Behavioral Efficacy of a Sexual Health Mobile App for Men Who Have Sex With Men: Randomized Controlled Trial of Mobile Messaging for Men.
Gay, bisexual, and other men who have sex with men (GBMSM) face the highest burden of HIV in the United States, and there is a paucity of efficacious mobile health (mHealth) HIV prevention and care interventions tailored specifically for GBMSM. We tested a mobile app combining prevention messages and access to core prevention services for GBMSM. This study aims to measure the efficacy of the Mobile Messaging for Men (M-cubed) app and related services to increase HIV prevention and care behaviors in diverse US GBMSM. We conducted a randomized open-label study with a waitlist control group among GBMSM in 3 groups (low-risk HIV-negative group, high-risk HIV-negative group, and living-with-HIV [LWH] group) recruited online and in venues in Atlanta, Detroit, and New York City. Participants were randomly assigned to receive access to the app immediately or at 9 months after randomization. The app provided prevention messages in 6 domains of sexual health and offered ordering of at-home HIV and sexually transmitted infection test kits, receiving preexposure prophylaxis (PrEP) evaluations and navigation, and service locators. Serostatus- and risk-specific prevention outcomes were evaluated at baseline, at the end of the intervention period, and at 3, 6, and 9 months after the intervention period. In total, 1226 GBMSM were enrolled and randomized; of these 611 (49.84%) were assigned to the intervention group and 608 (99.51%) were analyzed, while 615 (50.16%) were assigned to the control group and 612 (99.51%) were analyzed. For high-risk GBMSM, allocation to the intervention arm was associated with higher odds of HIV testing during the intervention period (adjusted odds ratio [aOR] 2.02, 95% CI 1.11-3.66) and with higher odds of using PrEP in the 3 months after the intervention period (aOR 2.41, 95% CI 1.00-5.76, P<.05). No changes in HIV prevention or care were associated with allocation to the intervention arm for the low-risk HIV-negative and LWH groups. Access to the M-cubed app was associated with increased HIV testing and PrEP use among high-risk HIV-negative GBMSM in 3 US cities. The app could be made available through funded HIV prevention providers; additional efforts are needed to understand optimal strategies to implement the app outside of the research setting. ClinicalTrials.gov NCT03666247; https://clinicaltrials.gov/ct2/show/NCT03666247. RR2-10.2196/16439.


Checkpoint Blockade in Lung Cancer and Mesothelioma.
In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.


Laser targeted photo-occlusion of rat choroidal neovascularization without collateral damage.
Laser targeted photo-occlusion (LTO) is a novel method being developed to treat choroidal neovascular membranes (CNV) in age-related and other macular degenerations. A photosensitive agent, encapsulated in heat-sensitive liposomes, is administered intravenously. A low power laser warms the targeted tissue and releases a bolus of photosensitizer. The photosensitizer is activated after it clears from the normal choriocapillaris but not from the CNV. Forty-five experimental CNV were induced in seven rats. Five weeks after LTO, complete occlusion was observed by laser targeted angiography (LTA) in 76% of treated CNV, and partial occlusion was found in the remaining 24%. The tissues outside the CNV but within the area treated by LTO showed no flow alteration and no dye leakage. All untreated CNV were patent on LTA at 5 weeks. Light microscopy and electron microscopy confirmed the results in treated and control lesions. Moreover, treated areas next to lesions showed normal photoreceptors, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris. These results indicate that LTO may improve current photodynamic therapy by alleviating the need for repeated treatments and by avoiding the long-term risks associated with damage to the RPE and occlusion of normal choriocapillaries.


GRIN planar waveguide concentrator used with a single axis tracker.
It is generally accepted that small to medium level concentrators could be used as cost-competitive replacements for tracked solar panels. The objective is to design a system that can reach a good level of sun concentration with only one sun-tracking axis and is cheap to fabricate. As the most critical parameter for all concentrator designs, optical efficiency needed improvement to reduce the cost of power produced by our system. By using a graded-index planar waveguide with an index profile similar to SELFOC fiber, the ray's path can be controlled. Also, the concentrator can be fabricated in a single block, which reduces Fresnel reflections. Overall, the optical efficiency can be improved by as much as 33% compared to the same system made with a homogeneous waveguide. Furthermore, the ability to cost-effectively fabricate the concentrator by molding can be preserved, making it possible to reduce the cost of the solar power produced.


Bottom-up processing of curvilinear visual features is sufficient for animate/inanimate object categorization.
Animate and inanimate objects differ in their intermediate visual features. For instance, animate objects tend to be more curvilinear compared to inanimate objects (e.g., Levin, Takarae, Miner, & Keil, 2001). Recently, it has been demonstrated that these differences in the intermediate visual features of animate and inanimate objects are sufficient for categorization: Human participants viewing synthesized images of animate and inanimate objects that differ largely in the amount of these visual features classify objects as animate/inanimate significantly above chance (Long, Stormer, & Alvarez, 2017). A remaining question, however, is whether the observed categorization is a consequence of top-down cognitive strategies (e.g., rectangular shapes are less likely to be animals) or a consequence of bottom-up processing of their intermediate visual features, per se, in the absence of top-down cognitive strategies. To address this issue, we repeated the classification experiment of Long et al. (2017) but, unlike Long et al. (2017), matched the synthesized images, on average, in the amount of image-based and perceived curvilinear and rectilinear information. Additionally, in our synthesized images, global shape information was not preserved, and the images appeared as texture patterns. These changes prevented participants from using top-down cognitive strategies to perform the task. During the experiment, participants were presented with these synthesized, texture-like animate and inanimate images and, on each trial, were required to classify them as either animate or inanimate with no feedback given. Participants were told that these synthesized images depicted abstract art patterns. We found that participants still classified the synthesized stimuli significantly above chance even though they were unaware of their classification performance. For both object categories, participants depended more on the curvilinear and less on the rectilinear, image-based information present in the stimuli for classification. Surprisingly, the stimuli most consistently classified as animate were the most dangerous animals in our sample of images. We conclude that bottom-up processing of intermediate features present in the visual input is sufficient for animate/inanimate object categorization and that these features may convey information associated with the affective content of the visual stimuli.


Immunohistochemical detection of mutations in the epidermal growth factor receptor gene in lung adenocarcinomas using mutation-specific antibodies.
The recent development of antibodies specific for the major hotspot mutations in the epidermal growth factor receptor (EGFR), L858R and E746_A750del, may provide an opportunity to use immunohistochemistry (IHC) as a screening test for EGFR gene mutations. This study was designed to optimize the IHC protocol and the criteria for interpretation of the results using DNA sequencing as the gold-standard. Tumor sections from fifty lung adenocarcinoma specimens from Chinese patients were immunostained using L858R and E746_A750del-specific antibodies using three different antigen retrieval solutions, and the results were evaluated using three different sets of criteria. The same specimens were used for DNA purification and analysis of EGFR gene mutations. In this study the optimal buffer for antigen retrieval was EDTA (pH 8.0), and the optimal scoring method was to call positive results when there was moderate to strong staining of membrane and/or cytoplasm in >10% of the tumor cells. Using the optimized protocol, L858R-specific IHC showed a sensitivity of 81% and a specificity of 97%, and E746_A750del-specific IHC showed a sensitivity of 59% and a specificity of 100%, both compared with direct DNA analysis. Additionally, the mutant proteins as assessed by IHC showed a more homogeneous than heterogeneous pattern of expression. Our data demonstrate that mutation-specific IHC, using optimized procedures, is a reliable prescreening test for detecting EGFR mutations in lung adenocarcinoma. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2059012601872392.


Locally Advanced Cervical Cancer in Pregnancy: Overcoming the Challenge. A Case Series and Review of the Literature.
Cervical cancer is the most common gynecological cancer occurring in pregnancy, creating a complex situation both for patient and physician. Neoadjuvant chemotherapy is an innovative way of managing cervical cancer in pregnancy. In our paper, we report a retrospective case series of 4 women treated with chemotherapy for invasive cervical cancer during pregnancy in our center over the last 5 years, and we summarize the available literature and guidelines. All the cases were locally advanced cervical cancers that received chemotherapy with platinum and/or taxanes. All patients showed a good response to chemotherapy and a radical surgery was performed with no additional morbidities at the cesarean delivery time in 3 of 4 cases. Three of 4 patients are alive and have a good outcome with no recurrence of disease up to date. One patient died because of recurrent disease 2 years after the first-line treatment during pregnancy. All babies are alive and well up to date (maximum follow-up, 63 months). Even if there are no standardized practices in the treatment of cervical cancer in pregnancy, in our opinion, neoadjuvant chemotherapy can be a very useful strategy for patients and physicians facing the challenge.


Cancer-associated fibroblasts support vascular growth through mechanical force.
The role of cancer-associated fibroblasts (CAFs) as regulators of tumor progression, specifically vascular growth, has only recently been described. CAFs are thought to be more mechanically active but how this trait may alter the tumor microenvironment is poorly understood. We hypothesized that enhanced mechanical activity of CAFs, as regulated by the Rho/ROCK pathway, contributes to increased blood vessel growth. Using a 3D in vitro tissue model of vasculogenesis, we observed increased vascularization in the presence of breast cancer CAFs compared to normal breast fibroblasts. Further studies indicated this phenomenon was not simply a result of enhanced soluble signaling factors, including vascular endothelial growth factor (VEGF), and that CAFs generated significantly larger deformations in 3D gels compared to normal fibroblasts. Inhibition of the mechanotransductive pathways abrogated the ability of CAFs to deform the matrix and suppressed vascularization. Finally, utilizing magnetic microbeads to mechanically stimulate mechanically-inhibited CAFs showed partial rescue of vascularization. Our studies demonstrate enhanced mechanical activity of CAFs may play a crucial and previously unappreciated role in the formation of tumor-associated vasculature which could possibly offer potential novel targets in future anti-cancer therapies.


GWAS for plant growth stages and yield components in spring wheat (Triticum aestivum L.) harvested in three regions of Kazakhstan.
Spring wheat is the largest agricultural crop grown in Kazakhstan with an annual sowing area of 12 million hectares in 2016. Annually, the country harvests around 15 million tons of high quality grain. Despite environmental stress factors it is predicted that the use of new technologies may lead to increases in productivity from current levels of 1.5 to up to 3 tons per hectare. One way of improving wheat productivity is by the application of new genomic oriented approaches in plant breeding projects. Genome wide association studies (GWAS) are emerging as powerful tools for the understanding of the inheritance of complex traits via utilization of high throughput genotyping technologies and phenotypic assessments of plant collections. In this study, phenotyping and genotyping data on 194 spring wheat accessions from Kazakhstan, Russia, Europe, and CIMMYT were assessed for the identification of marker-trait associations (MTA) of agronomic traits by using GWAS. Field trials in Northern, Central and Southern regions of Kazakhstan using 194 spring wheat accessions revealed strong correlations of yield with booting date, plant height, biomass, number of spikes per plant, and number of kernels per spike. The accessions from Europe and CIMMYT showed high breeding potential for Southern and Central regions of the country in comparison with the performance of the local varieties. The GGE biplot method, using average yield per plant, suggested a clear separation of accessions into their three breeding origins in relationship to the three environments in which they were evaluated. The genetic variation in the three groups of accessions was further studied using 3245 polymorphic SNP (single nucleotide polymorphism) markers. The application of Principal Coordinate analysis clearly grouped the 194 accessions into three clades according to their breeding origins. GWAS on data from nine field trials allowed the identification of 114 MTAs for 12 different agronomic traits. Field evaluation of foreign germplasm revealed its poor yield performance in Northern Kazakhstan, which is the main wheat growing region in the country. However, it was found that EU and CIMMYT germplasm has high breeding potential to improve yield performance in Central and Southern regions. The use of Principal Coordinate analysis clearly separated the panel into three distinct groups according to their breeding origin. GWAS based on use of the TASSEL 5.0 package allowed the identification of 114 MTAs for twelve agronomic traits. The study identifies a network of key genes for improvement of yield productivity in wheat growing regions of Kazakhstan.


Searching for globally optimal functional forms for interatomic potentials using genetic programming with parallel tempering.
Molecular dynamics and other molecular simulation methods rely on a potential energy function, based only on the relative coordinates of the atomic nuclei. Such a function, called a force field, approximately represents the electronic structure interactions of a condensed matter system. Developing such approximate functions and fitting their parameters remains an arduous, time-consuming process, relying on expert physical intuition. To address this problem, a functional programming methodology was developed that may enable automated discovery of entirely new force-field functional forms, while simultaneously fitting parameter values. The method uses a combination of genetic programming, Metropolis Monte Carlo importance sampling and parallel tempering, to efficiently search a large space of candidate functional forms and parameters. The methodology was tested using a nontrivial problem with a well-defined globally optimal solution: a small set of atomic configurations was generated and the energy of each configuration was calculated using the Lennard-Jones pair potential. Starting with a population of random functions, our fully automated, massively parallel implementation of the method reproducibly discovered the original Lennard-Jones pair potential by searching for several hours on 100 processors, sampling only a minuscule portion of the total search space. This result indicates that, with further improvement, the method may be suitable for unsupervised development of more accurate force fields with completely new functional forms.


Korean Asthma Guideline 2014: Summary of Major Updates to the Korean Asthma Guideline 2014.
Asthma is a prevalent and serious health problem in Korea. Recently, the Korean Asthma Guideline has been updated by The Korean Academy of Tuberculosis and Respiratory Diseases (KATRD) in an effort to improve the clinical management of asthma. This guideline focuses on adult patients with asthma and aims to deliver up to date scientific evidence and recommendations to general physicians for the management of asthma. For this purpose, this guideline was updated following systematic review and meta-analysis of recent studies and adapting some points of international guidelines (Global Initiative for Asthma [GINA] report 2014, National Asthma Education and Prevention Program [NAEPP] 2007, British Thoracic Society [BTS/SIGN] asthma guideline 2012, and Canadian asthma guideline 2012). Updated issues include recommendations derived using the population, intervention, comparison, and outcomes (PICO) model, which produced 20 clinical questions on the management of asthma. It also covers a new definition of asthma, the importance of confirming various airflow limitations with spirometry, the epidemiology and the diagnostic flow of asthma in Korea, the importance and evidence for inhaled corticosteroids (ICS) and ICS/formoterol as a single maintenance and acute therapy in the stepwise management of asthma, assessment of severity of asthma and management of exacerbation, and an action plan to cope with exacerbation. This guideline includes clinical assessments, and treatment of asthma-chronic obstructive pulmonary disease overlap syndrome, management of asthma in specific conditions including severe asthma, elderly asthma, cough variant asthma, exercise-induced bronchial contraction, etc. The revised Korean Asthma Guideline is expected to be a useful resource in the management of asthma.


Self-administration of cannabinoids by experimental animals and human marijuana smokers.
Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-naïve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.


Megavoltage cone beam computed tomography: Commissioning and evaluation of patient dose.
The improvement in conformal radiotherapy techniques enables us to achieve steep dose gradients around the target which allows the delivery of higher doses to a tumor volume while maintaining the sparing of surrounding normal tissue. One of the reasons for this improvement was the implementation of intensity-modulated radio therapy (IMRT) by using linear accelerators fitted with multi-leaf collimator (MLC), Tomo therapy and Rapid arc. In this situation, verification of patient set-up and evaluation of internal organ motion just prior to radiation delivery become important. To this end, several volumetric image-guided techniques have been developed for patient localization, such as Siemens OPTIVUE/MVCB and MVision megavoltage cone beam CT (MV-CBCT) system. Quality assurance for MV-CBCT is important to insure that the performance of the Electronic portal image device (EPID) and MV-CBCT is suitable for the required treatment accuracy. In this work, the commissioning and clinical implementation of the OPTIVUE/MVCB system was presented. The geometry and gain calibration procedures for the system were described. The image quality characteristics of the OPTIVUE/MVCB system were measured and assessed qualitatively and quantitatively, including the image noise and uniformity, low-contrast resolution, and spatial resolution. The image reconstruction and registration software were evaluated. Dose at isocenter from CBCT and the EPID were evaluated using ionization chamber and thermo-luminescent dosimeters; then compared with that calculated by the treatment planning system (TPS- XiO 4.4). The results showed that there are no offsets greater than 1 mm in the flat panel alignment in the lateral and longitudinal direction over 18 months of the study. The image quality tests showed that the image noise and uniformity were within the acceptable range, and that a 2 cm large object with 1% electron density contrast can be detected with the OPTIVUE/MVCB system with 5 monitor units (MU) protocol. The registration software was accurate within 2 mm in the anterior-posterior, left-right, and superior-inferior directions. The additional dose to the patient from MV-CBCT study set with 5 MU at the isocenter of the treatment plan was 5 cGy. For Electronic portal image device (EPID) verification using two orthogonal images with 2 MU per image the additional dose to the patient was 3.8 cGy. These measured dose values were matched with that calculated by the TPS-XiO, where the calculated doses were 5.2 cGy and 3.9 cGy for MVCT and EPID respectively.


Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine-depleted mice.
Early non-motor symptoms such as mood disorders and cognitive deficits are increasingly recognised in Parkinson's disease (PD). They may precede the characteristic motor symptomatology caused by dopamine (DA) neuronal loss in the substantia nigra pars compacta (SNc). It is well known that striatal cholinergic interneurons (ChIs) are emerging as key regulators of PD motor symptom, however, their involvement in the cognitive and affective alterations occurring in the premotor phase of PD is poorly understood. We used optogenetic photoinhibition of striatal ChIs in mice with mild nigrostriatal 6-hydroxydopamine (6-OHDA) lesions and assessed their role in anxiety-like behaviour in the elevated plus maze, social memory recognition of a congener and visuospatial object recognition. In transgenic mice specifically expressing halorhodopsin (eNpHR) in cholinergic neurons, striatal ChIs photoinhibition reduced the anxiety-like behaviour and reversed social and spatial short-term memory impairment induced by moderate DA depletion (e.g., 50% loss of tyrosine hydroxylase TH-positive neurons in the SNc). Systemic injection of telenzepine (0.3 mg/kg), a preferential M1 muscarinic cholinergic receptors antagonist, improved anxiety-like behaviour, social memory recognition but not spatial memory deficits. Our results suggest that dysfunction of the striatal cholinergic system may play a role in the short-term cognitive and emotional deficits of partially DA-depleted mice. Blocking cholinergic activity with M1 muscarinic receptor antagonists may represent a possible therapeutic target, although not exclusive, to modulate these early non-motor deficits.


Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice.
Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-α signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.


Distributed birefringence measurement with beat period detection of homodyne Brillouin optical time-domain reflectometry.
We report a distributed optical fiber birefringence measurement method based on homodyne Brillouin optical time-domain reflectometry (BOTDR). Unlike conventional BOTDR, which requires scanning of the local oscillator to get the Brillouin spectrum, instead we propose the beat period measurement of fast and slow components of the backscattered Brillouin signal in single-mode fibers using homodyne detection. The beat period is measured by detecting the envelope of the Brillouin beat signal, which gives the beat length at different fiber locations, so that birefringence can be calculated accordingly. The distributed birefringence of a 1.7 km SMF-28 and a 4.3 km large-effective-area fiber were measured with 0.6 m spatial resolution without frequency scanning of the Brillouin spectrum.


Return of collective rotation in 157Er and 158Er at ultrahigh spin.
A new frontier of discrete-line gamma-ray spectroscopy at ultrahigh spin has been opened in the rare-earth nuclei (157,158) Er. Four rotational structures, displaying high moments of inertia, have been identified, which extend up to spin approximately 65 variant Planck's over 2pi and bypass the band-terminating states in these nuclei which occur at approximately 45 variant Planck's over 2pi. Cranked Nilsson-Strutinsky calculations suggest that these structures arise from well-deformed triaxial configurations that lie in a valley of favored shell energy which also includes the triaxial strongly deformed bands in (161-167) Lu.


Tumor Sphericity Predicts Response in Neoadjuvant Chemotherapy for Invasive Breast Cancer.
This retrospective study examined magnetic resonance imaging (MRI)-derived tumor sphericity (SPH) as a quantitative measure of breast tumor morphology, and investigated the association between SPH and reader-assessed morphological pattern (MP). In addition, association of SPH with pathologic complete response was evaluated in patients enrolled in an adaptively randomized clinical trial designed to rapidly identify new agents for breast cancer. All patients underwent MRI examinations at multiple time points during the treatment. SPH values from pretreatment (T0) and early-treatment (T1) were investigated in this study. MP on T0 dynamic contrast-enhanced MRI was ranked from 1 to 5 in 220 patients. Mean SPH values decreased with the increased order of MP. SPH was higher in patients with pathologic complete response than in patients without (difference at T0: 0.04, 95% confidence interval [CI]: 0.02-0.05, P < .001; difference at T1: 0.03, 95% CI: 0.02-0.04, P < .001). The area under the receiver operating characteristic curve was estimated as 0.61 (95% CI, 0.57-0.65) at T0 and 0.58 (95% CI, 0.55-0.62) at T1. When the analysis was performed by cancer subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, highest area under the receiver operating characteristic curve were observed in HR-/HER2+: 0.67 (95% CI, 0.54-0.80) at T0, and 0.63 (95% CI, 0.51-0.76) at T1. Tumor SPH showed promise to quantify MRI MPs and as a biomarker for predicting treatment outcome at pre- or early-treatment time points.


Does Chronic Kidney Disease Facilitate Malignant Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction of Hypertensive Origin?
In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives (n = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio ≥ 30 mg/g). Specific immunoassays were performed to determine biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination. A comparison with non-HF showed that the biomarker combination presence was increased in HFpEF patients, being associated with CKD in all patients. CKD influenced the association of the biomarker combination and HFpEF (p for interaction ≤ 0.019). The E:e' ratio was associated with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with the biomarker combination exhibited higher (p = 0.016) E:e' ratio than those without the pattern. These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in hypertensive HFpEF patients.


Plasmid construction using recombination activity in the fission yeast Schizosaccharomyces pombe.
Construction of plasmids is crucial in modern genetic manipulation. As of now, the common method for constructing plasmids is to digest specific DNA sequences with restriction enzymes and to ligate the resulting DNA fragments with DNA ligase. Another potent method to construct plasmids, known as gap-repair cloning (GRC), is commonly used in the budding yeast Saccharomyces cerevisiae. GRC makes use of the homologous recombination activity that occurs within the yeast cells. Due to its flexible design and efficiency, GRC has been frequently used for constructing plasmids with complex structures as well as genome-wide plasmid collections. Although there have been reports indicating GRC feasibility in the fission yeast Schizosaccharomyces pombe, this species is not commonly used for GRC as systematic studies of reporting GRC efficiency in S. pombe have not been performed till date. We investigated GRC efficiency in S. pombe in this study. We first showed that GRC was feasible in S. pombe by constructing a plasmid that contained the LEU2 auxotrophic marker gene in vivo and showed sufficient efficiency with short homology sequences (>25 bp). No preference was shown for the sequence length from the cut site in the vector plasmid. We next showed that plasmids could be constructed in a proper way using 3 DNA fragments with 70% efficiency without any specific selections being made. The GRC efficiency with 3 DNA fragments was dramatically increased >95% in lig4Delta mutant cell, where non-homologous end joining is deficient. Following this approach, we successfully constructed plasmid vectors with leu1+, ade6+, his5+, and lys1+ markers with the low-copy stable plasmid pDblet as a backbone by applying GRC in S. pombe. We concluded that GRC was sufficiently feasible in S. pombe for genome-wide gene functional analysis as well as for regular plasmid construction. Plasmids with different markers constructed in this research are available from NBRP-yeast (http://yeast.lab.nig.ac.jp/).


Medication Overdoses at a Public Emergency Department in Santiago, Chile.
While a nationwide poison control registry exists in Chile, reporting to the center is sporadic and happens at the discretion of the treating physician or by patients' self-report. Moreover, individual hospitals do not monitor accidental or intentional poisoning in a systematic manner. The goal of this study was to identify all cases of intentional medication overdose (MO) that occurred over two years at a large public hospital in Santiago, Chile, and examine its epidemiologic profile. This study is a retrospective, explicit chart review conducted at Hospital Sótero del Rio from July 2008 until June 2010. We included all cases of identified intentional MO. Alcohol and recreational drugs were included only when they were ingested with other medications. We identified 1,557 cases of intentional MO and analyzed a total of 1,197 cases, corresponding to 0.51% of all emergency department (ED) presentations between July 2008 and June 2010. The median patient age was 25 years. The majority was female (67.6%). Two peaks were identified, corresponding to the spring of each year sampled. The rate of hospital admission was 22.2%. Benzodiazepines, selective serotonin reuptake inhibitors, and tricyclic antidepressants (TCA) were the causative agents most commonly found, comprising 1,044 (87.2%) of all analyzed cases. Acetaminophen was involved in 81 (6.8%) cases. More than one active substance was involved in 35% of cases. In 7.3% there was ethanol co-ingestion and in 1.0% co-ingestion of some other recreational drug (primarily cocaine). Of 1,557 cases, six (0.39%) patients died. TCA were involved in two of these deaths. Similar to other developed and developing nations, intentional MO accounts for a significant number of ED presentations in Chile. Chile is unique in the region, however, in that its spectrum of intentional overdoses includes an excess burden of tricyclic antidepressant and benzodiazepine overdoses, a relatively low rate of alcohol and recreational drug co-ingestion, and a relatively low rate of acetaminophen ingestion.


Cow and herd variation in milk urea nitrogen concentrations in lactating dairy cattle.
Milk urea nitrogen (MUN) is correlated with N balance, N intake, and dietary N content, and thus is a good indicator of proper feeding management with respect to protein. It is commonly used to monitor feeding programs to achieve environmental goals; however, genetic diversity also exists among cows. It was hypothesized that phenotypic diversity among cows could bias feed management decisions when monitoring tools do not consider genetic diversity associated with MUN. The objective of the work was to evaluate the effect of cow and herd variation on MUN. Data from 2 previously published research trials and a field trial were subjected to multivariate regression analyses using a mixed model. Analyses of the research trial data showed that MUN concentrations could be predicted equally well from diet composition, milk yield, and milk components regardless of whether dry matter intake was included in the regression model. This indicated that cow and herd variation could be accurately estimated from field trial data when feed intake was not known. Milk urea N was correlated with dietary protein and neutral detergent fiber content, milk yield, milk protein content, and days in milk for both data sets. Cow was a highly significant determinant of MUN regardless of the data set used, and herd trended to significance for the field trial data. When all other variables were held constant, a percentage unit change in dietary protein concentration resulted in a 1.1mg/dL change in MUN. Least squares means estimates of MUN concentrations across herds ranged from a low of 13.6 mg/dL to a high of 17.3 mg/dL. If the observed MUN for the high herd were caused solely by high crude protein feeding, then the herd would have to reduce dietary protein to a concentration of 12.8% of dry matter to achieve a MUN concentration of 12 mg/dL, likely resulting in lost milk production. If the observed phenotypic variation is due to genetic differences among cows, genetic choices could result in herds that exceed target values for MUN when adhering to best management practices, which is consistent with the trend for differences in MUN among herds.


Independent molecular pathways in initiation and loss of hormone responsiveness of breast carcinomas.
These studies were set up to determine whether those oncogenes participating in the initiation of mammary carcinogenesis (for example, ras oncogenes) play a direct role in the outcome of events associated with the late stages of tumor development such as loss of hormone dependency. Mammary carcinomas induced by a single carcinogenic insult in pubescent rats was selected as an in vivo model system with direct relevance to human breast cancer. Acquisition of hormone-independent growth in these carcinogen-induced tumors was found to be independent of the activation of ras oncogenes during the early stages of carcinogenesis. In agreement with these observations, introduction of a human ras oncogene into human MCF-7 breast carcinoma cells did not abrogate their hormonal dependency for growth in vivo. These findings suggest that those events responsible for the critical stages of breast cancer development occur independently and in an uncoordinated manner.


Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension.
Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population. In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured. Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes. Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.


Global control of cysteine metabolism by CymR in Bacillus subtilis.
YrzC has previously been identified as a repressor controlling ytmI expression via its regulation of YtlI activator synthesis in Bacillus subtilis. We identified YrzC as a master regulator of sulfur metabolism. Gene expression profiles of B. subtilis delta yrzC mutant and wild-type strains grown in minimal medium with sulfate as the sole sulfur source were compared. In the mutant, increased expression was observed for 24 genes previously identified as repressed in the presence of sulfate. Since several genes involved in the pathways leading to cysteine formation were found, we propose to rename YrzC CymR, for "cysteine metabolism repressor." A CymR-dependent binding to the promoter region of the ytlI, ssuB, tcyP, yrrT, yxeK, cysK, or ydbM gene was demonstrated using gel shift experiments. A potential CymR target site, TAAWNCN2ANTWNAN3ATMGGAATTW, was found in the promoter region of these genes. In a DNase footprint experiment, the protected region in the ytlI promoter region contained this consensus sequence. Partial deletion or introduction of point mutations in this sequence confirmed its involvement in ytlI, yrrT, and yxeK regulation. The addition of O-acetylserine in gel shift experiments prevented CymR-dependent binding to DNA for all of the targets characterized. Transcriptome analysis of a delta cymR mutant and the wild-type strain also brought out significant changes in the expression level of a large set of genes related to stress response or to transition toward anaerobiosis.


Rapid activation of Rac GTPase in living cells by force is independent of Src.
It is well known that mechanical forces are crucial in regulating functions of every tissue and organ in a human body. However, it remains unclear how mechanical forces are transduced into biochemical activities and biological responses at the cellular and molecular level. Using the magnetic twisting cytometry technique, we applied local mechanical stresses to living human airway smooth muscle cells with a magnetic bead bound to the cell surface via transmembrane adhesion molecule integrins. The temporal and spatial activation of Rac, a small guanosine triphosphatase, was quantified using a fluorescent resonance energy transfer (FRET) method that measures changes in Rac activity in response to mechanical stresses by quantifying intensity ratios of ECFP (enhanced cyan fluorescent protein as a donor) and YPet (a variant yellow fluorescent protein as an acceptor) of the Rac biosensor. The applied stress induced rapid activation (less than 300 ms) of Rac at the cell periphery. In contrast, platelet derived growth factor (PDGF) induced Rac activation at a much later time (>30 sec). There was no stress-induced Rac activation when a mutant form of the Rac biosensor (RacN17) was transfected or when the magnetic bead was coated with transferrin or with poly-L-lysine. It is known that PDGF-induced Rac activation depends on Src activity. Surprisingly, pre-treatment of the cells with specific Src inhibitor PP1 or knocking-out Src gene had no effects on stress-induced Rac activation. In addition, eliminating lipid rafts through extraction of cholesterol from the plasma membrane did not prevent stress-induced Rac activation, suggesting a raft-independent mechanism in governing the Rac activation upon mechanical stimulation. Further evidence indicates that Rac activation by stress depends on the magnitudes of the applied stress and cytoskeletal integrity. Our results suggest that Rac activation by mechanical forces is rapid, direct and does not depend on Src activation. These findings suggest that signaling pathways of mechanical forces via integrins might be fundamentally different from those of growth factors.


Network-based analysis of metabolic regulation in the human red blood cell.
Reconstruction of cell-scale metabolic networks is now possible. A description of allowable metabolic network functions can be obtained using extreme pathways, which are the convex basis vectors of the solution space containing all steady state flux distributions. However, only a portion of these allowable network functions are physiologically possible due to kinetic and regulatory constraints. Methods are now needed that enable us to take a defined metabolic network and deduce candidate regulatory structures that control the selection of these physiologically relevant states. One such approach is the singular value decomposition (SVD) of extreme pathway matrices (P), which allows for the characterization of steady state solution spaces. Eigenpathways, which are the left singular vectors from the SVD of P, can be described and categorized by their biochemical function. SVD of P for the human red blood cell showed that the first five eigenpathways, out of a total of 23, effectively characterize all the relevant physiological states of red blood cell metabolism calculated with a detailed kinetic model. Thus, with five degrees of freedom the magnitude and nature of the regulatory needs are defined. Additionally, the dominant features of these first five eigenpathways described key metabolic splits that are indeed regulated in the human red blood cell. The extreme pathway matrix is derived directly from network topology and only knowledge of Vmax values is needed to reach these conclusions. Thus, we have implemented a network-based analysis of regulation that complements the study of individual regulatory events. This topological approach may provide candidate regulatory structures for metabolic networks with known stoichiometry but poorly characterized regulation.


One fungus, one name: defining the genus Fusarium in a scientifically robust way that preserves longstanding use.
In this letter, we advocate recognizing the genus Fusarium as the sole name for a group that includes virtually all Fusarium species of importance in plant pathology, mycotoxicology, medicine, and basic research. This phylogenetically guided circumscription will free scientists from any obligation to use other genus names, including teleomorphs, for species nested within this clade, and preserve the application of the name Fusarium in the way it has been used for almost a century. Due to recent changes in the International Code of Nomenclature for algae, fungi, and plants, this is an urgent matter that requires community attention. The alternative is to break the longstanding concept of Fusarium into nine or more genera, and remove important taxa such as those in the F. solani species complex from the genus, a move we believe is unnecessary. Here we present taxonomic and nomenclatural proposals that will preserve established research connections and facilitate communication within and between research communities, and at the same time support strong scientific principles and good taxonomic practice.


High prevalence rate of human papillomavirus infection and association with abnormal papanicolaou smears in sexually active adolescents.
Human papillomaviruses (HPVs) are associated with neoplastic and malignant lesions of the uterine cervix. Cervical neoplasia is associated with onset of sexual activity at an early age. Therefore, this study sought to define the prevalence rates of HPV infection and cytologic abnormalities in adolescents. Sexually active females 13 to 21 years of age undergoing routine cervical cytologic screening were evaluated in the adolescent clinic of an urban hospital. Cells collected by cervicovaginal lavage from 249 subjects were analyzed for HPV DNA by Southern blot hybridization with probes for HPV types 6/11, 16, and 18. The HPV DNA was detected in 95 (38.2%) of 249 patients. Teenagers between the ages of 13 and 18 years with multiple lifetime sexual partners were at higher risk for HPV infection (38/71 [54%]) compared with patients of the same age who had only a single partner (25/74 or [34%]). Twenty (8.3%) of 241 patients had abnormal Papanicolaou smears with atypia, koilocytosis, or low-grade cervical intraepithelial neoplasia. Cytologic abnormalities were detected in 16 (17%) of 94 adolescents with HPV present, but in only 4 (2.7%) of 147 of the uninfected patients. Thus, HPV emerged as a common pathogen in female adolescents, and infected patients are at increased risk for cervical epithelial abnormalities.


The association between workplace bullying and depressive symptoms: the role of the perpetrator.
The aim of the present study was to investigate whether the depressive symptoms of the bullied respondents differed according to who the perpetrator was. We used cross-sectional questionnaire data from two representative cohorts: the Danish Working Environment Cohort Study (DWECS 2010) and the Work and Health Study (WH 2012). After excluding respondents not having a leader, or being self-employed, assisting spouses, and those reporting multiple perpetrators in WH 2012, the statistical analysis included 2478 bullied individuals. We compared respondents reporting being bullied by their (1) leader, (2) subordinates, (3) clients / customers / patients / students, or (4) colleagues, respectively. The occurrence of depressive symptoms was measured by the Major Depression Inventory (MDI). The most frequent perpetrator of bullying was clients (41.5 %) in DWECS 2010 and colleagues (60.3 %) in WH 2012. In DWECS 2010, the MDI score of those being bullied by clients were significantly lower than the MDI scores of the other groups. In WH 2012, respondents who reported bullying from leaders had a significantly higher mean MDI score than participants being bullied by colleagues. Also in WH 2012, our results indicated that those who were bullied by leaders had a higher MDI score than those bullied by clients, although this difference was not statistically significant at conventional levels. Our findings indicated a similar pattern in the two cohorts, with a tendency of more severe depressive symptoms among employees who are exposed to bullying by their leaders, and the least severe symptoms among those who are bullied by clients.


Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and Wales.
To estimate long-term trends in cannabis use and projections of schizophrenia assuming a causal relation between cannabis use and schizophrenia. Trends in cannabis use were estimated from a national survey, 2003; and incidence of schizophrenia was derived from surveys in three English cities, 1997-99. A difference equation cohort model was fitted against estimates of schizophrenia incidence, trends in cannabis exposure and assumptions on association between cannabis and schizophrenia. The model projects trends in schizophrenia incidence, prevalence and attributable fraction of cannabis induced schizophrenia. Between 1970 and 2002 cannabis exposure increased: incidence by fourfold; period prevalence by 10-fold; and use among under 18-year-olds by 18-fold. In 1997-99 incidence and prevalence of schizophrenia were 17 per 100 000 and 0.63% among men and 7.3 per 100 000 and 0.23% among women, respectively. If cannabis use causes schizophrenia, earlier increases in cannabis use would lead to increases in overall schizophrenia incidence and prevalence of 29% and 12% among men between 1990 and 2010. By 2010 model projections which assume an association between schizophrenia and light and heavy users suggest that approximately one-quarter of new schizophrenia cases could be due to cannabis, whereas if the association is twofold and confined to heavy cannabis users, then approximately 10% of schizophrenia cases may be due to cannabis. If cannabis use causes schizophrenia, and assuming other causes are unchanged, then relatively substantial increases in both prevalence and incidence of schizophrenia should be apparent by 2010. More accurate data on cannabis consumption and future monitoring of schizophrenia are critical.


Final destination of an ingested needle: the liver.
Foreign body ingestion is a common problem in children, but it is also seen among adults. Most foreign bodies pass through the gastrointestinal tract without causing complications. Perforation of the gut by a foreign body, followed by migration of the foreign body to the liver is quite rare. Herein we report a case of inadvertent ingestion of a sewing needle that perforated the duodenum and migrated to the liver. The patient was monitored weekly with abdominal radiographs, but displacement of the needle could not be observed. At follow-up, right upper quadrant pain was noted. Two weeks later, computed tomography revealed that the needle was completely buried into the right lobe of the liver. Ultrasonographic examination successfully showed the extracapsular displacement of the needle. Eventually, laparoscopic removal of the needle was easily performed.


Kapitza resistance at water-graphene interfaces.
Heat transfer across fluid-solid interfaces in nanoconfinement has received significant attention due to its relevance in nanoscale systems. In this study, we investigate the Kapitza resistance at the water-graphene interface with the help of classical molecular dynamics simulation techniques in conjunction with our recently proposed equilibrium molecular dynamics (EMD) method [S. Alosious et al., J. Chem. Phys. 151, 194502 (2019)]. The size effect of the Kapitza resistance on different factors such as the number of graphene layers, the cross-sectional area, and the width of the water block was studied. The Kapitza resistance decreases slightly with an increase in the number of layers, while the influence of the cross-sectional area and the width of the water block is negligible. The variation in the Kapitza resistance as a function of the number of graphene layers is attributed to the large phonon mean free path along the graphene cross-plane. An optimum water-graphene system, which is independent of size effects, was selected, and the same was used to determine the Kapitza resistance using the predicted EMD method. The values obtained from both the EMD and the non-equilibrium molecular dynamics (NEMD) methods were compared for different potentials and water models, and the results are shown to be in good agreement. Our method allows us to compute the Kapitza resistance using EMD simulations, which obviates the need to create a large temperature gradient required for the NEMD method.


Tracheostomy and percutaneous endoscopic gastrostomy in the management of the head-injured trauma patient.
Forty-three trauma patients underwent tracheostomy (TRACH) and percutaneous endoscopic gastrostomy (PEG) over 21 months. Thirty-one patients had a head injury with Abbreviated Injury Scale > or = 3 associated with multi-trauma. This study was undertaken to analyze demographic and outcome variables with respect to timing of TRACH/PEG in this population. Patients were divided into EARLY (< or = 7 days) and LATE (> 7 days) groups and were analyzed for admission Glasgow Coma Scale, Apache II, Injury Severity Score, and [(A-a)DO2] at time of TRACH/PEG. Outcome variables were ICU length of stay (LOS), hospital LOS, days of mechanical ventilation (MV) post-TRACH/PEG, complications, and mortality. Esophagogastroduodenoscopy findings with PEG and days to full enteral nutrition were recorded. All demographic variables were statistically similar between the EARLY and LATE groups. The EARLY group had shorter hospital LOS (P < 0.05), total Intensive Care Unit LOS (P < 0.05), ICU LOS post-TRACH/PEG (P < 0.05), and fewer days of MV post-TRACH/PEG (P < 0.05). There were no procedure-related complications of TRACH/PEG in either group. Full Esophagogastroduodenoscopy performed at the time of PEG had a high diagnostic yield in both groups. We conclude that TRACH/PEG performed within the first 7 days of injury in the head trauma patient is the procedure of choice for long-term airway protection, mechanical ventilation, and enteral nutrition. Combined use of these procedures reduces ICU and hospital LOS and shortens the course of MV.


Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin.
Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded trinucleotide (CAG) repeat in exon 1 of the huntingtin gene (Htt). This expansion creates a toxic polyglutamine tract in the huntingtin protein (HTT). Currently, there is no treatment for either the progression or prevention of the disease. RNA interference (RNAi) technology has shown promise in transgenic mouse models of HD by reducing expression of mutant HTT and slowing disease progression. The advancement of RNAi therapies to human clinical trials is hampered by problems delivering RNAi to affected neurons in a robust and sustainable manner. Mesenchymal stem cells (MSC) have demonstrated a strong safety profile in both completed and numerous ongoing clinical trials. MSC exhibit a number of innate therapeutic effects, such as immune system modulation, homing to injury, and cytokine release into damaged microenvironments. The ability of MSC to transfer larger molecules and even organelles suggested their potential usefulness as delivery vehicles for therapeutic RNA inhibition. In a series of model systems we have found evidence that MSC can transfer RNAi targeting both reporter genes and mutant huntingtin in neural cell lines. MSC expressing shRNA antisense to GFP were found to decrease expression of GFP in SH-SY5Y cells after co-culture when assayed by flow cytometry. Additionally MSC expressing shRNA antisense to HTT were able to decrease levels of mutant HTT expressed in both U87 and SH-SY5Y target cells when assayed by Western blot and densitometry. These results are encouraging for expanding the therapeutic abilities of both RNAi and MSC for future treatments of Huntington's disease.


IgE to recombinant allergens Api m 1, Ves v 1, and Ves v 5 distinguish double sensitization from crossreaction in venom allergy.
Diagnostic tests in patients with Hymenoptera venom allergy are frequently positive to venoms of both honey bee and wasp (Vespula). Component-resolved analysis with recombinant species-specific major allergens (rSSMA) may help to distinguish true double sensitization from crossreactivity. Included were 121 patients with systemic allergic reactions to Hymenoptera stings, 76 with double positivity of serum-specific IgE (sIgE) to both venoms, 45 with single positivity to bee or wasp venom, and 32 controls without history of systemic reactions to Hymenoptera stings and no sIgE to whole venoms. In venom-allergic patients and controls, sIgE to rSSMA Api m 1 of bee venom and to Ves v 1 and Ves v 5 of wasp venom were tested by ImmunoCAP. Only 47% of 76 patients with double positivity to whole venoms reacted also to rSSMA of both species. Specificity of sIgE to the 3 rSSMA was very high, with no sIgE to rSSMA of the other species in single-positive venom-allergic patients and only one control with low sIgE to Ves v 1. All wasp-allergic single-positive patients had sIgE to Ves v 5 and/or Ves v 1, and 78.3% of single-positive bee venom-allergic patients had sIgE to Api m 1. Specificity of sIgE to rSSMA of both species is excellent. Sensitivity of sIgE to rSSMA was optimal for wasp venom. Sensitivity of bee venom Api m 1 could be increased by adding rSSMA of other important bee venom allergens.


Review article: hepatitis C virus infection and type-2 diabetes mellitus in renal diseases and transplantation.
A link between hepatitis C virus infection and development of diabetes mellitus has been suggested by many investigators; however, this remains controversial. The mechanisms underlying the association between hepatitis C virus and diabetes mellitus are unclear but a great majority of clinical surveys have found a significant and independent relationship between hepatitis C virus and diabetes mellitus after renal transplantation and orthotopic liver transplantation. We have systematically reviewed the scientific literature to explore the association between hepatitis C virus and diabetes mellitus in end-stage renal disease; in addition, data on patients undergoing orthotopic liver transplantation were also analysed. The unadjusted odds ratio for developing post-transplant diabetes mellitus in hepatitis C virus-infected renal transplant recipients ranged between 1.58 and 16.5 across the published studies. The rate of anti-hepatitis C virus antibody in serum was higher among dialysis patients having diabetes mellitus (odds ratio 9.9; 95% confidence interval 2.663-32.924). Patients with type-2 diabetes-related glomerulonephritis had the highest anti-hepatitis C virus prevalence [19.5% (24/123) vs. 3.2% (73/2247); P < 0.001] in a large cohort of Japanese patients who underwent renal biopsy. The link between hepatitis C virus and diabetes mellitus may explain, in part, the detrimental role of hepatitis C virus on patient and graft survival after orthotopic liver transplantation and/or renal transplantation. Preliminary evidence suggests that anti-viral therapies prior to renal transplantation and novel immunosuppressive regimens may lower the occurrence of diabetes mellitus in hepatitis C virus-infected patients after renal transplantation. Clinical trials are under way to assess if the hepatitis C virus-linked predisposition to new onset diabetes mellitus after renal transplantation may be reduced by newer immunosuppressive medications.


Selection and phylogenetics of salmonid MHC class I: wild brown trout (Salmo trutta) differ from a non-native introduced strain.
We tested how variation at a gene of adaptive importance, MHC class I (UBA), in a wild, endemic Salmo trutta population compared to that in both a previously studied non-native S. trutta population and a co-habiting Salmo salar population (a sister species). High allelic diversity is observed and allelic divergence is much higher than that noted previously for co-habiting S. salar. Recombination was found to be important to population-level divergence. The α1 and α2 domains of UBA demonstrate ancient lineages but novel lineages are also identified at both domains in this work. We also find examples of recombination between UBA and the non-classical locus, ULA. Evidence for strong diversifying selection was found at a discrete suite of S. trutta UBA amino acid sites. The pattern was found to contrast with that found in re-analysed UBA data from an artificially stocked S. trutta population.


The effect of methylphenidate on very low frequency electroencephalography oscillations in adult ADHD.
Altered very low-frequency electroencephalographic (VLF-EEG) activity is an endophenotype of ADHD in children and adolescents. We investigated VLF-EEG case-control differences in adult samples and the effects of methylphenidate (MPH). A longitudinal case-control study was conducted examining the effects of MPH on VLF-EEG (.02-0.2Hz) during a cued continuous performance task. 41 untreated adults with ADHD and 47 controls were assessed, and 21 cases followed up after MPH treatment, with a similar follow-up for 38 controls (mean follow-up=9.4months). Cases had enhanced frontal and parietal VLF-EEG and increased omission errors. In the whole sample, increased parietal VLF-EEG correlated with increased omission errors. After controlling for subthreshold comorbid symptoms, VLF-EEG case-control differences and treatment effects remained. Post-treatment, a time by group interaction emerged; VLF-EEG and omission errors reduced to the same level as controls, with decreased inattentive symptoms in cases. Reduced VLF-EEG following MPH treatment provides preliminary evidence that changes in VLF-EEG may relate to MPH treatment effects on ADHD symptoms; and that VLF-EEG may be an intermediate phenotype of ADHD. Further studies of the treatment effect of MPH in larger controlled studies are required to formally evaluate any causal link between MPH, VLF-EEG and ADHD symptoms.


Archaeal viruses at the cell envelope: entry and egress.
The cell envelope represents the main line of host defense that viruses encounter on their way from one cell to another. The cytoplasmic membrane in general is a physical barrier that needs to be crossed both upon viral entry and exit. Therefore, viruses from the three domains of life employ a wide range of strategies for perforation of the cell membrane, each adapted to the cell surface environment of their host. Here, we review recent insights on entry and egress mechanisms of viruses infecting archaea. Due to the unique nature of the archaeal cell envelope, these particular viruses exhibit novel and unexpected mechanisms to traverse the cellular membrane.


Transendoscopic Nd:YAG laser ablation of vaginal septa in a bitch.
A vaginal septum was diagnosed in an English bulldog bitch during routine estrous cycle staging. The septum extended 16 cm from the vestibulo-vaginal junction to just caudal to the cervix. The septum was removed by two applications of an Nd:YAG laser via a flexible fiberoptic endoscope. Complete healing occurred over a 5-week period and was uneventful. The bitch was bred and subsequently delivered four puppies vaginally. Transendoscopic laser ablation provided a noninvasive approach to surgically remove a vaginal septum in the dog.


Woodlice and their parasitoid flies: revision of Isopoda (Crustacea, Oniscidea) - Rhinophoridae (Insecta, Diptera) interaction and first record of a parasitized Neotropical woodlouse species.
Terrestrial isopods are soil macroarthropods that have few known parasites and parasitoids. All known parasitoids are from the family Rhinophoridae (Insecta: Diptera). The present article reviews the known biology of Rhinophoridae flies and presents the first record of Rhinophoridae larvae on a Neotropical woodlouse species. We also compile and update all published interaction records. The Neotropical woodlouse Balloniscusglaber was parasitized by two different larval morphotypes of Rhinophoridae. Including this new record, there are 18 Isopoda species known to be parasitized and 13 Rhinophoridae species with known hosts, resulting in 35 interactions. There are a total of 53 interaction records from Holarctic and Neotropical countries. Of the 18 known isopod hosts, only five species have more than one parasitoid, including the new Neotropical host record presented in this work.


Synthetic extracellular matrices for in situ tissue engineering.
Cell interactions with the extracellular matrix play important roles in guiding tissue morphogenesis. The matrix stimulates cells to influence such things as differentiation and the cells actively remodel the matrix via local proteolytic activity. We have designed synthetic hydrogel networks that participate in this interplay: They signal cells via bound adhesion and growth factors, and they also respond to the remodeling influence of cell-associated proteases. Poly(ethylene glycol)-bis-vinylsulfone was crosslinked by a Michael-type addition reaction with a peptide containing three cysteine residues, the peptide sequence being cleavable between each cysteine residue by the cell-associated protease plasmin. Cells were able to invade gel networks that contained adhesion peptides and were crosslinked by plasmin-sensitive peptides, while materials lacking either of these two characteristics resisted cell infiltration. Incorporated bone morphogenetic protein-2 (BMP-2) induced bone healing in a rat model in materials that were both adhesive and plasmin-sensitive, while materials lacking plasmin sensitivity resisted formation of bone within the material. Furthermore, when a heparin bridge was incorporated as a BMP-2 affinity site, mimicking yet another characteristic of the extracellular matrix, statistically improved bone regeneration was observed.


Use of a bacterial fluorescence imaging system to target wound debridement and accelerate healing: a pilot study.
Optimal wound-bed preparation consists of regular debridement to remove devitalised tissues, reduce bacterial load, and to establish an environment that promotes healing. However, lack of diagnostic information at point-of-care limits effectiveness of debridement. This observational case series investigated use of point-of-care fluorescence imaging to detect bacteria (loads >104CFU/g) and guide wound bed preparation. Lower extremity hard-to-heal wounds were imaged over a 12-week period for bacterial fluorescence and wound area. A total of 11 wounds were included in the study. Bacterial fluorescence was present in 10 wounds and persisted, on average, for 3.7 weeks over the course of the study. The presence of red or cyan fluorescent signatures from bacteria correlated with an average increase in wound area of 6.5% per week, indicating stalled or delayed wound healing. Fluorescence imaging information assisted in determining the location and extent of wound debridement, and the selection of dressings and/or antimicrobials. Elimination of bacterial fluorescence signature with targeted debridement and other treatments correlated with an average reduction in wound area of 27.7% per week (p<0.05), indicative of a healing trajectory. These results demonstrate that use of fluorescence imaging as part of routine wound care enhances assessment and treatment selection, thus facilitating improved wound healing.


Dual color optogenetic control of neural populations using low-noise, multishank optoelectrodes.
Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intra- and extra-cellular electrophysiological recordings. Genetically-identified classes of neurons are optically manipulated, though the versatility of optogenetics would be increased if independent control of distinct neural populations could be achieved on a sufficient spatial and temporal resolution. We report a scalable multi-site optoelectrode design that allows simultaneous optogenetic control of two spatially intermingled neuronal populations in vivo. We describe the design, fabrication, and assembly of low-noise, multi-site/multi-color optoelectrodes. Each shank of the four-shank assembly is monolithically integrated with 8 recording sites and a dual-color waveguide mixer with a 7 × 30 μm cross-section, coupled to 405 nm and 635 nm injection laser diodes (ILDs) via gradient-index (GRIN) lenses to meet optical and thermal design requirements. To better understand noise on the recording channels generated during diode-based activation, we developed a lumped-circuit modeling approach for EMI coupling mechanisms and used it to limit artifacts to amplitudes under 100 μV upto an optical output power of 450 μW. We implanted the packaged devices into the CA1 pyramidal layer of awake mice, expressing Channelrhodopsin-2 in pyramidal cells and ChrimsonR in paravalbumin-expressing interneurons, and achieved optical excitation of each cell type using sub-mW illumination. We highlight the potential use of this technology for functional dissection of neural circuits.


Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference.
Kidney transplantation is the most desired and cost-effective modality of renal replacement therapy for patients with irreversible chronic kidney failure (end-stage renal disease, stage 5 chronic kidney disease). Despite emerging evidence that the best outcomes accrue to patients who receive a transplant early in the course of renal replacement therapy, only 2.5% of incident patients with end-stage renal disease undergo transplantation as their initial modality of treatment, a figure largely unchanged for at least a decade. The National Kidney Foundation convened a Kidney Disease Outcomes Quality Initiative (KDOQI) conference in Washington, DC, March 19 through 20, 2007, to examine the issue. Fifty-two participants representing transplant centers, dialysis providers, and payers were divided into three work groups to address the impact of early transplantation on the chronic kidney disease paradigm, educational needs of patients and professionals, and finances of renal replacement therapy. Participants explored the benefits of early transplantation on costs and outcomes, identified current barriers (at multiple levels) that impede access to early transplantation, and recommended specific interventions to overcome those barriers. With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.


Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk.
To determine whether inhibition of Syk would be useful in FcgammaR-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, mouse models were used to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic. Thus, phase 2 clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Doses were increased until a persistent response was seen, toxicity occurred, or 175 mg twice daily was reached. Eight patients achieved persistent responses with platelet counts greater than 50 x 10(9)/L (50 000 mm(3)) on more than 67% (actually 95%) of their study visits, including 3 who had not persistently responded to thrombopoietic agents. Four others had nonsustained responses. Mean peak platelet count exceeded 100 x 10(9)/L (100 000 mm(3)) in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis. In conclusion, inhibition of Syk was an efficacious means of increasing and maintaining the platelet count in half the patients with chronic refractory ITP. (ClinicalTrials.gov, no. NCT00706342).


Exposure to chlorpyrifos in gaseous and particulate form in greenhouses: a pilot study.
Phase distribution of airborne chemicals is important because intake and uptake mechanisms of each phase are different. The phase distribution and concentrations are needed to determine strategies of exposure assessment, hazard control, and worker protection. However, procedures for establishing phase distribution and concentration have not been standardized. The objective of this study was to compare measurements of an airborne semivolatile pesticide (chlorpyrifos) by phase using two different procedures. Six pesticide applications in two facilities were studied and at each site, samples were collected for three time slots: T1, the first 1 or 2 hr after the commencement of application; T2, a 6-hr period immediately following T1; and T3, a 6-hr period after the required re-entry interval (24 hr for chlorpyrifos).Two phase-separating devices were co-located at the center of each greenhouse: semivolatile aerosol dichotomous sampler (SADS) using flow rates of 1.8 l x min(-1) and 0.2 l x min(-1), corresponding to a total inlet flow rate of 2.0 l x min(-1) with a vapor phase flow fraction of 0.1; and an electrostatic precipitator (ESP), along with a standard OVS XAD-2 tube. Chlorpyrifos in vapor and particulate form in a SADS sampling train and that in vapor form in an ESP sampling train were collected in OVS tubes. Chlorpyrifos in particulate form in the ESP setting would have been collected on aluminum substrate. However, no chlorpyrifos in particulate form was recovered from the ESP. Overall (vapor plus particle) concentrations measured by OVS ranged 11.7-186.6 μg/m(3) at T1 and decreased on average 77.1% and 98.9% at T2 and T3, respectively. Overall concentrations measured by SADS were 66.6%, 72.7%, and 102% of those measured by OVS on average at T1, T2, and T3, respectively. Particle fractions from the overall concentrations measured by SADS were 60.0%, 49.2%, and 13.8%, respectively, for T1, T2, and T3. SADS gives better guidance on the distribution of chlorpyrifos than does the ESP, although the accuracy of the concentration distribution cannot be verified in the absence of a standardized procedure for determining phase division.


The clinical and cost effectiveness of a Breathlessness Intervention Service for patients with advanced non-malignant disease and their informal carers: mixed findings of a mixed method randomised controlled trial.
Breathlessness is the most common and intrusive symptom of advanced non-malignant respiratory and cardiac conditions. The Breathlessness Intervention Service (BIS) is a multi-disciplinary complex intervention, theoretically underpinned by a palliative care approach, utilising evidence-based non-pharmacological and pharmacological interventions to support patients with advanced disease in managing their breathlessness. Having published the effectiveness and cost effectiveness of BIS for patients with advanced cancer and their carers, we sought to establish its effectiveness, and cost effectiveness, in advanced non-malignant conditions. This was a single-centre Phase III fast-track single-blind mixed method RCT of BIS versus standard care for breathless patients with non-malignant conditions and their carers. Randomisation was to one of two groups (randomly permuted blocks). Eighty-seven patients referred to BIS were randomised (intervention arm n = 44; control arm n = 43 received BIS after four-week wait); 79 (91 %) completed to key outcome measurement. The primary outcome measure was 0-10 numeric rating scale for patient distress due to breathlessness at four weeks. Secondary outcome measures were Chronic Respiratory Questionnaire, Hospital Anxiety and Depression Scale, Client Service Receipt Inventory, EQ-5D and topic-guided interviews. Qualitative analyses showed the positive impact of BIS on patients with non-malignant conditions and their carers; quantitative analyses showed a non-significant greater reduction in the primary outcome ('distress due to breathlessness'), when compared to standard care, of -0.24 (95 % CI: -1.30, 0.82). BIS resulted in extra mean costs of £799, reducing to £100 when outliers were excluded; neither difference was statistically significant. The quantitative findings contrasted with those previously reported for patients with cancer and their carers, which showed BIS to be both clinically and cost effective. For patients with non-malignant conditions there was a notable trend of improvement over both trial arms to the key measurement point; participants may have experienced a therapeutic effect from the research interviews, diluting the intervention's impact. BIS had a statistically non-significant effect for patients with non-malignant conditions, and slightly increased service costs, but had a qualitatively positive impact consistent with findings for advanced cancer. Trials of palliative care interventions should consider multiple, mixed method, primary outcomes and ensure that protocols limit potential contaminating therapeutic effects in study designs. Current Controlled Trials ISRCTN04119516 (December 2008); ClinicalTrials.gov NCT00678405 (May 2008).


Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.
We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD. Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60)), survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74)), and age at onset of ALS (R(2) = 0.86, p = 5.96x10(-66)). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively. Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.


Can an attribution assessment be made for Yellow Rain? Systematic reanalysis in a chemical-and-biological-weapons use investigation.
In intelligence investigations, such as those into reports of chemical- or biological-weapons (CBW) use, evidence may be difficult to assemble and, once assembled, to weigh. We propose a methodology for such investigations and then apply it to a large body of recently declassified evidence to determine the extent to which an attribution can now be made in the Yellow Rain case. Our analysis strongly supports the hypothesis that CBW were used in Southeast Asia and Afghanistan in the late 1970s and early 1980s, although a definitive judgment cannot be made. The proposed methodology, while resource-intensive, allows evidence to be assembled and analyzed in a transparent manner so that assumptions and rationale for decisions can be challenged by external critics. We conclude with a discussion of future research directions, emphasizing the use of evolving information-extraction (IE) technologies, a sub-field of artificial intelligence (AI).


Opioids: Clinical Practice, Monitoring, and Medicolegal Considerations.
In the past decade, opioid use in the general population of the US has increased dramatically. Concomitantly, opioid-related morbidity and mortality have also risen steeply. The causes of opioid over-prescribing are multifactorial, with pressure from medical agencies, patients, aggressive patient-directed marketing, and use of patient surveys as an evaluation tool to unduly influence medical providers' decision-making. Providers also have significant concerns regarding scrutiny from their medical board and exposure to medicolegal liability. To provide the basis for best practice recommendations, several aspects of modern opioid prescribing practice require review. The practicing clinician should be aware of: (a) the pervasiveness of current opioid prescribing within the US; (b) the availability and applicability of clinical tools used to assess patient risk; (c) the new guidelines designed to facilitate appropriate and safe medical use of opioids; (d) the incorporation of clinical tools and best documentation practices to reduce medicolegal exposure. On completion of this review, the reader should be able to recognize the magnitude of the problem of opioid over-prescribing in the US and identify several patient risk factors for opioid misuse, abuse, and/or diversion. Specifically, better familiarity with the recently published CDC guidelines for opioid prescribing will help ensure the adoption of best-use practices that maximize therapeutic efficacy while attenuating the possibility of harm to patients. A thorough review of the legal principles and risk-mitigation strategies relevant to opioid prescribing will also lessen the clinician's exposure to medicolegal liability.


Magnetic resonance imaging findings in horses with septic arthritis.
Fourteen horses with septic arthritis underwent high-field (1.5 T) magnetic resonance imaging (MRI). Septic arthritis was diagnosed based on results from historical and clinical findings, synovial fluid analyses and culture, and radiographic, ultrasonographic, arthroscopic, and histopathologic findings. MR findings included diffuse hyperintensity within bone and extracapsular tissue on fat-suppressed images in 14/14 horses (100%), joint effusion, synovial proliferation, and capsular thickening in 13/14 horses (93%), bone sclerosis in 11/14 horses (79%), and evidence of cartilage and subchondral bone damage in 8/14 horses (57%). Intravenous gadolinium was administered to five of the 14 horses and fibrin deposition was noted in all horses. Other findings after gadolinium administration included synovial enhancement in 4/5 (80%) horses, and bone enhancement in 1/5 (20%) horses. The MR findings of septic arthritis in horses were consistent with those reported in people. MRI may allow earlier and more accurate diagnosis of septic arthritis in horses as compared with other imaging modalities, especially when the clinical diagnosis is challenging. It also provides additional information not afforded by other methods that may influence and enhance treatment.


Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold.
Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases.


The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease.
Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.


Transfemoral Implantation of a Fully Repositionable and Retrievable Transcatheter Valve for Noncalcified Pure Aortic Regurgitation.
This study sought to evaluate the use of the Direct Flow Medical (DFM) transcatheter heart valve (Direct Flow Medical, Santa Rosa, California) for the treatment of noncalcific pure aortic regurgitation (AR). The treatment of noncalcific AR has remained a relative contraindication with transcatheter heart valves due to challenges in anchoring devices in the absence of calcium, concerns of valve embolization, and the high risk of significant residual paravalvular leak. The study population consisted of patients treated for severe noncalcific pure AR with transfemoral implantation of a DFM transcatheter heart valve at 6 European centers. The primary endpoint was the composite endpoint of device success and the secondary endpoint was the composite early safety endpoint (according to the VARC-2 criteria). Eleven high-risk (STS score 8.84 ± 8.9, Logistic EuroSCORE 19.9 ± 7.1) patients (mean age 74.7 ± 12.9 years) were included. Device success was achieved in all patients. In 1 patient, the initial valve prosthesis was retrieved after pull-through, and a second valve was successfully deployed. The early safety endpoint was reached in 91% of the patients, with 1 patient requiring surgical aortic valve replacement secondary to downward dislocation of the prosthesis that was successfully managed with surgical aortic valve replacement. DFM implantation resulted in excellent hemodynamics with none or trivial paravalvular regurgitation in 9 patients and a transprosthetic gradient of 7.7 ± 5.1 mm Hg at 30-day follow up. All patients derived symptomatic benefit following the procedure, with 72% in New York Heart Association functional class I or II. This study reports the feasibility of treating severe noncalcific AR with the Direct Flow prosthesis via the transfemoral route.


Asymmetric ommatidia count and behavioural lateralization in the ant Temnothorax albipennis.
Workers of the house-hunting ant Temnothorax albipennis rely on visual edge following and landmark recognition to navigate their rocky environment, and they also exhibit a leftward turning bias when exploring unknown nest sites. We used electron microscopy to count the number of ommatidia composing the compound eyes of workers, males and queens, to make an approximate assessment of their relative sampling resolution; and to establish whether there is an asymmetry in the number of ommatidia composing the workers' eyes, which might provide an observable, mechanistic explanation for the turning bias. We hypothesise that even small asymmetries in relative visual acuity between left and right eyes could be magnified by developmental experience into a symmetry-breaking turning preference that results in the inferior eye pointing toward the wall. Fifty-six workers were examined: 45% had more ommatidia in the right eye, 36% more in the left, and 20% an equal number. A tentative connection between relative ommatidia count for each eye and turning behaviour was identified, with a stronger assessment of behavioural lateralization before imaging and a larger sample suggested for further work. There was a clear sexual dimorphism in ommatidia counts between queens and males.


Gaussian process approach to spiking neurons for inhomogeneous Poisson inputs.
This article presents a new theoretical framework to consider the dynamics of a stochastic spiking neuron model with general membrane response to input spike. We assume that the input spikes obey an inhomogeneous Poisson process. The stochastic process of the membrane potential then becomes a gaussian process. When a general type of the membrane response is assumed, the stochastic process becomes a Markov-gaussian process. We present a calculation method for the membrane potential density and the firing probability density. Our new formulation is the extension of the existing formulation based on diffusion approximation. Although the single Markov assumption of the diffusion approximation simplifies the stochastic process analysis, the calculation is inaccurate when the stochastic process involves a multiple Markov property. We find that the variation of the shape of the membrane response, which has often been ignored in existing stochastic process studies, significantly affects the firing probability. Our approach can consider the reset effect, which has been difficult to deal with by analysis based on the first passage time density.


Cartilage injuries in distal radial fractures.
Subchondral hematomas have been found with arthroscopy in one third of patients with dislocated distal radial fractures. The aim of the present, prospective study was to determine whether these hematomas might cause radiographic osteoarthrosis. We studied 41 patients (age 20-57 years, 22 women) with a dislocated distal radial fracture. At the time of fracture, 12 patients had subchondral hematomas in a radiocarpal compartment without a fracture line, as defined by arthroscopy. The 1-year follow-up included clinical and radiographic examinations. At follow-up, radiographic subchondral bone plate changes occurred in unfractured compartments in 8 patients, of whom 7 had had a previous arthroscopically diagnosed subchondral hematoma (p = 0.02) in the same compartment. Of the 8 patients with radiographic changes, 4 had also developed joint space narrowing (osteoarthrosis (OA) grade 1) after 1 year and 6 after 3 years. All but 1 had had a hematoma in the same compartment. More importantly, 3 of the 16 patients with entirely extra-articular fractures had subchondral bone plate changes in a compartment corresponding to a previous subchondral hematoma (p = 0.02). One of these had also developed joint space narrowing. The patients with radiographic changes had a worse outcome, as measured with the Gartland and Werley wrist score (p = 0.06). In conclusion, subchondral hematomas in distal radial fractures can lead to early onset of mild OA and worse outcome after 1 year.


Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine/paracrine effects on the growth and signaling pathways in H295R cells.
Adrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone-related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP(1-34) on H295R cells derived from an ACC. PTH-R1 mRNA and proteins were detected by real-time PCR and Western blotting in all the ACT samples and in H295R cells. Their concentrations did not differ significantly from one ACT to another. PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in 90% of ACC, and in 10% of ACA. There was a positive correlation with the prognostic factors, McFarlane stage and Weiss score. Tissue-specific PTHrP protein processing was shown by Western blotting. Immunohistochemical staining revealed numerous, dense foci of PTHrP-containing cells in ACC, but few positive cells in ACA or normal tissue. PTHrP stimulated the growth of H295R cells, whereas a specific anti-PTHrP antibody and a PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium/protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to poor prognosis in ACC, in which it may act as an autocrine/paracrine factor in tumor growth and malignancy.