea was the only clinical sign that tended to be positively associated with GMC:M ratio after adjustment (p = 0.08). In conclusion, our data suggest that a relationship might exist between molecular mechanisms regulating GMC formation and mast cell recruitment in the equine lung. The same mechanisms could lead to tachypnea even in the absence of respiratory effort at rest. We suggest including GMC count in the basic cytological assessment of BALF samples to gain more insights into their role in equine asthma.


A survey of the attitudes of physician specialists toward capitation-based health plans with primary care gatekeepers.
A survey of 414 Washington state physicians board certified in one of seven non-primary care specialties (gastroenterology, cardiology, dermatology, otolaryngology, orthopedics, psychiatry, and general surgery) assessed physician attitudes towards capitation-based health plans with primary care gatekeepers. Responses indicated significant differences in attitude according to specialty. Negative attitudes were more prevalent among physicians in solo practices and those practicing in smaller communities and were related to quality of care provided, lack of information regarding benefits, loss of physician autonomy, and heavy administrative demands in these plans. Although most respondents disapproved of capitation-based health plans, a significant number agreed that gatekeeper-based plans serve to increase public awareness about health care costs as well as to control health care costs.


Investigating the genetic profile of dopaminergic neurons in the VTA in response to perinatal nicotine exposure using mRNA-miRNA analyses.
Maternal smoking during pregnancy is associated with an increased risk of developmental, behavioral, and cognitive deficits. Nicotine, the primary addictive component in tobacco, has been shown to modulate changes in gene expression when exposure occurs during neurodevelopment. The ventral tegmental area (VTA) is believed to be central to the mechanism of addiction because of its involvement in the reward pathway. The purpose of this study was to build a genetic profile for dopamine (DA) neurons in the VTA and investigate the disruptions to the molecular pathways after perinatal nicotine exposure. Initially, we isolated the VTA from rat pups treated perinatally with either nicotine or saline (control) and collected DA neurons using fluorescent-activated cell sorting. Using microarray analysis, we profiled the differential expression of mRNAs and microRNAs from DA neurons in the VTA in order to explore potential points of regulation and enriched pathways following perinatal nicotine exposure. Furthermore, mechanisms of miRNA-mediated post-transcriptional regulation were investigated using predicted and validated miRNA-gene targets in order to demonstrate the role of miRNAs in the mesocorticolimbic DA pathway. This study provides insight into the genetic profile as well as biological pathways of DA neurons in the VTA of rats following perinatal nicotine exposure.


Localization of (-)-[125I]cyanopindolol binding in guinea-pig heart: characteristics of non-beta-adrenoceptor related binding in cardiac pacemaker and conducting regions.
Receptor autoradiography was used in guinea-pig heart to locate binding sites for the beta-adrenoceptor ligand (-)[125I]cyanopindolol (CYP) resistant to blockade by the beta-adrenoceptor antagonist (-)-propranolol (1 microM). Highly localized binding was observed to regions closely associated with the sinoatrial node, atrioventricular node and bundle of His but was not observed on myocardial, pacemaker, conducting cells or adipose tissue. Free [125I] also bound to identical sites. Binding was enhanced in the presence of ascorbic acid but was completely inhibited by (-)-isoprenaline (100 microM), serotonin (5-HT) (10 microM) and phentolamine (10 microM).


Identifying disease progression in chronic kidney disease using proton magnetic resonance spectroscopy.
Chronic kidney disease (CKD) affects approximately 10% of the world population, higher still in some developing countries, and can cause irreversible kidney damage eventually leading to kidney failure requiring dialysis or kidney transplantation. However, not all patients with CKD will progress to this stage, and it is difficult to distinguish between progressors and non-progressors at the time of diagnosis. Current clinical practice involves monitoring estimated glomerular filtration rate and proteinuria to assess CKD trajectory over time; however, there remains a need for novel, validated methods that differentiate CKD progressors and non-progressors. Nuclear magnetic resonance techniques, including magnetic resonance spectroscopy and magnetic resonance imaging, have the potential to improve our understanding of CKD progression. Herein, we review the application of magnetic resonance spectroscopy both in preclinical and clinical settings to improve the diagnosis and surveillance of patients with CKD.


The expression of presenilin 1 mRNA in skin fibroblasts and brains from sporadic Alzheimer's disease.
We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer's disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.


Digoxin radioimmunoassay: a comparison of the assay performances using tritiated and 125I radioiodinated tracers.
The preparation of 125I-labelled tracer for digoxin radioimmunoassay (125I monoiodinated 3-succinyl digoxigenin-1-tyrosine) is described, and its performance in radioimmunoassay of plasma samples is compared with that obtained with tritiated digoxin. The accuracy levels were assessed through the evaluation of different potential sources of systematic errors, such as interference from digoxin-related molecules and plasma proteins and methodological artefacts possibly associated with the immunocomplex instability, and through a series of checks including the recovery and parallelism tests and the correspondence of results obtained with the two tracers. The slope and the repeatability with time of the calibration curves and the spread of replicate estimates were taken into consideration to assess the assay precision. An essential equivalence in terms of reliability of measurement was proved for the two methodological variants, so that practical aspects and economic factors remain the main criteria to evaluate the relative merits: from this point of view, the advantages of using 125I-labelled tracer, as an alternative to tritiated digoxin, are discussed.


Analysis of mouse metaphase II oocytes as an assay for chemically induced aneuploidy.
Our initial objective was to develop an in vivo mammalian, female aneuploid assay that is consistent, time efficient, and that yields a large number of oocytes amenable to objective analyses. Subsequently, we desired to use such an assay for identifying chemicals and dosages that could increase the incidence of aneuploidy in mouse metaphase II oocytes. The experimental protocol involved superovulating CD-1 mice with PMS; HCG was given 48 h later. At the time of HCG injection, different dosages od diethylstilbestrol diphosphate, cadmium chloride, chloral hydrate, or colchicine were injected intraperitoneally. 17 h later, oocytes were collected and fixed prior to C-banding the chromosomes. The procedure required about 3 h to process oocytes from 25 mice and yielded over 100 analyzable metaphase II oocytes. Colchicine was the only compound tested that resulted in a statistically significant (P less than 0.01) increase in hyperploid (N greater than 20) oocytes over controls. The incidence of hyperploid oocytes in the colchicine group was 2/167, 1/182, 21/220, and 38/202, for control, 0.1 mg/kg, 0.2 mg/kg, and 0.3 mg/kg, respectively. This assay appears sensitive for aneuploidy detection but requires further validation.


On stopping rules and the sex ratio at birth.
One popular stopping rule intended to increase the rate of male births is to keep having babies until the first male is born. We show that such a stopping rule does not change the sex ratio at birth when the probability p that a birth produces a male is constant across a population. We show, however, that when p varies across couples, as evidence suggests that it does in the human population, with mean around 0.515 and standard deviation 0.05, then such a stopping rule tends to favour female births and the correct rule should be to stop procreating until the first female is born. But we also show that it does not seem that such stopping rules, even if favouring male births, can account for the dramatic increase in the rate of male births registered in some countries. Most of these conclusions have appeared in some form or other in various studies, but they are scattered across the literature and are very often presented using some heavy mathematical techniques. In this paper, we try to bring together these ideas and make them more accessible by analysing these stopping rules using the simplest mathematical tools possible.


Homeostatic synaptic plasticity as a metaplasticity mechanism - a molecular and cellular perspective.
The molecular mechanisms underlying various types of synaptic plasticity are historically regarded as separate processes involved in independent cellular events. However, recent progress in our molecular understanding of Hebbian and homeostatic synaptic plasticity supports the observation that these two types of plasticity share common cellular events, and are often altered together in neurological diseases. Here, we discuss the emerging concept of homeostatic synaptic plasticity as a metaplasticity mechanism with a focus on cellular signaling processes that enable a direct interaction between Hebbian and homeostatic plasticity. We also identify distinct and shared molecular players involved in these cellular processes that may be explored experimentally in future studies to test the hypothesis that homeostatic synaptic plasticity serves as a metaplasticity mechanism to integrate changes in neuronal activity and support optimal Hebbian learning.


Influence of parent material on soil chemical characteristics in a semi-arid tropical region of Northeast Brazil.
Soil parental material is one of the main factors that influence pedogenesis. Several studies evaluated the relationship between the parent material and soil chemistry, but few studies have assessed such a relationship in semi-arid tropical regions. This investigation was carried out to assess the effect of different parent materials on the chemical composition and available concentrations of macronutrients and micronutrients, including potentially toxic elements (Cd, Cr, Ni, and Pb) in soils in a semi-arid tropical setting. The chemical composition of the soils inherited the geochemical signature of their parent materials. Quartz sandstones, augen gneisses, and peraluminous granites exhibited the lowest reservoirs of plant nutrients and formed sandy, acid, and infertile soils. On the other hand, alkaline soils and soils with high concentrations of nutrients formed on ultramafic rocks (harzburgite), marble, and anorthosite. The pH, clay content, and CEC were the main attributes of the soils governing the availability of macro and micronutrients. The low soil organic carbon contents did not influence the availability of the nutrients. The parent material also influenced the soil texture. Parent materials that are richer in silica formed more sandy soils. The availability of Cd, Cr, and Pb in soils was low; however, the elevated Ni concentrations of soils derived from ultramafic rocks may pose risks to the environment and human health. Cluster and discriminant analyses were used to discriminate the natural fertility of soils. These results are useful for the agro-pedological zoning of the Brazilian semi-arid tropical region and for land use planning.


Alcohol Consumption Among Adults With a Cancer Diagnosis in the All of Us Research Program.
Alcohol consumption is associated with adverse oncologic and treatment outcomes among individuals with a diagnosis of cancer. As a key modifiable behavioral factor, alcohol consumption patterns among cancer survivors, especially during treatment, remain underexplored in the United States. To comprehensively characterize alcohol consumption patterns among US cancer survivors. This cross-sectional study used data from May 6, 2018, to January 1, 2022, from the National Institutes of Health All of Us Research Program, a diverse US cohort with electronic health record (EHR) linkage, and included 15 199 participants who reported a cancer diagnosis and 1839 patients among a subset with EHR data who underwent treatment within the past year of the baseline survey. Data analysis was performed from October 1, 2022, to January 31, 2023. Prevalence of current drinking and of risky drinking behaviors, including exceeding moderate drinking (>2 drinks on a typical drinking day), binge drinking (≥6 drinks on 1 occasion), and hazardous drinking (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] score ≥3 for women or ≥4 for men). This study included 15 199 adults (mean [SD] age at baseline, 63.1 [13.0] years; 9508 women [62.6%]) with a cancer diagnosis. Overall, 11 815 cancer survivors (77.7%) were current drinkers. Among current drinkers, 1541 (13.0%) exceeded moderate drinking, 2812 (23.8%) reported binge drinking, and 4527 (38.3%) engaged in hazardous drinking. After multivariable adjustment, survivors who were younger than 65 years, men, or of Hispanic ethnicity or who received a diagnosis before 18 years of age or ever smoked were more likely to exceed moderate drinking (aged <50 years: odds ratio [OR], 2.90 [95% CI, 2.41-3.48]; aged 50-64 years: OR, 1.84 [95% CI, 1.58-2.15]; men: OR, 2.38 [95% CI, 2.09-2.72]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.04-1.64]; aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.04-2.24]; former smokers: OR, 2.46 [95% CI, 2.16-2.79]; current smokers: OR, 4.14 [95% CI, 3.40-5.04]) or binge drink (aged <50 years: OR, 4.46 [95% CI, 3.85-5.15]; aged 50-64 years: OR, 2.15 [95% CI, 1.90-2.43]; men: OR, 2.10 [95% CI, 1.89-2.34]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.09-1.58]; aged <18 years at diagnosis: OR, 1.71 [95% CI, 1.24-2.35]; former smokers: OR, 1.69 [95% CI, 1.53-1.87]; current smokers: OR, 2.27 [95% CI, 1.91-2.71]). Survivors with cancer diagnosed before 18 years of age or who ever smoked were more likely to be hazardous drinkers (aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.11-2.08]; former smokers: OR, 1.83 [95% CI, 1.68-1.99]; current smokers: OR, 2.13 [95% CI, 1.79-2.53]). Of 1839 survivors receiving treatment as captured in the EHR, 1405 (76.4%) were current drinkers, and among these, 170 (12.1%) exceeded moderate drinking, 329 (23.4%) reported binge drinking, and 540 (38.4%) engaged in hazardous drinking, with similar prevalence across different types of cancer treatment. This cross-sectional study of a diverse US cohort suggests that alcohol consumption and risky drinking behaviors were common among cancer survivors, even among individuals receiving treatment. Given the adverse treatment and oncologic outcomes associated with alcohol consumption, additional research and implementation studies are critical in addressing this emerging concern among cancer survivors.


Photothermal biosensor for HPV16 based on strand-displacement amplification and gold nanoparticles using a thermometer as readout.
Gold nanoparticles (AuNPs) in aggregated state have a strong near infrared region (NIR) absorption and the causes a much stronger photothermal effect than that of the dispersed AuNPs. Strand-displacement amplification (SDA) can produce large amount of single-stranded DNA (ssDNA), which in turn effectively prevent AuNPs from aggregation. In this study, these characteristics had been applied to design a photothermal biosensor for human papilloma virus (HPV and HPV16 were chosen as model target) detection. In the absence of HPV16, AuNPs was in the aggregated state and large temperature rise can be detected after the irradiation by 808 nm laser. The presence of HPV16 triggers the SDA reaction with the help of Bst DNA polymerase and Nt.BstNBI nicking endonuclease resulting in the production of large amounts of ssDNA; this protects unmodified AuNPs from salt-induced aggregation. Therefore, AuNPs was in a dispersed state and the temperature change was not significant after the irradiation of 808 nm laser. The difference of the temperature changing can be applied for the quantitative detection of HPV16 using a thermometer as readout. The linear response range is 1.0 fM ~ 50 pM with a detection limit of 0.3 fM. The proposed method has been applied to detect HPV16 in clinical cervical sample and is competent for clinical analysis.


Coagulase-negative variants of methicillin-resistant Staphylococcus aureus subsp. aureus strains isolated from hospital specimens.
At the Department of Clinical Bacteriology of Medical University of Warsaw, S. aureus strains displaying negative reactions in the coagulase tube-test were isolated with a relatively high frequency from clinical specimens. As many as seventeen of such strains all from different patients were isolated during 1994 among MRSA strains. Despite coagulase negativity all strains were positive in tests for clumping factor (CF), protein A and thermonuclease. Biochemical characteristics, phage patterns and antibiotic resistance characteristics of these strains were tested. Most of the coagulase-negative strains possessed a heterogenous type of methicillin resistance. Apart from methicillin most of them were resistant to many other antimicrobials. All were resistant to gentamicin, tetracyclines and macrolide-lincosamide-streptogramine B. An occurrence of coagulase-negative S. aureus strains may lead to problems in their identification and the necessity of an application of other methods like CF, protein A or biochemical reactions.


Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine-tuning of GM-CSF receptor signaling.
Fine-tuning of immune receptor signaling is critical for the development and functioning of immune cells. Moreover, GM-CSF receptor (GM-CSFR) signaling plays an essential role in the development of certain myeloid lineage cells, including alveolar macrophages (AMs). However, the significance of fine-tuning of GM-CSFR signaling in AMs and its relevance in allergic inflammation have not been reported. Our aim was to explore whether phosphatase Ssu72, originally identified as a regulator of RNA polymerase II activity, regulates AM development and allergic airway inflammation by regulating GM-CSF signaling. To address these issues, we generated LysM-CreSsu72fl/fl and Cd11c-CreSsu72fl/fl mice and used ovalbumin- or house dust mite-induced allergic asthma models. Following GM-CSF stimulation, Ssu72 directly bound to the GM-CSFR β-chain in AMs, preventing phosphorylation. Consistently, mature Ssu72-deficient AMs showed higher phosphorylation of the GM-CSFR β-chain and downstream molecules, which resulted in greater dysregulation of cell cycle, cell death, cell turnover, mitochondria-related metabolism, and LPS responsiveness in AMs than in mature wild-type AMs. The dysregulation was restored by using a Janus kinase 2 inhibitor, which reduced GM-CSFR β-chain phosphorylation. LysM-CreSsu72fl/fl mice exhibited deficits in development and maturation of AMs, which were also seen postnatally in Cd11c-CreSsu72fl/fl mice. Furthermore, LysM-CreSsu72fl/fl mice were less responsive to ovalbumin- or house dust mite-induced allergic asthma models than the control mice were; however, their responsiveness was restored by adoptive transfer of JAK2 inhibitor-pretreated mature Ssu72-deficient AMs. Our results demonstrate that Ssu72 fine-tunes GM-CSFR signaling by both binding to and reducing phosphorylation of GM-CSFR β-chain, thereby regulating the development, maturation, and mitochondrial functions of AMs and allergic airway inflammation.


B cell depletion and inhibition in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is characterized by autoantibody expression and aberrant autoreactive B cells contribute to disease progression; therefore, B cell inhibition has been an attractive target for novel therapies. However, after more than two decades of research and over 40 randomized clinical trials, only one such therapy, belimumab, has been approved for use in SLE. In this review, we discuss the evidence for B cell-targeted therapies in SLE and lupus nephritis. Belimumab has been successful in several large clinical trials and is approved in several countries for use in SLE and lupus nephritis. Despite a lack of supporting phase III evidence, rituximab is used off-label in SLE. Several other B cell-targeted therapies have failed to meet their end points in late-stage clinical trials. Successful phase II trials have recently been reported for obinutuzumab and telitacicept with larger confirmatory trials currently underway. Refinements in pharmaceutical mechanisms of action, trial design, and patient selection have resulted in recent preliminary successes, offering renewed optimism for B-cell targeted therapeutics in SLE management.


Oncogenic FGFR1 mutation and amplification in common cellular origin in a composite tumor with neuroblastoma and pheochromocytoma.
Neuroblastoma (NB) and pheochromocytoma (PCC) are derived from neural crest cells (NCCs); however, composite tumors with NB and PCC are rare, and their underlying molecular mechanisms remain unknown. To address this issue, we performed exome and transcriptome sequencing with formalin-fixed paraffin-embedded (FFPE) samples from the NB, PCC, and mixed lesions in a patient with a composite tumor. Whole-exome sequencing revealed that most mutations (80%) were shared by all samples, indicating that NB and PCC evolved from the same clone. Notably, all samples harbored both mutation and focal amplification in the FGFR1 oncogene, resulting in an extraordinarily high expression, likely to be the main driver of this tumor. Transcriptome sequencing revealed undifferentiated expression profiles for the NB lesions. Considering that a metastatic lesion was also composite, most likely, the primitive founding lesions should differentiate into both NB and PCC. This is the first reported case with composite-NB and PCC genetically proven to harbor an oncogenic FGFR1 alteration of a common cellular origin.


Efficacy and Safety of Valsartan or Chlorthalidone vs. Combined Valsartan and Chlorthalidone in Patients With Mild to Moderate Hypertension: The VACLOR Study.
To evaluate the efficacy and safety of valsartan (V) or chlorthalidone (C) monotherapy in comparison with a fixed combination of valsartan and chlorthalidone (V + C). This 12-week multicenter randomized three-arm open-label study randomly allocated 72 patients to V or C as monotherapy or a combination of V + C. The aim was to measure changes in office systolic blood pressure (SBP) and diastolic blood pressure (DBP) and in 24-hour ambulatory blood pressure monitoring (ABPM) from baseline to week 12, in addition to medication tolerability. The proportion of patients achieving target BP in office at week 12 was not statistically different for the three groups. However, comparisons of daytime and nighttime 24-hour ABPM values from baseline to week 12 revealed significant differences in nighttime mean SBP for the three groups, due to a significantly greater reduction in the values in patients assigned to the V + C group (-14.7 vs. -8.7 vs. -10.7, P = .042, V+C; V; C, respectively). Although patients assigned to the V + C group also had greater nighttime reduction in mean DBP values compared with those in the other groups, this difference was not statistically significant. The incidence of adverse events did not differ significantly. In patients with hypertension treated with V, C, and both medications combined, the fixed combination of V + C provided a significantly greater reduction of late night to early morning BP values when interventions were assessed with 24-hour ABPM. clinicaltrials.gov Identifier: NCT.01850160, https://clinicaltrials.gov/ct2/show/NCT01850160.


Smooth muscle in the annulus fibrosus of the tympanic membrane: physiological effects on sound transmission in the gerbil.
In a wide variety of mammals, the rim of the tympanic membrane (annulus fibrosus) has an array of contractile elements, either smooth muscle [Henson and Henson, J. Assoc. Res. Otolaryngol. 1 (2000) 25-32] or myofibroblasts [Kuijpers et al., Hear. Res. 128 (1999) 80-88]. These elements are anchored peripherally to the bony tympanic ring and centrally to incoming fibers of the pars tensa. Their arrangement suggests that they are involved in the control of tympanic membrane tension. In this study, cochlear microphonic (CM) threshold changes were recorded in gerbils to study the physiological effects of these contractile elements. It was demonstrated that the application of substances known to make smooth muscle contract (vanadate and norepinephrine) caused concentration-dependent elevations in CM thresholds. Maximum changes of 8-9 dB occurred with the lowest frequency tested (2.16 kHz). The application of muscle-relaxing drugs reversed these effects. Controls showed that the threshold changes were not induced by effects on middle or inner ear structures. These results add to emerging evidence that the tympanic membrane has intrinsic control of tension and is potentially able to have some control over energy levels reaching the cochlea.


Salt effects on internal motions of superhelical and linear pUC8 DNA. Dynamic light scattering studies.
The plasmid pUC8 (2717 bp) has been studied in its native superhelical and Eco RI-linearized forms by dynamic light scattering at NaCl concentrations from 1.1 mM to 1 M. The data were analyzed using the biexponential model for the dynamic structure factor described by us in a previous paper (J. Langowski, U. Giesen and C. Lehmann, Biophys. Chem. 25 (1986) 191). As before, we could identify two decay components corresponding to the center-of-mass diffusion and to internal motions of the DNA, where the fast component could be identified as a rotational diffusion contribution in the case for superhelical, but not for linear DNA. We found that the conformation of superhelical pUC8 is not affected by changing the ionic strength, while the amplitude of the internal relaxation increases approx. 2-fold when [NaCl] is raised from 1.1 mM to 1 M. The linearized DNA shows an increase of the diffusion coefficient with ionic strength which is, however, not quite as pronounced as that found by others (Z. Kam, N. Borochov and H. Eisenberg, Biopolymers 20 (1981) 2671), and, together with the unchanged conformation of the superhelical DNA, suggests a persistence length which is not strongly dependent on ionic strength. In contrast to the increasing amplitude of internal relaxation for the superhelical DNA, this amplitude remains constant or decreases slightly for linear DNA on going from 1.1 mM to 1 M salt. Our findings are further discussed with respect to possible models of the interwound form of superhelical DNA.


Adjunctive handgrip during dobutamine stress echocardiography: invasive assessment of myocardial oxygen consumption in humans.
Adjunctive isometric exercise in the form of sustained submaximal handgrip (HG) is considered to increase the sensitivity of dobutamine stress echo (DSE) for detection of functionally significant coronary artery disease. The study was undertaken to quantify invasively the impact of HG in humans on hemodynamics and myocardial oxygen consumption (MVO2) during DSE. An invasive hemodynamic evaluation was performed during DSE and with addition of adjunctive HG in 11 subjects. Coronary sinus (CS) blood flow, right-sided and systemic pressures, oxygen saturations, and transthoracic two-dimensional echocardiography were obtained at each 3-min stage and after adding HG at peak DSE. Myocardial oxygen consumption was calculated by the Fick method and circumferential end-systolic wall stress (ESWS) by Mirsky's formula. At peak DSE, heart rate, left ventricular ejection fraction, CS flow, and MVO2 increased, whereas pulmonary capillary wedge pressure (PCWP) and circumferential end-systolic wall stress (ESWS) decreased from baseline. Compared with peak DSE, the addition of isometric HG at peak DSE caused an increase in PCWP (7 +/- 3 vs. 8.4 +/- 3 mmHg, p < 0.05), ESWS (112 +/- 25 x 103 vs. 125 +/- 32 x 103 dyne x s x cm2, p = 0.02), and CS flow (260 +/- 92 vs. 301 +/- 105 ml/min, p < 0.05). There was a minimal increase in left ventricular volumes, heart rate, and systolic blood pressure. The MVO2 increased from 29 +/- 8 ml/min at peak DSE to 31 +/- 9 ml/min with adjunctive HG (p = 0.03). Handgrip adjunctive to peak DSE results in a modest increase in MVO2, primarily by an increase in end-systolic wall stress.


Cost-effectiveness of lung MRI in lung cancer screening.
Recent studies with lung MRI (MRI) have shown high sensitivity (Sn) and specificity (Sp) for lung nodule detection and characterization relative to low-dose CT (LDCT). Using this background data, we sought to compare the potential screening performance of MRI vs. LDCT using a Markov model of lung cancer screening. We created a Markov cohort model of lung cancer screening which incorporated lung cancer incidence, progression, and mortality based on gender, age, and smoking burden. Sensitivity (Sn) and Sp for LDCT were taken from the MISCAN Lung Microsimulation and Sn/Sp for MRI was estimated from a published substudy of the German Lung Cancer Screening and Intervention Trial. Screening, work-up, and treatment costs were estimated from published data. Screening with MRI and LDCT was simulated for a cohort of male and female smokers (2 packs per day; 36 pack/years of smoking history) starting at age 60. We calculated the screening performance and cost-effectiveness of MRI screening and performed a sensitivity analysis on MRI Sn/Sp and cost. There was no difference in life expectancy between MRI and LDCT screening (males 13.28 vs. 13.29 life-years; females 14.22 vs. 14.22 life-years). MRI had a favorable cost-effectiveness ratio of $258,169 in men and $403,888 in women driven by fewer false-positive screens. On sensitivity analysis, MRI remained cost effective at screening costs < $396 dollars and Sp > 81%. In this Markov model of lung cancer screening, MRI has a near-equivalent life expectancy benefit and has superior cost-effectiveness relative to LDCT. • In this Markov model of lung cancer screening, there is no difference in mortality between yearly screening with MRI and low-dose CT. • Compared to low-dose CT, screening with MRI led to a reduction in false-positive studies from 26 to 2.8% in men and 26 to 2.6% in women. • Due to similar life-expectancy and reduced false-positive rate, we found a favorable cost-effectiveness ratio of $258,169 in men and $403,888 in women of MRI relative to low-dose CT.


Looking ahead: questions for and about behavioral scientists and practitioners.
In this article Robin B. Jarrett reflects on the early years in which female investigators were a minority in the field and on her participation in the Trailblazers' panel discussion at the Association for Behavioral and Cognitive Therapies on November 29, 2009. Dr. Jarrett writes these reflections in the form of a letter to current and future professionals (of all demographics) dedicated to behavioral science and its practice; she poses questions about what the future may hold.


New cycloalkyl[b]thiophenylnicotinamide-based α-glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations.
In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC50 = 258.5 μM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC50 value of 9.9 μM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.


Relationship between Dose of Bolus Dialysate Infusion and Blood Pressure in Intermittent Infusion Hemodiafiltration.
Intermittent infusion hemodiafiltration is a recently developed convective method of renal replacement therapy using cyclic back-filtration infusion. Quick and regular infusion prevents intradialytic hypotension. However, the optimal dose of bolus dialysate infusion required to stabilize blood pressure has not been reported. Here, we investigated the relationship between the dose of bolus dialysate infusion and blood pressure. A total of 77 patients on maintenance hemodialysis were enrolled in this study. Dialysate was infused rapidly by backward filtration at a rate of 150 mL/min at 30-min intervals using an automated dialysis machine. The effects with two bolus infusion volumes (100 and 200 mL) were compared, each for an observation period of 2 weeks. Systolic blood pressure (SBP) was measured at the start and at the end of each dialysis session, and the highest SBP and lowest SBP measurements were also recorded. Patients were divided according to dry weight into a <52 kg group and a ≥52 kg group, and various parameters were compared between the 100 and 200 mL bolus infusion volumes in each group. Among patients in the <52 kg group, SBP did not vary at any of the time points. However, for patients in the ≥52 kg group, SBP at the end of treatment was significantly lower in the 100-mL group than in the 200-mL group (141 ± 20 vs. 144 ± 21 mm Hg, p = 0.041), and the minimum SBP was also lower in the 100-mL group than in the 200-mL group (127 ± 17 vs. 131 ± 18 mm Hg, p = 0.010). Key Messages: Among patients with a dry weight of ≥52 kg, blood pressure was more stable when a bolus fluid volume of 200 mL was used, compared with a volume of 100 mL. However, for patients with a dry weight of <52 kg, the significance of the difference in bolus fluid volumes disappeared. Thus, the replacement fluid volume might be better determined based on the patient's dry weight. UMIN 000028145, Registered July 10, 2017.


Prognostic implications of symptomatic versus asymptomatic (silent) myocardial ischemia induced by exercise in mildly symptomatic and in asymptomatic patients with angiographically documented coronary artery disease.
Patients with coronary artery disease (CAD) may undergo periods of reversible myocardial ischemia without experiencing angina. To study the prognostic implications of "silent" myocardial ischemia induced by exercise, exercise electrocardiography and radionuclide angiography were performed in 131 consecutive patients with CAD, preserved left ventricular (LV) function at rest and mild or no symptoms during medical therapy. All patients who died during medical therapy were in the subgroup of patients with 3-vessel CAD in whom exercise-induced ischemia developed, which was characterized by both a decrease in LV ejection fraction and ST-segment depression. Patients in whom angina pectoris developed during exercise (54% of all patients) had a greater prevalence of this combined ischemic response to exercise than patients without angina (61% vs 27%, p less than 0.001) and also a greater prevalence of left main or 3-vessel CAD (59% vs 25%, p less than 0.001). However, when inducible ischemia was demonstrated, risk stratification and prognosis were the same whether the ischemic episode was symptomatic or silent. Among patients having both a reduction in ejection fraction and a positive ST-segment response, the likelihood of significant left main narrowing (13% vs 26%), 3-vessel CAD (56% vs 51%) and death during subsequent medical therapy (16% vs 9%) was similar in patients with silent compared to those with symptomatic ischemia. These data indicate that patients in whom angina develops during exercise have a greater prevalence of high-risk coronary anatomy and of inducible ischemia than patients without angina. However, once inducible ischemia is documented, the symptomatic response to exercise appears irrelevant for prognostic or risk stratification considerations.


Discovery of thiadiazole amides as potent, S1P₃-sparing agonists of sphingosine-1-phosphate 1 (S1P₁) receptor.
High-throughput screening of GSK compound collection led to the discovery of a novel series of thiadiazole amides as potent and S1P(3)-sparing sphingosine-1-phosphate 1 (S1P(1)) receptor agonists. Synthesis, structure and activity relationship, selectivity, and some developability properties are described.


Food manufacturing foreign divestment and domestic investment in developed countries.
Whilst there is some literature on the effect of inward foreign direct investment on domestic investment for the whole economy and the agricultural sector, that of foreign divestment on domestic investment for food manufacturing is rare. This paper contributes to the literature by estimating the crowding effect of foreign divestment on domestic investment in the food manufacturing sector using an unbalanced panel of 29 countries from 1991 to 2019. Foreign divestment crowded out domestic investment for developed countries in the short and long runs. In terms of the absolute reduction in domestic investment, the short-run effect is higher than the long-run effect. Policies to attract inward foreign direct investment and retain it should be pursued.


Albumin-binding prodrugs via reversible iminoboronate forming nanoparticles for cancer drug delivery.
Albumin-based nanomedicines are important nanoplatforms for cancer drug delivery. The drugs are either physically encapsulated or covalently conjugated to albumin or albumin-based nanosystems. Physical encapsulation is advantageous due to requiring no chemical modification of drug molecules, but many drugs, for instance, camptothecin (CPT) and curcumin (CCM), though very hydrophobic, can't be loaded in or form nanoformulations with albumin. Herein, we demonstrate prodrugs readily binding to proteins via iminoboronates and forming nanoparticles for cancer drug delivery. CPT and CCM were functionalized with 2-acetylphenylboronic acid (2-APBA) to produce prodrugs CPT-SS-APBA and CCM- APBA. The prodrugs bound to bovine serum albumin (BSA) via formation of iminoboronates and the produced BSA/prodrug readily self-assembled into well-defined nanoparticles with high loading efficiency, improved colloidal stability, and much-improved pharmacokinetics. The nanoparticles effectively released drugs in the intracellular acidic environment or the cytosol rich in glutathione (GSH). In vivo, the nanoparticles showed enhanced anticancer efficacy compared with clinically used irinotecan or sorafenib in subcutaneous 4 T1 or HepG2 tumor models. This work demonstrates a versatile protein-binding prodrug platform applicable to protein-based drug formulations and even antibody-drug conjugates.


Podocyte antigens and glomerular disease.
Membranous nephropathy (MN), a major cause of nephrotic syndrome in the adult, is an immune-mediated disease characterized by the accumulation of subepithelial immune deposits leading to complement activation and podocyte injury. However, the target antigens of circulating antibodies are unknown. Current treatments for patients with MN are entirely empirical, and concept-driven therapies are dramatically lacking. Specificity of circulating antibodies and composition of glomerular deposits were analyzed in Heymann nephritis (HN), a faithful rat model of MN, and in a subset of patients with antenatal MN. 20 years after the identification of megalin as the podocyte target antigen of nephritogenic antibodies in HN, we identified the human counterpart of megalin, the enzymatic podocyte antigen neutral endopeptidase (NEP). Antibodies to megalin or NEP induce formation of subepithelial immune deposits and of C5b-9, the membrane attack complex of complement. It is likely that antigens involved in idiopathic MN are expressed at the podocyte membrane. Their identification together with that of immunodominant epitopes may lead to specific antigen/ epitope-based immunotherapy aimed at inducing specific tolerance.


WeChat as a platform for blending problem/case-based learning and paper review methods in undergraduate paediatric orthopaedics internships: a feasibility and effectiveness study.
Paediatric orthopaedics is a significant and difficult for undergraduate students to master. During the COVID-19 pandemic, we used the WeChat platform to combine the advantages offered by problem-based learning (PBL), case-based learning (CBL) and paper review teaching methods to establish a new blended online teaching model and demonstrated its feasibility and effectiveness. This study aims to demonstrate the feasibility and effectiveness of a new blended pedagogical method that uses the WeChat platform and combines PBL, CBL and paper review. We enrolled 22 students participating in the Department of Paediatric Orthopaedics. They participated in the WeChat blended pedagogy mode. Their departmental rotation examination scores were compared with those of 23 students who participated in the traditional teaching method. Moreover, an anonymous questionnaire was used to evaluate students' perceptions and experiences. The total average scores of students who participated in the WeChat blended pedagogy mode and the traditional teaching method were 47.27 and 44.52, respectively. There were no statistically significant differences between the online teaching mode and the traditional teaching method in terms of possessing professional accomplishment, gaining knowledge and promoting interpersonal skills (P = 0.07, P = 0.12 and P = 0.65, respectively). In terms of independent clinical thinking, self-improving capability and improving clinical skills, the scores associated with the WeChat blended pedagogy mode were 8.00, 8.00 and 6.00, whereas those associated with the traditional teaching method were 6.70, 6.87 and 7.48. The overall satisfaction with the WeChat blended pedagogy mode reached 100%. A total of 64%, 86%, 68%, 64% and 59% of students chose very large or large in response to the items concerning professional accomplishment, knowledge absorption, independent clinical thinking skills, English reading and literature exploring capacity, as well as interpersonal skills, respectively. Fifteen participants claimed that the WeChat blended pedagogy mode was less helpful to them with regard to promoting the improvement of their clinical skills. Nine students claimed that the WeChat blended pedagogy mode was time-consuming. Our study verified the feasibility and effectiveness of the WeChat blended pedagogy mode for undergraduate paediatric orthopaedics internships. Retrospectively registered.


Laser light-scattering study of the effect of progesterone on sperm motility.
It is known that progestins can induce in the secretory cells of the cervix the excretion of a mucus that is highly viscuos, scanty, and impenetrable to spermatozoa. Mucus of this type is similar to that excreted during the luteal phase of the normal human menstrual cycle and the cow estrous cycle. It is a natural sequence to ask the question, do progestins also have a direct effect on sperm motility? With dynamic laser light-scattering we measured the motility of freshly washed human spermatozoa and of spermatozoa in the presence of a progesterone, both in terms of their swimming speed distribution as expressed in the spectrum of scattered light. The swimming speed was significantly reduced when the concentration of progesterone was three orders of magnitude greater than that of the physiologic level. This finding confirms the finding in earlier biochemical studies that progesterone has a distinct spermiostatic effect. We suggest this answer to the above question: progestin-releasing contraceptive devices may act on spermatozoa directly as well as in the secretory cells of the cervix.


Intimal thickening after arterial balloon injury is increased by intermittent repetitive hypoxia, but intermittent repetitive hyperoxia is not protective.
Hypoxia increases and hyperoxia decreases experimental atherosclerosis, but it is unclear if repetitive hypoxic and hyperoxic insults affect intimal thickening after arterial injury. Rabbits on 2% cholesterol diet for 6 weeks underwent balloon injury to the abdominal aorta (AA) after week 3, and were then exposed to normoxia (n = 6), or 12 h daily of intermittent repetitive hypoxia (n = 6) or hyperoxia (n = 6). After week 6, damaged AA and undamaged thoracic aorta (TA) were assessed for intimal thickening and lipid content. Compared with normoxia, hypoxia and hyperoxia did not alter the rise in serum cholesterol related to cholesterol feeding. However, compared to normoxia, hypoxia markedly increased the intima-to-media ratio in AA (1.18 +/- 0.09 versus 1.96 +/- 0.14, P < 0.01) and TA (0.15 +/- 0.02 versus 0.41 +/- 0.01, P < 0.01) whereas hyperoxia had no effect on AA disease and increased intimal thickening in TA (0.26 +/- 0.03, P < 0.01). Hyperoxia promoted positive arterial remodeling in both TA and AA, resulting in larger luminal size. The cholesterol content in AA was increased by hypoxia and decreased by hyperoxia, but decreased by both treatments in TA. Lipophilic antioxidants and the proportion of arterial lipids that was oxidized were not altered by hypoxia or hyperoxia. These results suggest that intermittent repetitive hyperoxia is not protective and intermittent repetitive hypoxia promotes arterial disease in normal and injured arteries independent of lipid peroxidation.


Vitamin E protects chondrocytes against hydrogen peroxide-induced oxidative stress in vitro.
This study evaluated the effect of an antioxidant, Vitamin E, on cultured chondrocytes against H₂O₂-induced damage in vitro. Rat chondrocytes isolated from articular cartilage. Chondrocytes were pretreated with either 50 or 100 μM Vitamin E or serum-free medium for 24 h followed by their exposure to 200 μM H₂O₂ for 3 h. Chondrocytes without exposure to H₂O₂ served as control group. The effect of Vitamin E pretreatment was evaluated by examining proteoglycan contents, nitrite levels, viability, apoptosis, and senescence of cultured chondrocytes. Proteoglycan contents increased in groups treated with Vitamin E. Semi-quantitative real-time PCR data also correlated with these results and demonstrated that Vitamin E up-regulated expression of Agc1, Col2a1, and PCNA genes along with down-regulation in the expression of Col1a1 and Casp3 genes. The differentiation index improved after Vitamin E pretreatment. Nitrite levels were reduced with a corresponding increase in cell viability. Reduction in apoptosis and senescence was also observed after Vitamin E pretreatment. Moreover, a dose-dependent effect of Vitamin E was seen. In contrast to 50 μM Vitamin E, 100 μM was more potent in inducing protection of chondrocytes from H₂O₂-induced oxidative damage. Vitamin E reversed the oxidant-induced alterations in chondrocytes and may be a good option to pretreat chondrocytes before transplantation.


[The pharmacological options for an immediate intervention in threatened premature labor].
The following preparations, with different mechanism of action, have been comparatively tested for induction of immediate tocolysis in case of threatened preterm labour: Hyoscine butylbromide, ritodrine, ketoprofen and the association of ritodrine with ketoprofen. Hyoscine butylbromide was found to be very easy to handle, but its myolytic effect is modest. Ritodrine and ketoprofen have shown a high and quantitatively similar tocolytic power. But even better results have been achieved with the association of ritodrine with ketoprofen which has shown a total myolytic effect. The authors suggest some hypotheses concerning the mechanism of action of these drugs, and some precautions for their correct clinical use.


An amine-functionalized titanium metal-organic framework photocatalyst with visible-light-induced activity for CO2 reduction.
Let your light shine: the photocatalytic reduction of carbon dioxide to the formate anion under visible light irradiation is for the first time realized over a photoactive Ti-containing metal-organic framework, NH(2)-MIL-125(Ti), which is fabricated by a facile substitution of ligands in the UV-responsive MIL-125(Ti) material.


SOX2 as a prognostic marker and a potential molecular target in cervical cancer: A meta-analysis.
Sex determining region Y-box 2 (SOX2) has been reported as a potential therapeutic target for cancer. However, the role of SOX2 in cervical cancer remains largely undetermined. This study was performed to evaluate the correlation of SOX2 with clinical characteristics and prognosis in cervical cancer. Multiple databases were systematically searched for eligible publications. The combined odds ratios (ORs) or hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were used to assess the effect sizes. A total of 17 studies with 1906 participants were identified. SOX2 expression was higher in cervical cancer than in the normal control group (OR = 10.83, 95% CI = 6.64-17.67, P < 0.001), while no significant difference was observed between cervical cancer and cervical intraepithelial neoplasia. SOX2 expression was not associated with age, tumor stage, and lymph node metastasis, but was correlated with tumor grade (grade 2-3 vs. grade 1: OR = 4.59, 95% CI = 2.76-7.62, P < 0.001) and tumor size (≥4 cm vs. ≤4 cm: OR = 1.66, 95% CI = 1.05-2.60, P = 0.028). Based on multivariate Cox analysis, SOX2 expression was not correlated with overall survival, but was closely associated with poor recurrence-free survival (HR = 5.83, 95% CI = 1.35-25.16, P = 0.018) and progress-free survival HR = 2.29, 95% CI = 1.01-5.19, P = 0.046). SOX2 may serve as a novel prognostic factor and a promising molecular target for cervical cancer.


Studies on the rabies virus RNA polymerase: 2. Possible relationships between the two forms of the non-catalytic subunit (P protein).
We investigated the relationship between the two forms of rabies virus P protein, a non-catalytic subunit of rabies virus RNA polymerase. The two displayed different electrophoretic mobilities as 37- and 40-kDa polypeptides, hence termed as p37 and p40, respectively. Double labeling experiments with [3H]leucine and [32P]orthophosphate demonstrated that p40 was much more phosphorylated than p37. Treatment of the virion proteins with alkaline phosphatase eliminated only p40, and not 37-kDa polypeptide. The p37 was a major product of the P gene, and was accumulated in the infected cell and incorporated into the virion. On the other hand, p40 was apparently detected only in the virion, and little detected in the cells. Treatment of infected cells with okadaic acid, however, resulted in significant accumulation of p40 in the cell, suggesting that p40 was continuously produced in the cell but dephosphorylated quickly. We detected both 37- and 40-kDa products in P cDNA-transfected animal cells, while only a 37-kDa product was produced in Escherichia coli. Incubation of 37-kDa products from E. coli with the lysates of animal cells in vitro resulted in the production of a 40-kDa product, which was also shown to be suppressed by the heparin. From these results, it is suggested that p40 is produced by the hyperphosphorylation of a 37-kDa polypeptide, which depends on certain heparin-sensitive cellular enzyme(s) and occurs even in the absence of the other viral gene products, and that p40 is reverted quickly to p37 in the infected cells, probably being dependent on some virus-induced factor(s).


DNA Damage Baseline Predicts Resilience to Space Radiation and Radiotherapy.
Deep space exploration will require real-time, minimally invasive monitoring of astronaut health to mitigate the potential health impairments caused by space radiation and microgravity. Genotoxic stress in humans can be monitored by quantifying the amount of DNA double-strand breaks (DSBs) in immune cells from a simple finger prick. In a cohort of 674 healthy donors, we show that the endogenous level of DSBs increases with age and with latent cytomegalovirus infection. To map the range of human responses to space radiation, we then study DSB induction and repair in immune cells from 319 healthy donors after the cells are exposed to galactic cosmic ray components and lymphocytes from 30 cancer patients after radiotherapy. Individuals with low baseline DSB have fewer clinical complications, enhanced DNA damage repair responses, and a functional dose-dependent cytokine response in healthy donor cells. This supports the use of DSB monitoring for health resilience in space.


Trends in the distribution of donor corneal tissue and indications for corneal transplantation: the New Zealand National Eye Bank Study 2000-2009.
To investigate the indications for corneal transplantation and the distribution of donor corneal tissue in New Zealand. Analysis of the prospective database of the New Zealand National Eye Bank. A total of 2205 corneal transplants were assessed. New Zealand National Eye Bank records were analysed for the decade 2000-2009. Variables analysed included donor corneal tissue distribution (including public and private sectors), indications for transplantation, donor corneal tissue recipient demographics (age and gender) and corneal transplantation type. An average of 220 corneal transplants were performed each year over the 10-year period (n=2205). The median recipient age was 45years (range 3 to 102years) and 54.0% of recipients were male. In total 71.8% of transplants were performed in the public health sector. Surgeons in the Auckland metropolitan area performed 47.2% of all corneal transplants. The most common indications for corneal transplantation were: keratoconus (41.1%), repeat transplant (17.0%), aphakic/pseudophakic bullous keratopathy (13.9%), corneal dystrophy (10.7%), keratitis (7.9%) and trauma (3.7%). Overall, penetrating keratoplasty accounted for 90.7% of all corneal transplants, however, during the latter half of the study there was a progressive shift in transplantation type, with deep anterior lamellar keratoplasty and Descemet's stripping endothelial keratoplasty combined accounting for 32.3% of all transplants in the final year of the study period. This New Zealand National Eye Bank study provides valuable data regarding the indications for corneal transplantation, transplant recipient demographics and changes in transplantation type in New Zealand over the past decade.


Determination of selected quaternary ammonium compounds by liquid chromatography with mass spectrometry. Part I. Application to surface, waste and indirect discharge water samples in Austria.
A method for simultaneous quantitative determination of alkyl benzyl, dialkyl and trialkyl quaternary ammonium compounds (QACs) has been developed, validated and subsequently applied to real water samples in Austria. The method employs liquid-liquid extraction (LLE) followed by liquid chromatography/tandem mass spectrometry (LC-MS/MS), using electrospray ionization (ESI) in positive mode. The overall method quantification limits range from 4 to 19ng/L for the enrichment of 500mL water samples and analyte recoveries are between 80 and 99%. The method was applied to 62 of the respective water samples without filtration to avoid the loss of the analytes due to the high adsorption capacity of these compounds. Maxima in the mg/L range, especially in the wastewater of hospitals and laundries, could be detected for the selected target compounds.


Ruptured aneurysm of the external iliac vein.
Primary iliac venous aneurysm is an extremely rare vascular abnormality that is associated with the likelihood of rupture, embolism, and thrombosis. In this report, we describe the case of a ruptured aneurysm of the external iliac vein in a 63-year-old woman who was admitted to the emergency department and diagnosed by computed tomography. Computed tomography indicated a 4 × 5-cm ruptured aneurysm in the right external iliac vein that was surrounded by hematoma in the right side of the pelvis. The aneurysm was successfully treated by tangential aneurysmectomy and lateral venorrhaphy.


Local suppressive effect of clonidine on penile erection in the dog.
Dogs, 8.5 to 10 kg. in weight, were anesthetized with sodium pentobarbital (35 mg./kg.), intraperitoneally. Penile erection as indicated by an increase in the intracorporal pressure (ICP-increase) was produced by electrical stimulation of the right cavernous nerves. Drugs were administered into the internal pudendal artery (IPA) and femoral vein. A low dose (0.2 to 0.4 microgram/kg.) of clonidine, an alpha 2 adrenoceptor agonist, which could not affect either ICP or systemic arterial pressure (SAP) through an intravenous route, did suppress the ICP-increase markedly via direct injection into the IPA which supplies the penile blood flow. By intra-IPA injection, yohimbine (2.5 micrograms/kg.), an alpha 2 adrenoceptor antagonist, remarkably restored the ICP to the erection state. By intravenous injection, clonidine at a dose of 1.6 to 3.2 micrograms/kg. also profoundly reduced the ICP-increase, but only negligibly lowered the SAP. The IPA blood flow (IPAF) decreased coincidentally when the ICP-increase was effectively reduced by either intravenous or intra-IPA injection of clonidine. These findings suggest clonidine could act locally in the penile structure to suppress penile erection, possibly resulting from a penile vasoconstriction involving alpha 2 adrenoceptor. Whether this vasoconstriction is caused by a direct alpha 2 stimulating effect on the vascular smooth muscle or by an alpha 2 presynaptic inhibition of the vasodilator nerve (cavernous nerve) endings has been discussed.


Resilience of visually guided weight shifting to a proprioceptive perturbation depends on the complexity of the guidance stimulus.
Whole-body tracking of visual motion cues is used in balance training to improve weight shifting ability in old age and sports. How tracking of a complex (pink noise) and a periodic visual target motion during anteroposterior weight shifting affects postural and muscle responses to unilateral hip vibration. Twenty-six participants performed 160 anteroposterior weight shifting cycles while tracking the vertical motion of a visual target, concurrently receiving Center of Pressure (CoP) feedback. They were randomly divided to groups; (a) the Constant group tracked a visual target motion constructed by 3 sinusoids of different amplitude, and (b) the Pink group tracked a complex visual target motion constructed by a pink noise generation process. Between the 60th and the 120th cycle, vibration was applied to the right gluteus medius, introducing a sideways CoP deviation. CoP displacement and electromyographic (EMG) responses of soleus, tibialis anterior and peroneus longus were recorded and summarized in blocks of 3 cycles. Sideways CoP deviation induced at the onset/offset of unilateral hip vibration was smaller for the Pink than the Constant group. The Pink group demonstrated greater tibialis anterior and peroneus longus EMG activity around the most anterior sway peak while soleus EMG was similar for the two groups. Both groups successfully coupled weight shifting amplitude to the target motion, but the Pink group tracked the target motion with a greater delay compared to the Constant group. Whole body tracking of complex visual motions evokes perception-based action and increases ankle muscle co-activation making sway more resilient to a proprioceptive perturbation induced by unilateral hip vibration. Complex visual guidance motions should be considered when designing balance rehabilitation regimes, aiming at improving weight shifting ability and dynamic balance control.


A Novel Technique to Convert Static Sling into a Dynamic Sling in Reconstruction of Total Lower Lip Defects Using Palmaris Longus Tendon with Free Radial Forearm Flap and Case Series.
Lower lip reconstruction has been a major challenge for the reconstructive surgeons since time immemorial. Various types of reconstruction had been described for the reconstruction of lower lip ranging from local flaps to free tissue transfer to free functioning muscle transfer. For complete lower lip defects, the free radial forearm flap with palmaris longus tendon has been the standard of reconstruction for many years. Literatures suggests various techniques for utilizing palmaris longus tendon sling as a static as well as dynamic structure. The limitation with static reconstruction is the loss of sling support with time leading to eversion and drooping of the reconstructed lower lip and drooling of saliva. In this article we describe a simpler and novel technique which converts static reconstruction into a dynamic one with a series of 5 patients. Aim of this prospective study was to evaluate the post operative functional and aesthetic outcome of our technique of total lower lip reconstruction using free radial forearm flap with palmaris longus sling reconstruction. The medical records included were demographics, including age, gender, and reason for the acquired defect, lip reconstructed, reconstructive method, flap survival, and outcomes. At 6 months follow up, all patients had satisfactory outcome and were able to take oral diets and none of the patients complained of drooling, an inability to eat in a public setting, or microstomia. This technique which is a simpler modification can be helpful in converting the traditional static sling reconstruction of lower lip into a dynamic one resulting in good aesthetic and functional outcomes.


Flow disturbances at the apex and lateral angles of a variety of bifurcation models and their role in development and manifestations of arterial disease.
Dye flow patterns were studied in 12 glass model bifurcations with angles of 45, 90, 135, and 180 degrees, and area ratios of 0.78, 1.03 and 1.27. At the apex, the dye formed a saddle zone, and streamlines from the core which entered this region were swept over the upper and lower surfaces to enter the lateral angles. Qualitatively, the shape and size of the apex played a key role in this effect. Boundary layer separation occurred in the lateral angles, and increased as flow into the branch was reduced. If the branch was occluded, a complex vortex developed in the first few diameters of the branch, and no flow occurred beyond this, even though the occlusion was about 20 diameters downstream. The results were comparable with steady and pulsatile flow. The implications of these results for the localization of atherosclerosis are discussed.


Bile acid sulfotransferase I from rat liver sulfates bile acids and 3-hydroxy steroids: purification, N-terminal amino acid sequence, and kinetic properties.
A bile acid:3'phosphoadenosine-5'phosphosulfate:sulfotransferase (BAST I) from adult female rat liver cytosol has been purified 157-fold by a two-step isolation procedure. The N-terminal amino acid sequence of the 30,000 subunit has been determined for the first 35 residues. The Vmax of purified BAST I is 18.7 nmol/min per mg protein with N-(3-hydroxy-5 beta-cholanoyl)glycine (glycolithocholic acid) as substrate, comparable to that of the corresponding purified human BAST (Chen, L-J., and I. H. Segel, 1985. Arch. Biochem. Biophys. 241: 371-379). BAST I activity has a broad pH optimum from 5.5-7.5. Although maximum activity occurs with 5 mM MgCl2, Mg2+ is not essential for BAST I activity. The greatest sulfotransferase activity and the highest substrate affinity is observed with bile acids or steroids that have a steroid nucleus containing a 3 beta-hydroxy group and a 5-6 double bond or a trans A-B ring junction. These substrates have normal hyperbolic initial velocity curves with substrate inhibition occurring above 5 microM. Of the saturated 5 beta-bile acids, those with a single 3-hydroxy group are the most active. The addition of a second hydroxy group at the 6- or 7-position eliminates more than 99% of the activity. In contrast, 3 alpha,12 alpha-dihydroxy-5 beta-cholan-24-oic acid (deoxycholic acid) is an excellent substrate. The initial velocity curves for glycolithocholic and deoxycholic acid conjugates are sigmoidal rather than hyperbolic, suggestive of an allosteric effect. Maximum activity is observed at 80 microM for glycolithocholic acid. All substrates, bile acids and steroids, are inhibited by the 5 beta-bile acid, 3-keto-5 beta-cholanoic acid. The data suggest that BAST I is the same protein as hydrosteroid sulfotransferase 2 (Marcus, C. J., et al. 1980. Anal. Biochem. 107: 296-304).


[Iodine 131 uptake by a bronchogenic cyst in a patient with differentiated carcinoma of the thyroid gland].
After thyroidectomy for differentiated thyroid carcinoma, extracervical uptake of iodine 131 is suggestive of metastasic dissemination. False positives can however occur. Differentiated thyroid carcinoma was found in a female patient with a non-functional nodule. Two years after subtotal thyroidectomy and an ablative dose of iodine 131, the whole body scan showed abdominal mediastinal uptake with low serum thyroglobulin level. Considering the possibility of tumor recurrence or lymph node metastasis, the mass was excised. The histology diagnosis was mediastinal bronchogenic cyst. To date, iodine uptake in a bronchogenic cyst has not been reported among other false-positives previously described. The pathophysiology of this iodine 131 uptake in a bronchogenic cyst is still unknown: the presence of NIS symporter or a protein which can organify iodine in the mucus cells of the cyst remains to be proven.


Ex vivo gliadin stimulation of intestinal cells.
Celiac disease is an autoimmune response to gluten proteins. While causes for celiac disease have been identified, there is no effective treatment other than diet control. In vitro models for celiac disease are important for quickly gaining understanding of the disease mechanism and testing potential treatments. Here we describe an ex vivo stimulation of intestinal epithelial cells with gliadin peptides as a method to induce celiac disease features in vitro.


The use of videos in road safety training: cognitive and emotional effects.
The aim of the study was to evaluate the use of videos in educational programs for improving road safety. Particularly, we evaluated the cognitive and emotional effects of viewing videos taken from cameras placed along Italian highways and showing car crashes or traffic flow images. One hundred and seventy students from the Sapienza University of Rome participated in the study as volunteers. Each participant was randomly assigned to one of three experimental groups ("Video", "Video plus commentary", "Written Description"). Results showed that the overall emotional activation was significantly higher in the two conditions that employed live video (both with and without verbal explanations). However, scores on the Information dimension were significantly higher in the conditions that contained only verbal descriptions or that combined video and verbal explanations. Results of this experiment suggest that live videos of car crashes have the primary feature of inducing a high emotional activation (especially when they represent action scenes, as car crashes) that can be modulated by co-occurring verbal explanations. When these videos are not integrated by an appropriate verbal explanation, they can be experienced as not fully instructive.


Ubiquinol-cytochrome c reductase core protein 1 overexpression protects H9c2 cardiac cells against mimic ischemia/reperfusion injury through PI3K/Akt/GSK-3β pathway.
Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) plays a key role in influencing mitochondrial function. Increasing evidence supports that UQCRC1 overexpression takes part in cardioprotection. However, it remains unclear about the signaling pathway mediating the protective role of UQCRC1 overexpression. Thus, the current study aimed to investigate the signaling pathway. Inhibition of PI3K completely abolished the protective effects of UQCRC1 overexpression on cell viability and mitochondrial membrane potential after OGD or hydrogen peroxide injury in H9c2 cardiac cells, while inhibition of ERK only partially abolished these effects. Moreover, UQCRC1 overexpression dramatically increased the phosphorylation of PI3K downstream signal molecules including Akt and GSK-3β. Finally, UQCRC1 overexpression upregulated the expression of antiapoptotic protein Bcl-2, downregulated the expression of proapoptotic protein Bax, decreased active caspase 3 expression and cell apoptosis, which were completely abolished by inhibition of PI3K. In conclusion, UQCRC1 overexpression protects H9c2 cardiac cells against mimic ischemia/reperfusion injury through mediating PI3K/Akt/GSK-3β pathway to regulate apoptosis-related proteins.


Quality changes of sea bass slices wrapped with gelatin film incorporated with lemongrass essential oil.
Microbiological, chemical and physical changes of sea bass slices wrapped with gelatin film incorporated with 25% (w/w) lemongrass essential oil (LEO) during storage of 12 days at 4 °C were investigated. Sea bass slices wrapped with LEO film had the retarded growth of lactic acid bacteria (LAB), psychrophilic bacteria and spoilage microorganisms including H₂S-producing bacteria and Enterobacteriaceae throughout storage of 12 days in comparison with the control and those wrapped with gelatin film without LEO (G film) (P<0.05). Lowered changes of colour, K value, total volatile base nitrogen (TVB) and TBARS value were also found in LEO film wrapped samples, compared with those wrapped with G film and control, respectively. Therefore, the incorporation of LEO into gelatin film could enhance the antimicrobial and antioxidative properties of the film, thereby maintaining the qualities and extending the shelf-life of the sea bass slices stored at refrigerated temperature.


Employee performance under transformational leadership and organizational citizenship behavior: A mediated model.
Globally, small and medium-sized enterprises (SMEs) compete and work on their sustainability in order to survive and thrive. SMEs rely only on their internal strength, and this strength lies mainly in their employees. Maintaining employees and their engagement increases productivity not only in terms of employee performance but also in terms of organizational performance. Based on social bond theory, the link between leaders and employees empowers the employees; in this context, the present research addresses how SMEs' potential effectiveness is derived from the employees when leadership plays its role efficiently and promotes voluntary work among employees. Using a sample of 405 employees from Pakistani SMEs, this paper assesses the effect on them of organizational citizenship behavior and transformational leadership, in terms of engaging them in voluntary work that ultimately improves performance; this helps SMEs flourish domestically and internationally. The present research also expands the literature by examining the mediating effect of organizational citizenship behavior and provides new directions for researchers to study transformational leadership and organizational citizenship behavior.


Massive gas gangrene secondary to occult colon carcinoma.
Gas gangrene is a rare but often fatal soft-tissue infection. Because it is uncommon and the classic symptom of crepitus does not appear until the infection is advanced, prompt diagnosis requires a high index of suspicion. We present a case report of a middle-aged man who presented with acute onset lower-extremity pain that was initially thought to be due to deep vein thrombosis. After undergoing workup for pulmonary embolism, he was found to have massive gas gangrene of the lower extremity secondary to an occult colon adenocarcinoma and died within hours of presentation from multisystem organ failure.


Characterising the material properties at the interface between skin and a skin vaccination microprojection device.
The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure. First, we used custom fabricated nanoindentation micro-probes to puncture skin at the micrometre scale, and show that puncture forces are ∼0.25-1.75mN for fresh mouse skin, in agreement with finite element simulations for our device. Then, we used two methods to perform strength tests of Nanopatch projections with varied aspect ratios. The first method used a nanoindenter to apply a force directly on the top or on the side of individual silicon projections (110μm in length, 10μm base radius), to measure the force of fracture. Our second method used an Instron to fracture full rows of projections and characterise a range of projection designs (with the method verified against previous nanoindentation experiments). Finally, we used Cryo-Scanning Electron Microscopy to visualise projections in situ in the skin to confirm the behaviour we quantified, qualitatively. Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro-scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi-implantable devices, which will require clear understanding of tissue behaviour and material characterisation.


Potential arthropod vectors of African swine fever virus in North America and the Caribbean basin.
In an effort to identify arthropods that might serve as vectors and perhaps reservoirs of African swine fever virus (ASFV) if it were to enter the U.S.A., the blood-sucking insect Triatoma gerstaeckeri and four species of ticks of the genus Ornithodoros were established in colonies capable of reproducing in numbers sufficient to enable thorough studies to be made of their ASFV vector potentials. A nymphal stage of T. gerstaeckeri carried the virus for 41 days and retained it through one molt, but was unable to transmit it to susceptible pigs. Studies on O. coriaceus revealed that the species is able to harbor and transmit the virus for greater than 440 days, passing it trans-stadially from the first nymphal stage to the adult, sustaining it through at least four molts. Trans-ovarial passage was not demonstrated and nearly 40% of the ticks died, apparently, of the ASFV infection. O. turicata collected in Florida was also found to be capable of becoming infected with ASFV and transmitting it by bite to susceptible pigs. O. puertoricensis collected during the ASF eradication programs in the Dominican Republic and Haiti was not only readily infected experimentally, but it was also able to transmit the virus trans-stadially and trans-ovarially. However, ASFV was not isolated from any of the 350 O. puertoricensis collected in the Dominican Republic and Haiti. O. parkeri from a long-established laboratory colony were able to carry the virus through at least one molt, but they were unable to transmit it to susceptible pigs.


Spondyloarthropathies: progress and challenges.
The spondyloarthropathies are a group of human rheumatic disorders that are often associated with extra-articular features. Although a substantial number of studies is undertaken each year, many issues concerning the pathogenesis remain unanswered. There are several unresolved questions with regard to pathogenesis and treatment in spondyloarthropathies. First, the precise sites where inflammation originates within the joints have been a matter of controversy as enthesitis, synovitis and even bone marrow inflammation can occur during the course of spondyloarthropathies. In addition, the genetic predisposition involved in the origin of the close linkage between gut and joint inflammation, a prominent feature of SpA, has gathered much attention lately. Finally, whereas the effect of tumour necrosis factor (TNF) blockers in modulating inflammatory symptoms in SpA is well established, their ability to prevent new bone formation is much less certain. In addition, some marked differences appear to exist in the ability of the different TNF-blocking agents to modulate extra-articular disease manifestations.


CERA: third-generation erythropoiesis-stimulating agent.
For 20 years, anemia has been treated with erythropoietin-stimulating agents (ESA). Until recently there have been only two ESA: recombinant erythropoietin and darbepoetin. In 2007 a third agent was approved for clinical use, CERA. This review covers all of the peer-reviewed literature regarding ESA. The review also covers unique aspects of the regulatory publications with the FDA and European Agency for the Evaluation of Medicinal Products. CERA is effective at correcting renal anemia. Compared to previous ESA, CERA has a dramatically lengthened half-life, making it the only ESA licensed for once-a-month dosing. However, like the previous ESA, CERA has not been shown to reduce morbidity or mortality and has only been shown to correct anemia and improve quality of life.


[Optimal intravascular brachytherapy: safety and radiation protection, reliability and precision guaranteed by guidelines, recommendations and regulatory requirements].
The success of intravascular brachytherapy relies entirely on the interdisciplinary approach. Interventional cardiologists, radiation oncologists and medical physicists must form a team from day 1. All members of the team need special knowledge and regular training in the field of vascular radiation therapy. Optimization of intravascular brachytherapy requires the use of standardized methods of dose specification, recording and reporting. This also implies using standardized methods of source calibration in terms of absorbed dose to water and having methods for simple internal control of the dosimetric quantities of new or replaced sources. Guidance is offered by international recommendations (AAPM TG 60, DGMP Report 16, NCS and EVA GEC-ESTRO). LEGAL REQUIREMENTS FOR RADIATION PROTECTION--WHAT'S NEW?: In Europe, new legal requirements on radiation protection issues have to be fulfilled. For Germany, the revised "Strahlenschutzverordnung" has been released recently. Nearly all organizational and medical processes are affected. For intravascular brachytherapy, several changes of requirements have to be considered. However, to follow these requirements does not cause serious problems. DGMP REPORT 16: GUIDELINES FOR MEDICAL PHYSICAL ASPECTS OF INTRAVASCULAR BRACHYTHERAPY: Evaluation of clinical results by comparison of intravascular brachytherapy treatment parameters is possible only if the prescribed dose and the applied dose distribution are reported clearly, completely and uniformly. The DGMP guidelines thus recommend to prescribe the dose to water at the system related reference point PRef at 2 mm radial distance for intracoronary application (and at 5 mm for peripheral vessels). The mean dose at 1 mm tissue depth (respectively at 2 mm) should be reported in addition. To safely define the planning target volume from the injured length, safety margins of at least 5 mm (10 mm) have to be taken into account on both ends. Safety margins have also to be considered for multisegmental treatment, to omit underdosage. IVUS based localization will support precise planning, avoid a geographic miss and edge effects and will allow for later evaluation. These DGMP recommendations are also included in the EVA GEC ESTRO recommendations and in the draft for an up-date of the AAPM TG 60 report. Medical physical quality management of intravascular brachytherapy is a necessary condition for optimal and safe treatment. Procedures, devices, and sources should fulfill the same degree of precision and safety as common in radiotherapy.


TOPOGRAPHIC CHANGES IN MACULAR GANGLION CELL-INNER PLEXIFORM LAYER THICKNESS AFTER VITRECTOMY WITH INDOCYANINE GREEN-GUIDED INTERNAL LIMITING MEMBRANE PEELING FOR IDIOPATHIC MACULAR HOLE.
To evaluate the topographic changes in macular ganglion cell-inner plexiform layer (GCIPL) thickness after vitrectomy with indocyanine green-guided internal limiting membrane (ILM) peeling in eyes with idiopathic macular hole. This is a retrospective analysis of 58 consecutive eyes with surgically closed macular hole after vitrectomy with indocyanine green-guided ILM peeling. Further, 31 eyes that had undergone vitrectomy without ILM peeling were used as the control group. The macular GCIPL thickness was measured with spectral domain optical coherence tomography before vitrectomy and at 1 month and 6 months after vitrectomy. The preoperative mean GCIPL thickness was 78.79 μm and mean thickness at 1 month and 6 months after surgery significantly reduced progressively to 70.93 μm and 67.64 μm (P < 0.001 and P < 0.001, respectively). The postoperative mean GCIPL thickness was significantly lower than that of the group without ILM peeling at 1 month and 6 months postoperatively (P < 0.001, P < 0.001, respectively). The GCIPL thickness in the temporal area was significantly lower than in the nasal area at 1 month and 6 months postoperatively (P < 0.001, P < 0.001, respectively). A reduction of the macular GCIPL thickness was observed after vitrectomy with indocyanine green-guided ILM peeling for idiopathic macular hole, especially in the temporal area.


Characterization of nuclear localization signals and cytoplasmic retention region in the nuclear receptor CAR.
The constitutive androstane receptor (CAR) is a ligand/activator-dependent transactivation factor that resides in the cytoplasm and forms part of an as yet unidentified protein complex. Upon stimulation, CAR translocates into the nucleus where it modulates the transactivation of target genes. However, CAR exogenously expressed in rat liver RL-34 cells is located in the nucleus even in the absence of activators. By transiently transfecting RL-34 cells with various mutated rat CAR segments, we identified two nuclear localization signals: a basic amino acid-rich sequence (RRARQARRR) between amino acids 100 and 108; and an assembly of noncontiguous residues widely spread over amino acid residues 111 to 320 within the ligand binding domain. A C-terminal leucine-rich segment corresponding to a previously reported murine xenochemical response signal was not found to exhibit nuclear import activity in cultured cells. Using rat primary hepatocytes transfected with various CAR segments, we identified the region required for the cytoplasmic retention of CAR. Based on these results, the intracellular localization of CAR would be determined by the combined effects of nuclear localization signals, the xenochemical response signal, and the cytoplasmic retention region.


Minority Recruitment Trends in Phase III Prostate Cancer Clinical Trials (2003 to 2014): Progress and Critical Areas for Improvement.
American minority groups have been historically underrepresented in phase III prostate cancer clinical trials despite often having higher risk disease. We analyzed enrollment trends of major racial/ethnic groups in the United States in phase III prostate cancer trials between 2003 and 2014 compared to SEER (Surveillance, Epidemiology and End Results) incidence data. Phase III prostate cancer trials primarily enrolling patients from the United States were identified in the ClinicalTrials.gov database. Enrollment trends were analyzed for major racial/ethnic groups. Prostate cancer incidence data from the SEER registry were used to identify enrollment targets. The enrollment difference was determined by calculating the absolute difference between the percent of a racial/ethnic subgroup in the SEER registry population and the percent of that subgroup in the phase III prostate cancer trial population. Among 39 studies identified African American enrollment in therapeutic trials increased across the study period (p <0.001). The enrollment difference for African Americans was -9.0% (95% CI -7.6- -10.5, p <0.001) in 2003 to 2005 and 1.4% (95% CI 0.2-2.6, p = 0.020) in 2012 to 2014. However, African American men were under enrolled in metastatic disease trials (enrollment difference -5.8%, 95% CI -4.8- -6.8, p <0.001). Latino and Asian American men were consistently under enrolled in all trial types. Minority groups in the United States were largely under enrolled in phase III prostate cancer trials between 2003 and 2014. While recruitment efforts may have had an impact, as demonstrated by increased enrollment of African American men, there remains a need to expand recruitment efforts to achieve diversity in trials.