The ALTERNATE trial: assessing a biomarker driven strategy for the treatment of post-menopausal women with ER+/Her2- invasive breast cancer.
The Alliance for Clinical Trials in Oncology cooperative group has designed a phase III neoadjuvant clinical trial (ALTERNATE trial) which randomizes women with cT2-4 N0-3 M0 ER+/Her2- invasive breast cancer to either anastrozole, fulvestrant or its combination to assess a biomarker-driven treatment strategy to identify women with a low risk of disease recurrence. This strategy incorporates the findings that: higher expression of the proliferation marker, Ki67, after 2 weeks of neoadjuvant endocrine therapy (ET), is associated with poor recurrence-free survival, and that patients with surgical findings of pT1/2, pN0 disease, Ki67 ≤2.7% and ER Allred score of 3-8 after neoadjuvant ET have extremely low recurrence rates. We present a description and rationale for the design of this trial.


Thirty years after anorexia nervosa onset, serum neurofilament light chain protein concentration indicates neuronal injury.
Little is known about the long-term consequences of anorexia nervosa (AN) in terms of possible brain neuronal injury. We aimed at investigating whether women with adolescent-onset AN exhibit increased serum levels of neurofilament light chain protein (NfL), a biomarker for neuronal injury, compared with matched controls at 30-year follow-up. Blood samples were collected from 34 women with adolescent-onset AN and 38 matched healthy comparison women (COMP), at a mean age of 44 years (range 38-48 years). NfL was measured in serum using the in-house single molecule array (Simoa) method. The individuals were asked whether they or their parents had been diagnosed with dementia. The Swedish National Patient Register was searched for diagnoses related to dementia. Serum NfL concentrations were significantly higher in the AN group (AN 27.7 pg/ml; COMP 19.0 pg/ml; p = 0.041). When individuals with medical/neurological disorders in the AN and COMP groups were excluded, there was a statistically non-significant trend towards higher concentrations in the AN group (AN 27.4 pg/ml; COMP 18.8 pg/ml; p = 0.060). None of the participants had been diagnosed with dementia. There was no significant correlation between serum NfL and AN duration (r = 0.15). There was a moderate negative correlation between the serum NfL concentration and the current BMI in the AN group (r = 0.44). This is the first time that serum NfL has been assessed in middle-aged women with a history of adolescent-onset AN. The results suggest that there might be increased axonal degeneration as a sequel of AN. Individuals remaining underweight had higher serum NfL concentrations than those with a normal/high BMI. Additional studies are needed to confirm increased serum NfL concentrations in individuals recovered from AN. There is a need for further study of axonal degeneration as a consequence of AN.


Sonography for the detection of cervical lymph node metastases among patients with tongue cancer: criteria for early detection and assessment of follow-up examination intervals.
Because the presence of cervical metastasis is one of the factors influencing the outcome of patients with carcinoma of the head and neck, its early detection is potentially very important. The purpose of this study was to evaluate the characteristic changes of cervical metastasis revealed by sonography during follow-up and to assess an adequate interval for follow-up sonography of the neck among patients with tongue cancer. Forty-three of 44 consecutive patients with squamous cell carcinoma of the tongue, who had undergone interstitial brachytherapy, were examined with sonography of the neck during the posttherapeutic follow-up period. Seventeen cervical lymph node metastases were found in 12 of 43 patients during follow-up. Of these 17 cervical metastases, 16 (94.1%) were accurately diagnosed and one (5.9%) was misdiagnosed as nonmetastatic based on sonographic findings. Sonography of the neck performed in seven patients at an interval of less than 1 month since the last follow-up imaging showed 9 (90.0%) of 10 metastases increased by up to 2 mm in short-axis diameter. Five patients who were followed up at an interval of more than 1 month since the last follow-up imaging had seven metastases increase by 3 to 8 mm in short-axis diameter or a change of echogenicity in the internal structure of lymph nodes or both. Pathologic examinations showed extranodal spread in 3 (42.9%) of these 7 metastases. Changes both in size and internal echogenicity can occur as quickly as 2 to 4 weeks between sonographic examinations. Therefore, in high-risk patients, or in those with suspicious sonographic findings, short-interval follow-up sonographic examinations are recommended at least during the first posttherapeutic year. Our findings suggest that follow-up sonography of the neck should be performed monthly, at least during the first posttherapeutic year.


Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator.
In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2]). Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.


Ecological specialization is associated with genetic structure in the ant-associated butterfly family Lycaenidae.
The role of specialization in diversification can be explored along two geological axes in the butterfly family Lycaenidae. In addition to variation in host-plant specialization normally exhibited by butterflies, the caterpillars of most Lycaenidae have symbioses with ants ranging from no interactions through to obligate and specific associations, increasing niche dimensionality in ant-associated taxa. Based on mitochondrial sequences from 8282 specimens from 967 species and 249 genera, we show that the degree of ecological specialization of lycaenid species is positively correlated with genetic divergence, haplotype diversity and an increase in isolation by distance. Nucleotide substitution rate is higher in carnivorous than phytophagous lycaenids. The effects documented here for both micro- and macroevolutionary processes could result from increased spatial segregation as a consequence of reduced connectivity in specialists, niche-based divergence or a combination of both. They could also provide an explanation for the extraordinary diversity of the Lycaenidae and, more generally, for diversity in groups of organisms with similar multi-dimensional ecological specialization.


JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients.
Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV.


Exercise and bone mass in adults.
There is a substantial body of evidence indicating that exercise prior to the pubertal growth spurt stimulates bone growth and skeletal muscle hypertrophy to a greater degree than observed during growth in non-physically active children. Bone mass can be increased by some exercise programmes in adults and the elderly, and attenuate the losses in bone mass associated with aging. This review provides an overview of cross-sectional and longitudinal studies performed to date involving training and bone measurements. Cross-sectional studies show in general that exercise modalities requiring high forces and/or generating high impacts have the greatest osteogenic potential. Several training methods have been used to improve bone mineral density (BMD) and content in prospective studies. Not all exercise modalities have shown positive effects on bone mass. For example, unloaded exercise such as swimming has no impact on bone mass, while walking or running has limited positive effects. It is not clear which training method is superior for bone stimulation in adults, although scientific evidence points to a combination of high-impact (i.e. jumping) and weight-lifting exercises. Exercise involving high impacts, even a relatively small amount, appears to be the most efficient for enhancing bone mass, except in postmenopausal women. Several types of resistance exercise have been tested also with positive results, especially when the intensity of the exercise is high and the speed of movement elevated. A handful of other studies have reported little or no effect on bone density. However, these results may be partially attributable to the study design, intensity and duration of the exercise protocol, and the bone density measurement techniques used. Studies performed in older adults show only mild increases, maintenance or just attenuation of BMD losses in postmenopausal women, but net changes in BMD relative to control subjects who are losing bone mass are beneficial in decreasing fracture risk. Older men have been less studied than women, and although it seems that men may respond better than their female counterparts, the experimental evidence for a dimorphism based on sex in the osteogenic response to exercise in the elderly is weak. A randomized longitudinal study of the effects of exercise on bone mass in elderly men and women is still lacking. It remains to be determined if elderly females need a different exercise protocol compared with men of similar age. Impact and resistance exercise should be advocated for the prevention of osteoporosis. For those with osteoporosis, weight-bearing exercise in general, and resistance exercise in particular, as tolerated, along with exercise targeted to improve balance, mobility and posture, should be recommended to reduce the likelihood of falling and its associated morbidity and mortality. Additional randomized controlled trials are needed to determine the most efficient training loads depending on age, sex, current bone mass and training history for improvement of bone mass.


OFDR with double interrogation for dynamic quasi-distributed sensing.
A method for phase sensitive quasi-distributed vibration and acoustical sensing is presented. The method is based on double optical frequency domain reflectometry interrogation of a sensing fiber with an array of discrete weak reflectors. Two replicas of the interrogation signal are launched into the sensing fiber. The time delay between the replicas is equal to the roundtrip time between two consecutive reflectors. Each peak in the spectrum of the returning signal is made from a coherent addition of the reflections of two consecutive reflectors. Its magnitude is highly sensitive to the optical phase in the fiber segment between the reflectors. The system was used to detect and locate the fall of a paperclip from height of 40 cm onto a sandbox where a 15 cm segment of the fiber was buried. In a different experiment the system successfully detected and located minute vibrations at 440 Hz that were induced by touching the fiber with a tuning fork.


Comparison of the sensitivity of different fish species to medical substances.
Formaldehyde, sodium chloride and potassium permanganate belong to the commonly used substances for fish treatment. The aim is to define and compare their acute toxicity and therapeutic index between two fish species - Danio rerio and Poecilia reticulata. To determine acute toxicity of these compounds, the semistatic method was implemented in compliance with the OECD No. 203 (Fish acute toxicity test). In each test series, 4 acute toxicity tests were performed. The results were subjected to the probit analysis to determine the 96hLC50 values. Therapeutic index (TI) was calculated with respect to short-term LC50 and effective therapeutic concentrations commonly used for fish treatment. The mean 96hLC50 values for sodium chloride were 21.69 +/- 0.92 g l-1 (TI = 1.4) for P. reticulata and 10.39 +/- 0.12 g l-1 (TI = 1.0) for D. rerio. The acute toxicity of formaldehyde for D. rerio expressed as 96LC50 was 0.12 +/- 0.003 ml l-1 (TI = 5.24) and for P. reticulata 0.1 +/- 0.003 ml l-1 (TI = 4.9). The acute toxicity of potassium permanganate for D. rerio expressed as 96LC50 was 1.25 +/- 0.15 mg l-1(TI = 1.5) and for P. reticulata 1.43 +/- 0.05 mg l-1 (TI = 2). P. reticulata showed significantly higher (p < 0.05) tolerance to sodium chloride than D. rerio, whereas D. rerio showed significantly higher (p < 0.05) tolerance to formaldehyde than P. reticulata. The acute toxicity of potassium permanganate was comparable for both fish species. Calculated therapeutic indexes of all tested substances were low; therefore it is important to conduct preliminary tolerance tests before application of treatment baths.


Change in eating-disorder psychopathology network structure in patients with anorexia nervosa treated with intensive cognitive behavior therapy.
This study was designed to compare the change in eating-disorder feature networks in patients with anorexia nervosa after treatment with intensive enhanced cognitive behavior therapy (CBT-E). Patients seeking treatment for anorexia nervosa were consecutively recruited from January 2016 to September 2020. All patients aged ≥16 years who completed a 20-week intensive CBT-E program (13 weeks of inpatient followed by 7 weeks of day-hospital treatment) were included in the study. Body mass index (BMI) was measured, and the Eating Disorder Examination Questionnaire completed for each patient, both at baseline and the end of treatment. The sample comprised 214 patients with anorexia nervosa. Treated patients showed significant improvements in BMI and eating-disorder psychopathology. Network analysis revealed a significant reduction in the network global and connection strengths at the end of treatment. The most central and highly interconnected nodes in the network at baseline were related to the drive for thinness, but at the end of treatment to body image concerns. Some edge connections were significantly stronger at baseline than at the end of treatment, while others were significantly stronger at the end of treatment than at baseline. CBT-E reduces the psychopathology network connectivity over time in patients with anorexia nervosa. The differences in central nodes and edge connections between baseline and end of treatment, not detected by classical inferential analysis, may be informative for understanding the centrality of symptoms in the psychopathology network, and how a specific treatment may act to reduce symptoms and change their connections over time.


Malaria Vaccines: Moving Forward After Encouraging First Steps.
An effective malaria vaccine that reduces morbidity and mortality and contributes to malaria elimination is a much-needed tool, particularly in endemic areas where health-care delivery and vector control efforts are difficult to sustain. RTS,S/AS01 is likely to be the first licensed malaria vaccine and represents an important step toward malaria control and elimination. However, a partially effective vaccine such as RTS,S/AS01 poses challenges for evaluating the efficacy of second-generation malaria vaccines. Whole-sporozoite immunization approaches have shown promising results, inducing sterile immunity in small-scale trials of malaria-naïve adults, but may not achieve durable sterile protection in endemic populations. Vaccines targeting both the pre-erythrocytic and the erythrocyte-invasive form of the parasite (merozoites) may abrogate breakthrough infections by neutralizing merozoites emerging from infected hepatocytes, whereas vaccines targeting the sexual stages seek to break the transmission cycle. Moving forward, a multi-stage vaccine could be the next step toward malaria elimination and eradication.


WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation.
During normal cerebellar development, the remarkable expansion of granule cell progenitors (GCPs) generates a population of granule neurons that outnumbers the total neuronal population of the cerebral cortex, and provides a model for identifying signaling pathways that may be defective in medulloblastoma. While many studies focus on identifying pathways that promote growth of GCPs, a critical unanswered question concerns the identification of signaling pathways that block mitogenic stimulation and induce early steps in differentiation. Here we identify WNT3 as a novel suppressor of GCP proliferation during cerebellar development and an inhibitor of medulloblastoma growth in mice. WNT3, produced in early postnatal cerebellum, inhibits GCP proliferation by down-regulating pro-proliferative target genes of the mitogen Sonic Hedgehog (SHH) and the bHLH transcription factor Atoh1. WNT3 suppresses GCP growth through a non-canonical Wnt signaling pathway, activating prototypic mitogen-activated protein kinases (MAPKs), the Ras-dependent extracellular-signal-regulated kinases 1/2 (ERK1/2) and ERK5, instead of the classical β-catenin pathway. Inhibition of MAPK activity using a MAPK kinase (MEK) inhibitor reversed the inhibitory effect of WNT3 on GCP proliferation. Importantly, WNT3 inhibits proliferation of medulloblastoma tumor growth in mouse models by a similar mechanism. Thus, the present study suggests a novel role for WNT3 as a regulator of neurogenesis and repressor of neural tumors.


Development of an Unbiased Validation Protocol to Assess the Biofidelity of Finite Element Head Models used in Prediction of Traumatic Brain Injury.
This study describes a method to identify laboratory test procedures and impact response requirements suitable for assessing the biofidelity of finite element head models used in prediction of traumatic brain injury. The selection of the experimental data and the response requirements were result of a critical evaluation based on the accuracy, reproducibility and relevance of the available experimental data. A weighted averaging procedure was chosen in order to consider different contributions from the various test conditions and target measurements based on experimental error. According to the quality criteria, 40 experimental cases were selected to be a representative dataset for validation. Based on the evaluation of response curves from four head finite element models, CORA was chosen as a quantitative method to compare the predicted time history response to the measured data. Optimization of the CORA global settings led to the recommendation of performing curve comparison on a fixed time interval of 0-30 ms for intracranial pressure and at least 0-40 ms for brain motion and deformation. The allowable maximum time shift was adjusted depending on the shape of the experimental curves (DMAX = 0.12 for intracranial pressure, DMAX = 0.40 for brain motion and DMAX = 0.25 for brain deformation). Finally, bigger penalization of ratings was assigned to curves with fundamentally incorrect shape compared to those having inaccuracies in amplitude or time shift (cubic vs linear). This rigorous approach is necessary to ensure confidence in the model results and progress in the usage of finite element head models for traumatic brain injury prediction.


A stochastic optimization method to estimate the spatial distribution of a pathogen from a sample.
Information on the spatial distribution of plant disease can be utilized to implement efficient and spatially targeted disease management interventions. We present a pathogen-generic method to estimate the spatial distribution of a plant pathogen using a stochastic optimization process which is epidemiologically motivated. Based on an initial sample, the method simulates the individual spread processes of a pathogen between patches of host to generate optimized spatial distribution maps. The method was tested on data sets of Huanglongbing of citrus and was compared with a kriging method from the field of geostatistics using the well-established kappa statistic to quantify map accuracy. Our method produced accurate maps of disease distribution with kappa values as high as 0.46 and was able to outperform the kriging method across a range of sample sizes based on the kappa statistic. As expected, map accuracy improved with sample size but there was a high amount of variation between different random sample placements (i.e., the spatial distribution of samples). This highlights the importance of sample placement on the ability to estimate the spatial distribution of a plant pathogen and we thus conclude that further research into sampling design and its effect on the ability to estimate disease distribution is necessary.


AdaBoost based multi-instance transfer learning for predicting proteome-wide interactions between Salmonella and human proteins.
Pathogen-host protein-protein interaction (PPI) plays an important role in revealing the underlying pathogenesis of viruses and bacteria. The need of rapidly mapping proteome-wide pathogen-host interactome opens avenues for and imposes burdens on computational modeling. For Salmonella typhimurium, only 62 interactions with human proteins are reported to date, and the computational modeling based on such a small training data is prone to yield model overfitting. In this work, we propose a multi-instance transfer learning method to reconstruct the proteome-wide Salmonella-human PPI networks, wherein the training data is augmented by homolog knowledge transfer in the form of independent homolog instances. We use AdaBoost instance reweighting to counteract the noise from homolog instances, and deliberately design three experimental settings to validate the assumption that the homolog instances are effective to address the problems of data scarcity and data unavailability. The experimental results show that the proposed method outperforms the existing models and some predictions are validated by the findings from recent literature. Lastly, we conduct gene ontology based clustering analysis of the predicted networks to provide insights into the pathogenesis of Salmonella.


Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy.
Inborn errors of bile acid metabolism may present as neonatal cholestasis and fat-soluble vitamin malabsorption or as late onset chronic liver disease. Our aim was to fully characterize a defect in bile acid synthesis in a 2-week-old African-American girl presenting with coagulopathy, vitamin D and E deficiencies, and mild cholestasis and in her sibling, whose liver had been used for orthotopic liver transplantation (OLT). Bile acids were measured by mass spectrometry in urine, bile, serum, and feces of the patient and in urine from the unrelated recipient. Liver biopsy specimens showed neonatal hepatitis with giant cell transformation and hepatocyte necrosis; peroxisomes were reduced in number. High concentrations of (25R)3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid in the urine, bile, and serum established a pattern similar to that of Zellweger syndrome and identical to the Alligator mississippiensis. Serum phytanic acid was normal, whereas pristanic acid was markedly elevated. Biochemical, MRI, and neurologic findings were inconsistent with a generalized defect of peroxisomal function and were unique. Analysis of the urine from the recipient of the deceased sibling's liver confirmed the same bile acid synthetic defect. A deficiency in 2-methylacyl-CoA racemase, which is essential for conversion of (25R)THCA to its 25S-isomer, the substrate to initiate peroxisomal beta-oxidation to primary bile acids, was confirmed by DNA analysis revealing a missense mutation (S52P) in the gene encoding this enzyme. Long-term treatment with cholic acid normalized liver enzymes and prevented progression of symptoms. This genetic defect further highlights bile acid synthetic defects as a cause of neonatal cholestasis.


Designing 3D COFs with enhanced hydrogen storage capacity.
Hydrogen storage properties have been studied on newly designed three-dimensional covalent-organic framework (3D-COF). The design of these materials was based on the ctn network of the ultralow density COF-102. The structures were optimized by multiscale techniques and the optimized structures were checked for their storage capacities by grand canonical Monte Carlo simulations. Our simulations demonstrate that the gravimetric uptake of one of these new COFs can overpass the value of 25 wt % in 77 K and reach the Department of Energy's target of 6 wt % in room temperature, classifying them between the top hydrogen storage materials.


Compound prism design principles, III: linear-in-wavenumber and optical coherence tomography prisms.
We extend the work of the first two papers in this series [Appl. Opt. 50, 4998-5011 (2011), Appl. Opt. 50, 5012-5022 (2011)] to design compound prisms for linear-in-wavenumber dispersion, especially for application in spectral domain optical coherence tomography (OCT). These dispersive prism designs are believed to be the first to meet the requirements of high resolution OCT systems in direct-view geometry, where they can be used to shrink system size, to improve light throughput, to reduce stray light, and to reduce errors resulting from interpolating between wavelength- and wavenumber-sampled domains. We show prism designs that can be used for thermal sources or for wideband superluminescent diodes centered around wavelengths 850, 900, 1300, and 1375 nm.


Regularising limited view tomography using anatomical reference images and information theoretic similarity metrics.
This paper is concerned with limited view tomography. Inspired by the application of digital breast tomosynthesis (DBT), which is but one of an increasing number of applications of limited view tomography, we concentrate primarily on cases where the angular range is restricted to a narrow wedge of approximately ±30°, and the number of views is restricted to 10-30. The main challenge posed by these conditions is undersampling, also known as the null space problem. As a consequence of the Fourier Slice Theorem, a limited angular range leaves large swathes of the object's Fourier space unsampled, leaving a large space of possible solutions, reconstructed volumes, for a given set of inputs. We explore the feasibility of using same- or different-modality images as anatomical priors to constrain the null space, hence the solution. To allow for different-modality priors, we choose information theoretic measures to quantify the similarity between reconstructions and their priors. We demonstrate the limitations of two popular choices, namely mutual information and joint entropy, and propose robust alternatives that overcome their limitations. One of these alternatives is essentially a joint mixture model of the image and its prior. Promising mitigation of the data insufficiency problem is demonstrated using 2D synthetic as well as clinical phantoms. This work initially assumes a priori registered priors, and is then extended to allow for the registration to be performed simultaneously with the reconstruction.


Tapered-cuff Endotracheal Tube Does Not Prevent Early Postoperative Pneumonia Compared with Spherical-cuff Endotracheal Tube after Major Vascular Surgery: A Randomized Controlled Trial.
Patients undergoing major vascular surgery often develop postoperative pneumonia that impacts their outcomes. Conflicting data exist concerning the potential benefit of tapered-shaped cuffs on tracheal sealing. The primary objective of this study was to assess the efficiency of a polyvinyl chloride tapered-cuff endotracheal tube at reducing the postoperative pneumonia rate after major vascular surgery. Secondary objectives were to determine its impact on microaspiration, ventilator-associated pneumonia rate, and inner cuff pressure. This prospective randomized controlled study included 109 patients who were randomly assigned to receive either spherical- (standard cuff) or taper-shaped (tapered cuff) endotracheal tubes inserted after anesthesia induction and then admitted to the intensive care unit after major vascular surgery. Cuff pressure was continuously recorded over 5 h. Pepsin and α-amylase concentrations in tracheal aspirates were quantified on postoperative days 1 and 2. The primary outcome was the early postoperative pneumonia frequency. Comparing the tapered-cuff with standard-cuff group, respectively, postoperative pneumonia rates were comparable (42 vs. 44%, P = 0.87) and the percentage (interquartile range) of cuff-pressure time with overinflation was significantly higher (16.1% [1.5 to 50] vs. 0.6% [0 to 8.3], P = 0.01), with a 2.5-fold higher coefficient of variation (20.2 [10.6 to 29.4] vs. 7.6 [6.2 to 10.2], P < 0.001). Although microaspiration frequencies were high, they did not differ between groups. For major vascular surgery patients, polyvinyl chloride tapered-cuff endotracheal tubes with intermittent cuff-pressure control did not lower the early postoperative pneumonia frequency and did not prevent microaspiration.


The effect of dose heterogeneity on radiation risk in medical imaging.
The current estimations of risk associated with medical imaging procedures rely on assessing the organ dose via direct measurements or simulation. The dose to each organ is assumed to be homogeneous. To take into account the differences in radiation sensitivities, the mean organ doses are weighted by a corresponding tissue-weighting coefficients provided by ICRP to calculate the effective dose, which has been used as a surrogate of radiation risk. However, those coefficients were derived under the assumption of a homogeneous dose distribution within each organ. That assumption is significantly violated in most medical-imaging procedures. In helical chest CT, for example, superficial organs (e.g. breasts) demonstrate a heterogeneous dose distribution, whereas organs on the peripheries of the irradiation field (e.g. liver) might possess a discontinuous dose profile. Projection radiography and mammography involve an even higher level of organ dose heterogeneity spanning up to two orders of magnitude. As such, mean dose or point measured dose values do not reflect the maximum energy deposited per unit volume of the organ. In this paper, the magnitude of the dose heterogeneity in both CT and projection X-ray imaging was reported, using Monte Carlo methods. The lung dose demonstrated factors of 1.7 and 2.2 difference between the mean and maximum dose for chest CT and radiography, respectively. The corresponding values for the liver were 1.9 and 3.5. For mammography and breast tomosynthesis, the difference between mean glandular dose and maximum glandular dose was 3.1. Risk models based on the mean dose were found to provide a reasonable reflection of cancer risk. However, for leukaemia, they were found to significantly under-represent the risk when the organ dose distribution is heterogeneous. A systematic study is needed to develop a risk model for heterogeneous dose distributions.


Bilastine: a new antihistamine with an optimal benefit-to-risk ratio for safety during driving.
Rational selection of a second-generation H1-antihistamine requires efficacy and safety considerations, particularly regarding central nervous system (CNS) effects (cognitive and psychomotor function), potential for driving impairment, minimal sedative effects and a lack of interactions. This review evaluates the key safety features of the non-sedating antihistamine, bilastine, during driving and in preventing road traffic accidents. Among the second-generation H1-antihistamines, sedative effects which can affect cognitive and psychomotor performance, and possibly driving ability, may not be similar. Bilastine is absorbed rapidly, undergoes no hepatic metabolism or cytochrome P450 interaction (minimal drug-drug interaction potential), and is a substrate for P-glycoprotein (limiting CNS entry). Positron emission tomography showed that, compared with other second-generation H1-antihistamines, bilastine has the lowest cerebral histamine H1-receptor occupancy. Bilastine 20 mg once daily (therapeutic dose) is non-sedating, does not enhance the effects of alcohol or CNS sedatives, does not impair driving performance and has at least similar efficacy as other second-generation H1-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria. Current evidence shows that bilastine has an optimal benefit-to-risk ratio, meeting all conditions for contributing to safety in drivers who need antihistamines, and hence for being considered as an antihistamine of choice for drivers.


Characterization of Alternaria alternata Causing Black Spot Disease of Pomegranate in Israel Using a Molecular Marker.
Black spot disease of pomegranate is a relatively new disease in Israel that is caused by Alternaria alternata. The symptoms include black spots on leaves and fruit. Only the outer part of the fruit is damaged; the edible tissue remains unaffected. In this study, we obtained 50 isolates of A. alternata from infected pomegranate plants that were classified based on pathogenicity tests using detached leaves. Using an arbitrarily primed polymerase chain reaction, we identified one primer (primer CAG) that reacted only with DNA of isolates that induced the most severe disease symptoms. Based on the sequence of the amplified fragment, we generated a specific primer (primer C) that recognizes these highly virulent isolates. Therefore, we suggest that primer C can be utilized as a molecular marker for the detection of A. alternata isolates that cause black spot disease of pomegranate.


Discovery of LH-regulated genes in the primate corpus luteum.
Circulating LH is essential for the development and function of the primate corpus luteum (CL) during the menstrual cycle. However, the cellular and molecular processes whereby LH controls luteal structure and function are poorly understood. Therefore, studies were initiated to identify gene products that are regulated by gonadotrophin in the monkey CL. Rhesus monkeys either were untreated (controls, CTRL; n = 3) or received the GnRH antagonist Antide (ANT; 3 mg/kg body weight, n = 3) to inhibit pituitary LH secretion on day 6 of the luteal phase in spontaneous menstrual cycles. The CL was removed 24 h later. RNA was extracted and converted to cDNA. The CTRL and ANT cDNA were differentially labelled with fluorescent dyes (Cy3-CTRL and Cy5-ANT) and hybridized onto microarrays containing 11,600 human cDNA. The selected cDNA were analysed further via semi-quantitative RT-PCR (a) to validate the microarray results and (b) to determine if their expression varies in the CL (n = 3/stage) between the mid (day 6-8), late (day 14-16), or very late (day 18-19, menses) luteal phase of the natural cycle. After normalization of the fluorescence data, 206 cDNA (1.8% of the total) exhibited > or = 2-fold change in expression after ANT. Of the 25 cDNA exhibiting a > or = 6-fold change, 6 were up-regulated and 19 were down-regulated. Twenty-two of these 25 cDNA were validated by RT-PCR as differentially expressed in the ANT group, relative to the CTRL group, and 11 of 25 changed (P < 0.05) correspondingly in the late-to-very late luteal phase. Thus, we have identified gene products that are regulated by gonadotrophin in the primate CL that may be important in luteal regression during the menstrual cycle.


Effect of interval training intensity on fat oxidation, blood lactate and the rate of perceived exertion in obese men.
The objectives of this study were to examine the effect of 4-week moderate- and high-intensity interval training (MIIT and HIIT) on fat oxidation and the responses of blood lactate (BLa) and rating of perceived exertion (RPE). Ten overweight/obese men (age = 29 ±3.7 years, BMI = 30.7 ±3.4 kg/m(2)) participated in a cross-over study of 4-week MIIT and HIIT training. The MIIT training sessions consisted of 5-min cycling stages at mechanical workloads 20% above and 20% below 45%VO2peak. The HIIT sessions consisted of intervals of 30-s work at 90%VO2peak and 30-s rest. Pre- and post-training assessments included VO2max using a graded exercise test (GXT) and fat oxidation using a 45-min constant-load test at 45%VO2max. BLa and RPE were also measured during the constant-load exercise test. There were no significant changes in body composition with either intervention. There were significant increases in fat oxidation after MIIT and HIIT (p ≤ 0.01), with no effect of intensity. BLa during the constant-load exercise test significantly decreased after MIIT and HIIT (p ≤ 0.01), and the difference between MIIT and HIIT was not significant (p = 0.09). RPE significantly decreased after HIIT greater than MIIT (p ≤ 0.05). Interval training can increase fat oxidation with no effect of exercise intensity, but BLa and RPE decreased after HIIT to greater extent than MIIT.


Metabolic profiling reveals key metabolic features of renal cell carcinoma.
Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumours. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. α-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate and glucose-1-phosphate contributed most to the tumour/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumour versus normal samples. Data on metastasized tumours suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid and myoinositol, provide leads for the characterization of novel pathways in RCC.


Dose-response relation between exposure to two types of hand-arm vibration and sensorineural perception of vibration.
31 railway workers and 32 lumberjacks were examined to compare the dose-response relation between the exposure to two types of hand-arm vibration and the sensory disturbances in peripheral nerves as evaluated by the vibration perception thresholds (VPTs). Clinical examinations were carried out that included measurements of the VPTs, and electroneuromyography (ENMG), and an inquiry to confirm the use of vibrating tools. Diseases of the central nervous system and neuropathies were checked by inquiry and a clinical examination, diabetes was excluded by a blood sample analysis, and the subjects with carpal tunnel syndrome confirmed with ENMG were excluded from the study. Lifetime use of hand held tamping machines (railway workers) and chain saws (lumberjacks) had a significant correlation with the VPTs at frequencies from 32 to 500 Hz. The increase of the VPTs (250 Hz) in relation to use of vibrating tools was 1.8-fold higher on average in the whole group and 2.3-fold higher in the young (< 45) railway workers who had used hand held tamping machines, than in the corresponding groups of lumberjacks, who had used chain saws, whereas the frequency weighted acceleration of vibration in tamping machines was fourfold. There was a significant dose-response relation between the exposure to hand-arm vibration and the VPTs. The VPTs as a function of the frequency weighted acceleration of vibration and the exposure to vibration gave promising results for assessment of the risk of damage to sensory nerves induced by vibration.


Permanent education as an inalienable responsibility of health councils: the current scenario in the Unified Health System.
To verify whether health councils in Brazil carry out permanent education activities for municipal, state and federal district councilors. This was a cross-sectional study with secondary data collection in the Health Council Monitoring System (Sistema de Acompanhamento dos Conselhos de Saúde - Siacs) from May to August 2017. The Siacs is publicly accessible and available on the internet. It provides data from thousands of health councils throughout Brazil. Analysis and interpretation of the data were based on the literature and the enacted legislation, particularly Resolution 453/2012 and the National Policy of Permanent Education for Social Control in the Unified Health System (Política Nacional de Educação Permanente para o Controle Social no Sistema Único de Saúde). Despite the fact that Resolution 453/2012 establishes the deliberation, elaboration, support and promotion of permanent education for social control as functions of the councils (in accordance with the guidelines of the National Policy of Permanent Education), approximately 40% of councils do not carry out permanent education. It is necessary to strengthen the role of health councils in the elaboration of educational initiatives across the national territory. This includes the allocation of financial resources to increase access to and participation in these initiatives, which would strengthen social control in the Unified Health System. This study emphasizes that the discussion of permanent education is not given sufficient attention in the agendas and routines of health councils. This compromises the effectiveness of councils' monitoring and deliberation of public health policy.


Upper Blue Nile Basin Water Budget from a Multi-Model Perspective.
Improved understanding of the water balance in the Blue Nile is of critical importance because of increasingly frequent hydroclimatic extremes under a changing climate. The intercomparison and evaluation of multiple land surface models (LSMs) associated with different meteorological forcing and precipitation datasets can offer a moderate range of water budget variable estimates. In this context, two LSMs, Noah version 3.3 (Noah3.3) and Catchment LSM version Fortuna 2.5 (CLSMF2.5) coupled with the Hydrological Modeling and Analysis Platform (HyMAP) river routing scheme are used to produce hydrological estimates over the region. The two LSMs were forced with different combinations of two reanalysis-based meteorological datasets from the Modern-Era Retrospective analysis for Research and Applications datasets (i.e., MERRA-Land and MERRA-2) and three observation-based precipitation datasets, generating a total of 16 experiments. Modeled evapotranspiration (ET), streamflow, and terrestrial water storage estimates were evaluated against the Atmosphere-Land Exchange Inverse (ALEXI) ET, in-situ streamflow observations, and NASA Gravity Recovery and Climate Experiment (GRACE) products, respectively. Results show that CLSMF2.5 provided better representation of the water budget variables than Noah3.3 in terms of Nash-Sutcliffe coefficient when considering all meteorological forcing datasets and precipitation datasets. The model experiments forced with observation-based products, the Climate Hazards group Infrared Precipitation with Stations (CHIRPS) and the Tropical Rainfall Measuring Mission (TRMM) Multi-Satellite Precipitation Analysis (TMPA), outperform those run with MERRA-Land and MERRA-2 precipitation. The results presented in this paper would suggest that the Famine Early Warning Systems Network (FEWS NET) Land Data Assimilation System incorporate CLSMF2.5 and HyMAP routing scheme to better represent the water balance in this region.


The Pentagon Copying Test and the Clock Drawing Test as Prognostic Markers in Dementia with Lewy Bodies.
To determine whether the pentagon copying test (PCT) and the clock drawing test (CDT) are associated with nursing home admission or survival in dementia with Lewy bodies (DLB). The PCT and/or the CDT were retrospectively collected from 103 clinically diagnosed probable DLB patients at a university medical center and general hospital. Patients with high versus low scores on these tests were compared. Kaplan-Meier analysis showed that patients with a low score on the PCT had a shorter time to nursing home admission than patients with a high score (log-rank χ2 = 6.1, p = 0.01). Patients with a low score on the PCT or the CDT had a shorter survival than patients with a high score (log-rank χ2 = 5.4, p = 0.02, and log-rank χ2 = 11.2, p < 0.001, respectively). Cox regression analyses showed the same associations with an HR of 2.2 (95% CI 1.2-4.1) for the PCT and an HR of 2.9 (95% CI 1.6-5.4) for the CDT. The PCT and the CDT may function as prognostic markers in DLB. This finding is clinically relevant as these tests can be applied easily in the clinical setting and can provide valuable prognostic information. Furthermore, it may improve disease management and patient selection for research purposes.


Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene.
Random monoallelic expression contributes to phenotypic variation of cells and organisms. However, the epigenetic mechanisms by which individual alleles are randomly selected for expression are not known. Taking cues from chromatin signatures at imprinted gene loci such as the insulin-like growth factor 2 gene 2 (IGF2), we evaluated the contribution of CTCF, a zinc finger protein required for parent-of-origin-specific expression of the IGF2 gene, as well as a role for allele-specific association with DNA methylation, histone modification and RNA polymerase II. Using array-based chromatin immunoprecipitation, we identified 293 genomic loci that are associated with both CTCF and histone H3 trimethylated at lysine 9 (H3K9me3). A comparison of their genomic positions with those of previously published monoallelically expressed genes revealed no significant overlap between allele-specifically expressed genes and colocalized CTCF/H3K9me3. To analyze the contributions of CTCF and H3K9me3 to gene regulation in more detail, we focused on the monoallelically expressed IGF2BP1 gene. In vitro binding assays using the CTCF target motif at the IGF2BP1 gene, as well as allele-specific analysis of cytosine methylation and CTCF binding, revealed that CTCF does not regulate mono- or biallelic IGF2BP1 expression. Surprisingly, we found that RNA polymerase II is detected on both the maternal and paternal alleles in B lymphoblasts that express IGF2BP1 primarily from one allele. Thus, allele-specific control of RNA polymerase II elongation regulates the allelic bias of IGF2BP1 gene expression. Colocalization of CTCF and H3K9me3 does not represent a reliable chromatin signature indicative of monoallelic expression. Moreover, association of individual alleles with both active (H3K4me3) and silent (H3K27me3) chromatin modifications (allelic bivalent chromatin) or with RNA polymerase II also fails to identify monoallelically expressed gene loci. The selection of individual alleles for expression occurs in part during transcription elongation.


Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis.
Junctional adhesion molecule (JAM)-A expressed in endothelial, epithelial, and blood cells can regulate permeability and leukocyte extravasation. Atherosclerosis develops at sites of disturbed flow in large arteries, but the mechanisms guiding inflammatory cells into these predilection sites remain unknown. To characterize cell-specific functions of JAM-A in atherosclerosis, we used apolipoprotein E-deficient mice with a somatic or endothelium-specific deficiency in JAM-A and bone marrow chimeras with JAM-A-deficient leukocytes. We show that impaired JAM-A expression in endothelial cells reduced mononuclear cell recruitment into the arterial wall and limited atherosclerotic lesion formation in hyperlipidemic mice. In contrast, JAM-A deficiency in bone marrow cells impeded monocyte de-adhesion, thereby increasing vascular permeability and lesion formation, whereas somatic JAM-A deletion revealed no significant effects. Regions with disturbed flow displayed a focal enrichment and luminal redistribution of endothelial JAM-A and were preferentially protected by its deficiency. The functional expression and redistribution of endothelial JAM-A was increased by oxidized low-density lipoprotein, but confined by atheroprotective laminar flow through an upregulation of microRNA (miR)-145, which repressed JAM-A. Our data identify endothelial JAM-A as an important effector molecule integrating atherogenic conditions to direct inflammatory cell entry at predilection sites of atherosclerosis.


Triclabendazole and its two main metabolites lack activity against Schistosoma mansoni in the mouse model.
Some have claimed that triclabendazole, a safe and efficacious drug for the treatment of fascioliasis, also exhibits antischistosomal properties, but results are conflicting. We assessed the effect of triclabendazole and its two main metabolites against two different strains of Schistosoma mansoni harbored in mice. Low worm burden reductions (18.6-35.9%) were observed in mice infected with an Egyptian strain of S. mansoni and treated with a single dose of 120 mg/kg 3 days before infection or single/double doses of 120-200 mg/kg 7 weeks after infection. Triclabendazole failed to significantly reduce hepatic and intestinal tissue egg loads, and eggs of all developmental stages were observed. Administration of 400 mg/kg of either triclabendazole, triclabendazole sulphone, or triclabendazole sulfphoxide to mice infected with a Liberian strain of S. mansoni resulted in worm burden reductions < 10%. In comparison, high worm burden reductions (82-100%) were observed in S. mansoni-infected mice treated with single oral doses of 400, 500, or 500 mg/kg twice a day praziquantel, regardless of the S. mansoni strain. We conclude that triclabendazole and its main metabolites display weak and inconsistent schistosomicidal activities.


Highly efficient, high-power, broadly tunable, cryogenically cooled and diode-pumped Yb:CaF2.
We present a high-power diode-pumped Yb:CaF(2) laser operating at cryogenic temperature (77 K). A laser output power of 97 W at 1034 nm was extracted for a pump power of 245 W. The corresponding global extraction efficiency (versus absorbed pump power) is 65%. The laser small signal gain was found to be equal to 3.1. The laser wavelength could be tuned between 990 and 1052 nm with peaks that correspond well to the structure of the gain cross-section spectra registered at low temperature.


Sequential reductive and oxidative biodegradation of chloroethenes stimulated in a coupled bioelectro-process.
This article for the first time demonstrates successful application of electrochemical processes to stimulate sequential reductive/oxidative microbial degradation of perchloroethene (PCE) in mineral medium and in contaminated groundwater. In a flow-through column system, hydrogen generation at the cathode supported reductive dechlorination of PCE to cis-dichloroethene (cDCE), vinyl chloride (VC), and ethene (ETH). Electrolytically generated oxygen at the anode allowed subsequent oxidative degradation of the lower chlorinated metabolites. Aerobic cometabolic degradation of cDCE proved to be the bottleneck for complete metabolite elimination. Total removal of chloroethenes was demonstrated for a PCE load of approximately 1.5 μmol/d. In mineral medium, long-term operation with stainless steel electrodes was demonstrated for more than 300 days. In contaminated groundwater, corrosion of the stainless steel anode occurred, whereas DSA (dimensionally stable anodes) proved to be stable. Precipitation of calcareous deposits was observed at the cathode, resulting in a higher voltage demand and reduced dechlorination activity. With DSA and groundwater from a contaminated site, complete degradation of chloroethenes in groundwater was obtained for two months thus demonstrating the feasibility of the sequential bioelectro-approach for field application.


Evolution of Plasmid Mobility: Origin and Fate of Conjugative and Nonconjugative Plasmids.
Conjugation drives the horizontal transfer of adaptive traits across prokaryotes. One-fourth of the plasmids encode the functions necessary to conjugate autonomously, the others being eventually mobilizable by conjugation. To understand the evolution of plasmid mobility, we studied plasmid size, gene repertoires, and conjugation-related genes. Plasmid gene repertoires were found to vary rapidly in relation to the evolutionary rate of relaxases, for example, most pairs of plasmids with 95% identical relaxases have fewer than 50% of homologs. Among 249 recent transitions of mobility type, we observed a clear excess of plasmids losing the capacity to conjugate. These transitions are associated with even greater changes in gene repertoires, possibly mediated by transposable elements, including pseudogenization of the conjugation locus, exchange of replicases reducing the problem of incompatibility, and extensive loss of other genes. At the microevolutionary scale of plasmid taxonomy, transitions of mobility type sometimes result in the creation of novel taxonomic units. Interestingly, most transitions from conjugative to mobilizable plasmids seem to be lost in the long term. This suggests a source-sink dynamic, where conjugative plasmids generate nonconjugative plasmids that tend to be poorly adapted and are frequently lost. Still, in some cases, these relaxases seem to have evolved to become efficient at plasmid mobilization in trans, possibly by hijacking multiple conjugative systems. This resulted in specialized relaxases of mobilizable plasmids. In conclusion, the evolution of plasmid mobility is frequent, shapes the patterns of gene flow in bacteria, the dynamics of gene repertoires, and the ecology of plasmids.


The neural correlates of grammatical gender: an fMRI investigation.
In an fMRI experiment, subjects saw a written noun and made three distinct decisions in separate sessions: Is its grammatical gender masculine or feminine (grammatical feature task)? Is it an animal or an artifact (semantic task)? Does it contain a /tch/ or a /k/ sound (phonological task)? Relative to the other experimental conditions, the grammatical feature task activated areas of the left middle and inferior frontal gyrus and of the left middle and inferior temporal gyrus. These activations fit in well with neuropsychological studies that document the correlation between left frontal lesions and damage to morphological processes in agrammatism, and the correlation between left temporal lesions and failure to access lexical representations in anomia. Taken together, these data suggest that grammatical gender is processed in a left frontotemporal network. In addition, the observation that the grammatical feature task and the phonology task activated neighboring but distinct regions of the left frontal lobe provides a plausible neuroanatomical basis for the systematic occurrence of phonological errors in aphasic subjects with morphological deficits.


Increasing adolescent firearm homicides and racial disparities following Florida's 'Stand Your Ground' self-defence law.
Establishing whether specific laws impact rates of firearm homicide in adolescents is critical for identifying opportunities to reduce preventable adolescent death. We evaluated Florida's Stand Your Ground law, enacted October 2005, using an interrupted time series design from 1999 to 2017. We used segmented quasi-Poisson regression to model underlying trends in quarterly rates of adolescent (15-19 years) firearm homicide in Florida and disaggregated by race (Black/White). We used synthetic and negative controls (firearm suicide) to address time-varying confounding. Before Florida's Stand Your Ground law, the mean quarterly rate was 1.53 firearm homicides per 100 000 adolescents. Black adolescents comprised 63.5% of all adolescent firearm homicides before and 71.8% after the law. After adjusting for trends, the law was associated with a 44.6% increase in adolescent firearm homicide. Our analysis indicates that Florida's Stand Your Ground is associated with a significant increase in firearm homicide and may also exacerbate racial disparities.


Fatty acids of Treponema pallidum and Borrelia burgdorferi lipoproteins.
A fundamental ultrastructural feature shared by the spirochetal pathogens Treponema pallidum subsp. pallidum (T. pallidum) and Borrelia burgdorferi, the etiological agents of venereal syphilis and Lyme disease, respectively, is that their most abundant membrane proteins contain covalently attached fatty acids. In this study, we identified the fatty acids covalently bound to lipoproteins of B. burgdorferi and T. pallidum and examined potential acyl donors to these molecules. Palmitate was the predominant fatty acid of both B. burgdorferi and T. pallidum lipoproteins. T. pallidum lipoproteins also contained substantial amounts of stearate, a fatty acid not typically prevalent in prokaryotic lipoproteins. In both spirochetes, the fatty acids of cellular lipids differed from those of their respective lipoproteins. To characterize phospholipids in these organisms, spirochetes were metabolically labeled with [3H]palmitate or [3H]oleate; B. burgdorferi contained only phosphatidylglycerol and phosphatidylcholine, while T. pallidum contained phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and cardiolipin. Although palmitate predominated in the lipoproteins, there were no apparent differences in the incorporation of these two fatty acids into phospholipids (putative acyl donors). Phospholipase A1 and A2 digestion of phosphatidylcholine from B. burgdorferi and T. pallidum labeled with either [3H]palmitate or [3H]oleate also revealed that neither fatty acid was incorporated preferentially into the 1 and 2 positions (potential acyl donor sites) of the glycerol backbone. The combined findings suggest that fatty acid utilization during lipoprotein synthesis is determined largely by the fatty acid specificities of the lipoprotein acyl transferases. These findings also provide the basis for ongoing efforts to elucidate the relationship between lipoprotein acylation and the physiological functions and inflammatory activities of these molecules.


Physical activity in patients with heart failure: barriers and motivations with special focus on sex differences.
Adherence to recommendations for physical activity is low in both male and female patients with heart failure (HF). Men are more physically active than women. In order to successfully promote physical activity, it is therefore essential to explore how much and why HF patients are physically active and if this is related to sex. The aim of this study was therefore to evaluate physical activity in HF patients, to describe the factors related to physical activity, and to examine potential barriers and motivations to physical activity with special focus on sex differences. The study had a cross-sectional survey design. HF patients living at home received a questionnaire during May-July 2014, with questions on physical activity (from the Short Form-International Physical Activity Questionnaire), and potential barriers and motivations to physical activity. A total of 154 HF patients, 27% women, with a mean age of 70±10 were included. In total, 23% of the patients reported a high level of physical activity, 46% a moderate level, and 34% a low level. Higher education, self-efficacy, and motivation were significantly associated with a higher amount of physical activity. Symptoms or severity of the disease were not related to physical activity. All the potential barriers to exercise were reported to be of importance. Psychological motivations were most frequently rated as being the most important motivation (41%) to be physically active. Physical motivations (33%) and social motivations were rated as the least important ones (22%). Women had significantly higher total motivation to be physically active. These differences were found in social, physical, and psychological motivations. One-third of the HF patients had a low level of physical activity in their daily life. Severity of the disease or symptoms were not related, whereas level of education, exercise self-efficacy, and motivation were important factors to take into account when advising a HF patient about physical activity. Women reported higher motivation to be physically active than men, but there was no difference in the reported level of physical activity.


The relevance of health state after treatment in prioritising between different patients.
In QALY-thinking, an activity that takes N people from a bad state (including 'dying') to the state of healthy for X years should have priority over an activity that takes N other people from the same bad state to a state of moderate illness for the same number of years (given equal costs). An empirical study indicates that this view may not be shared by the general public in Norway. Subjects tended to emphasise equality in value of life and in entitlement to treatment rather than level of health after treatment. The relevance of costs per QALY in prioritising between different health care programmes in Norway is thereby brought in to doubt. While the sample in the study is too small to support firm policy conclusions, the results should contribute to an increased interest among health economists in actually measuring people's ethical preferences in matters of prioritising, rather than taking it for granted that their own values are shared by the general public.


Transversal ultrahigh-resolution polarizationsensitive optical coherence tomography for strain mapping in materials.
Optical coherence tomography (OCT) and its extension, polarization-sensitive (PS-)OCT, are techniques for contactless and nondestructive imaging of internal structures. In this work, we apply PS-OCT for material characterization. We use a transversal scanning, ultra-high resolution (UHR-)PS-OCT setup providing cross-sectional as well as inplane information about the internal microstructure, the birefringence and the orientation of the optical axis within the material. We perform structural analysis and strain-mapping for different samples: we show the necessity of UHR imaging for a highly strained elastomer sample, and we discuss the effect of large birefringence on the PS-OCT images. Furthermore, we investigate high-aspect ratio photoresist moulds for the production of microelectromechanical parts (MEMS), demonstrating that transversal UHR-PSOCT is a promising tool for non-destructive strain-mapping.


Ankyrin repeat and suppressor of cytokine signaling box containing protein-10 is associated with ubiquitin-mediated degradation pathways in trabecular meshwork cells.
Ankyrin repeat and suppressor of cytokine signaling (SOCS) box containing protein-10 (ASB10) was recently identified as a gene that causes primary open-angle glaucoma. Here, we investigated endogenous ASB10 protein expression in human trabecular meshwork (HTM) cells to provide the first clues to the biologic function of this protein. Primary HTM cells were cultured and immunostained with anti-ASB10 and various biomarkers of the ubiquitin-mediated proteasomal and autophagy-lysosomal degradation pathways. Cells were imaged with confocal and high-resolution structured illumination microscopy. Colocalization was quantified using Imaris Bitplane software, which generated a Pearson's correlation coefficient value. Coimmunoprecipitation of ASB10-transfected cells was performed. Immunofluorescence and confocal analysis showed that ASB10 was localized in intracellular structures in HTM cells. Two populations were observed: small, spherical vesicles and larger, less abundant structures. In the ASB10-silenced cells, the number of large structures was significantly decreased. ASB10 partially colocalized with biomarkers of the ubiquitin-mediated proteasomal pathway including ubiquitin and the α4 subunit of the 20S proteasome. However, ASB10 itself was not ubiquitinated. ASB10 also colocalized with numerous biomarkers of specific autophagic structures: aggresomes (histone deacetylase 6 [HDAC6] and heat shock protein 70 [HSP70]), autophagosomes (light chain 3 [LC3] and p62), amphisomes (Rab7), and lysosomes (lysosomal-associated membrane protein 1 [LAMP1]). Pearson coefficients indicated strong colocalization of large ASB10-stained structures with the α4 subunit of the 20S proteasome, K48 and K63-linked ubiquitin antibodies, p62, HSP70, and HDAC6 (Pearson's range, 0.59-0.82). Coimmunoprecipitation assays showed a positive interaction of ASB10 with HSP70 and with the α4 subunit of the 20S proteasome. Super-resolution structured illumination confocal microscopy suggested that the smaller ASB10-stained vesicles aggregated into the larger structures, which resembled aggresome-like induced structures. Treatment of HTM cells with an autophagy activator (MG132) or inhibitors (wortmannin, bafilomycin A1) significantly increased and decreased the number of small ASB10-stained vesicles, respectively. No discernible differences in the colocalization of large ASB10-stained structures with ubiquitin or HDAC6 were observed between dermal fibroblasts derived from a normal individual and a patient with primary open-angle glaucoma carrying a synonymous ASB10 mutation. Our evidence suggests that ASB10 may play a role in ubiquitin-mediated degradation pathways in TM cells.


Permanent carbon dioxide storage in deep-sea sediments.
Stabilizing the concentration of atmospheric CO(2) may require storing enormous quantities of captured anthropogenic CO(2) in near-permanent geologic reservoirs. Because of the subsurface temperature profile of terrestrial storage sites, CO(2) stored in these reservoirs is buoyant. As a result, a portion of the injected CO(2) can escape if the reservoir is not appropriately sealed. We show that injecting CO(2) into deep-sea sediments below [corrected] 3,000-m water depth and a few hundred meters of sediment provides permanent geologic storage even with large geomechanical perturbations. At the high pressures and low temperatures common in deep-sea sediments, CO(2) resides in its liquid phase and can be denser than the overlying pore fluid, causing the injected CO(2) to be gravitationally stable. Additionally, CO(2) hydrate formation will impede the flow of CO(2)(l) and serve as a second cap on the system. The evolution of the CO(2) plume is described qualitatively from the injection to the formation of CO(2) hydrates and finally to the dilution of the CO(2)(aq) solution by diffusion. If calcareous sediments are chosen, then the dissolution of carbonate host rock by the CO(2)(aq) solution will slightly increase porosity, which may cause large increases in permeability. Karst formation, however, is unlikely because total dissolution is limited to only a few percent of the rock volume. The total CO(2) storage capacity within the 200-mile economic zone of the U.S. coastline is enormous, capable of storing thousands of years of current U.S. CO(2) emissions.


Macrophage activation syndrome as a complication of rheumatologic disorders, a report from Iran.
The objective was to evaluate the clinical and laboratory manifestations and outcomes of the MAS cases in the context of systemic juvenile idiopathic arthritis (SJIA), systemic lupus erythematosus (SLE), Kawasaki disease, poly-articular juvenile idiopathic arthritis (PJIA). Twenty consecutive patients diagnosed with MAS between 2005 and 2016 entered the study. The cases were divided into two groups: in the first, MAS emerged in the context of a previously diagnosed rheumatologic disease, while in the second, MAS was the first presentation of a rheumatologic disease. In the other classification, the cases were divided into recurrent and non-recurrent cases. Laboratory data were recorded at three times: before MAS attack, during MAS attack, and 1 month after discharge from hospital. Nineteen cases with the median age of 5.9 (3.6-10) years entered the study. Four cases (21.1%) showed recurrent attacks of MAS. MAS was the first presentation of disease in 10 cases. The median age of the patients in the underlying disease group (10 years) was significantly higher than in the first presentation group [4.5(1.7-6.1) years, p=0.003]. The median fibrinogen value during MAS attack in the underlying disease group (601 mg/ dL) was also significantly higher than in the first presentation group (174 mg/dL, p=0.038). The platelet count during MAS attack in the recurrent group (30,500/microliter) was significantly lower than in the non-recurrent group (135,000/microliter, p=0.042). Our series of MAS cases demonstrated an overview of the symptoms, signs, laboratory manifestations, treatment, and prognosis of these cases. The higher median fibrinogen in MAS in the underlying disease group revealed that a decreasing level of fibrinogen in chronic disease is more significant than a single cut off value. Indeed, the lower platelet count in the recurrent MAS group may indicate greater platelet consumption due to organomegaly. Early diagnosis and treatment may save the patients' lives.


Surgical anatomy of the trachea.
Anatomy as the foundation of surgery is a concept no better exemplified than by the history of tracheal surgery. Incremental advancements in our understanding of the trachea's position, structure, blood supply and adjacent organs each allowed for stepwise improvements in the thoracic surgeon's ability to address upper airway disease. As such, the mastery of tracheal anatomy is fundamental to those clinicians responsible for treating such ailments. In this article, tracheal anatomy is reviewed and points critical to the thoracic surgeon are highlighted. The structure and location of the trachea, the blood supply to the trachea, and the trachea's spatial relationship to critical mediastinal organs are presented. This material provides the groundwork for understanding all aspects of tracheal surgery today.


Aggregation kinetics of SERS-active nanoparticles in thermally stirred sessile droplets.
The aggregation kinetics of silver nanoparticles in sessile droplets were investigated both experimentally and through numerical simulations as a function of temperature gradient and evaporation rate, in order to determine the hydrodynamic and aggregation parameters that lead to optimal surface-enhanced Raman spectroscopic (SERS) detection. Thermal gradients promote effective stirring within the droplet. The aggregation reaction ceases when the solvent evaporates forming a circular stain consisting of a high concentration of silver nanoparticle aggregates, which can be interrogated by SERS leading to analyte detection and identification. We introduce the aggregation parameter, Γa ≡ τ(evap)/τ(a), which is the ratio of the evaporation to the aggregation time scales. For a well-stirred droplet, the optimal condition for SERS detection was found to be Γ(a,opt) = kc(NP)τ(evap) ≈ 0.3, which is a product of the dimerization rate constant (k), the concentration of nanoparticles (cNP), and the droplet evaporation time (τ(evap)). Near maximal signal (over 50% of maximum value) is observed over a wide range of aggregation parameters 0.05 < Γa < 1.25, which also defines the time window during which trace analytes can be easily measured. The results of the simulation were in very good agreement with experimentally acquired SERS spectra using gas-phase 1,4-benzenedithiol as a model analyte.


Wavelet-based multi-resolution statistics for optical imaging signals: Application to automated detection of odour activated glomeruli in the mouse olfactory bulb.
Optical imaging techniques offer powerful solutions to capture brain networks processing in animals, especially when activity is distributed in functionally distinct spatial domains. Despite the progress in imaging techniques, the standard analysis procedures and statistical assessments for this type of data are still limited. In this paper, we perform two in vivo non-invasive optical recording techniques in the mouse olfactory bulb, using a genetically expressed activity reporter fluorescent protein (synaptopHfluorin) and intrinsic signals of the brain. For both imaging techniques, we show that the odour-triggered signals can be accurately parameterized using linear models. Fitting the models allows us to extract odour specific signals with a reduced level of noise compared to standard methods. In addition, the models serve to evaluate statistical significance, using a wavelet-based framework that exploits spatial correlation at different scales. We propose an extension of this framework to extract activation patterns at specific wavelet scales. This method is especially interesting to detect the odour inputs that segregate on the olfactory bulb in small spherical structures called glomeruli. Interestingly, with proper selection of wavelet scales, we can isolate significantly activated glomeruli and thus determine the odour map in an automated manner. Comparison against manual detection of glomeruli shows the high accuracy of the proposed method. Therefore, beyond the advantageous alternative to the existing treatments of optical imaging signals in general, our framework propose an interesting procedure to dissect brain activation patterns on multiple scales with statistical control.


A new group of cosmopolitan bacteriophages induce a carrier state in the pandemic strain of Vibrio parahaemolyticus.
A clonal population of pathogenic Vibrio parahaemolyticus O3 : K6 serovar has spread in coastal waters, causing outbreaks worldwide since 1996. Bacteriophage infection is one of the main factors affecting bacterial strain concentration in the ocean. We studied the occurrence and properties of phages infecting this V. parahaemolyticus pandemic strain in coastal waters. Analysing 143 samples, phages were found in 13. All isolates clustered in a closely related group of podophages with at least 90% nucleotide sequence identity in three essential genes, despite distant geographical origins. These bacteriophages were able to multiply on the V. parahaemolyticus pandemic strain, but the impact on host concentration and subsequent growth was negligible. Infected bacteria continued producing the phage but were not lysogenized. The phage genome of prototype strain VP93 is 43 931 nucleotides and contains 337 bp direct terminal repeats at both ends. VP93 is the first non-Pseudomonas phage related to the PhiKMV-like subgroup of the T7 supergroup. The lack of a major effect on host growth suggests that these phages exert little control on the propagation of the pandemic strain in the environment. This form of phage growth can be modelled if phage-sensitive and -resistant cells that convert to each other with a high frequency are present in clonal cultures of pandemic V. parahaemolyticus.


Essential oil composition and antibacterial activity of Pteridium aquilinum (L.) Kuhn.
The present work aims to study the chemical composition of Pteridium aquilinum (L.) Kuhn essential oil and its antibacterial activity against three important phytopathogenic Gram-negative bacteria: Erwinia amylovora, Pectobacterium carotovorum subsp. caroto-vorum, and Pseudomonas savastanoi pv. savastanoi. The chemical composition of P. aquilinum L. essential oil produced by hydrodistillation was determined by gas chromatography-mass spectrometry. The antibacterial activity was tested using disk diffusion method and by determination of minimum inhibitory concentration values. The major components were linalool (10.29%), carvacrol (8.15%), benzaldehyde (5.95%), 2-undecanone (5.32%), and cuminaldehyde (4.57%). The essential oil tested revealed a powerful antibacterial effect against all tested strains, with inhibition zone diameters ranging from 32.0 ± 0.58 to 33.7 ± 0.88 mm. P. aquilinum EO contained 32.86% of oxygenated monoterpenes, which are known for their very powerful antimicrobial activities. The minimum inhibitory concentration values showed that P. aquilinum essential oil has very strong activity against E. amylovora (0.625 ul/ml), followed by P. carotovorum subsp. carotovorum (2.50 ul/ml) and P. savastanoi pv. savastanoi (5.00 ul/ml). The results obtained could contribute to the development of new potential agents for the control of bacterial diseases.


Enhanced plasma ghrelin levels in Helicobacter pylori-colonized, interleukin-1-receptor type 1-homozygous knockout (IL-1R1-/-) mice.
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor, and it plays a role in stimulating the growth hormone secretion, food intake, body weight gain and gastric motility. Eradication of Helicobacter pylori (H pylori) was shown to be associated with increase of the body weight. On the other hand, H pylori infection evokes the release of gastric IL-1beta. The present study was designed to investigate the involvement of the gastric IL-1 signal in the ghrelin dynamics in H pylori-colonized mice. Twelve-week-old female IL-1-receptor type 1-homozygous-knockout mice (IL-1R1(-/-)) and their wild-type littermates (WT) were orally inoculated with H pylori (Hp group), while other cohorts received oral inoculation of culture medium (Cont group). Thirteen weeks after the inoculation, the mice were examined. The plasma and stomach ghrelin levels and the gastric preproghrelin mRNA were measured. Although the WT mice with H pylori infection showed a significantly decreased body weight as compared with that of the animals without H pylori infection, H pylori infection did not influence the body weight of the IL-1R1-knockout (IL-1R1(-/-)) mice. In the H pylori-infected IL-1R1(-/-) mice, the total and active ghrelin levels in the plasma were significantly increased, and the gastric ghrelin level was decreased. No significant differences were noted in the gastric preproghrelin mRNA expression. Ghrelin secretion triggered by H pylori infection might be suppressed by IL-1beta, the release of which is also induced by the infection, resulting in the body weight loss of mice with H pylori infection.


Improving the implementation of health workforce policies through governance: a review of case studies.
Responsible governance is crucial to national development and a catalyst for achieving the Millennium Development Goals. To date, governance seems to have been a neglected issue in the field of human resources for health (HRH), which could be an important reason why HRH policy formulation and implementation is often poor. This article aims to describe how governance issues have influenced HRH policy development and to identify governance strategies that have been used, successfully or not, to improve HRH policy implementation in low- and middle-income countries (LMIC). We performed a descriptive literature review of HRH case studies which describe or evaluate a governance-related intervention at country or district level in LMIC. In order to systematically address the term 'governance' a framework was developed and governance aspects were regrouped into four dimensions: 'performance', 'equity and equality', 'partnership and participation' and 'oversight'. In total 16 case studies were included in the review and most of the selected studies covered several governance dimensions. The dimension 'performance' covered several elements at the core of governance of HRH, decentralization being particularly prominent. Although improved equity and/or equality was, in a number of interventions, a goal, inclusiveness in policy development and fairness and transparency in policy implementation did often not seem adequate to guarantee the corresponding desirable health workforce scenario. Forms of partnership and participation described in the case studies are numerous and offer different lessons. Strikingly, in none of the articles was 'partnerships' a core focus. A common theme in the dimension of 'oversight' is local-level corruption, affecting, amongst other things, accountability and local-level trust in governance, and its cultural guises. Experiences with accountability mechanisms for HRH policy development and implementation were lacking. This review shows that the term 'governance' is neither prominent nor frequent in recent HRH literature. It provides initial lessons regarding the influence of governance on HRH policy development and implementation. The review also shows that the evidence base needs to be improved in this field in order to better understand how governance influences HRH policy development and implementation. Tentative lessons are discussed, based on the case studies.


Immunophenotypic criteria for the diagnosis of non-Hodgkin's lymphoma.
This study examines the immunohistologic profiles of a large series of histologically proven benign and malignant lymphoproliferative processes in order to define immunophenotypic criteria useful in the diagnosis of non-Hodgkin's lymphoma. Using a method of analysis relying solely on immunoarchitectural features of a given case, the authors were able to define immunologic criteria capable of differentiating benign from malignant lymphoid processes independent from conventional morphologic analysis. In general, these criteria involved identification of abnormal expression or loss of antigens in B- and T-lineage populations. Among B-lineage populations the following features were associated with malignant histology: 1) light-chain-restricted B lineage, 2) light chain -B lineage, 3) Leu-1+ B lineage, 4) L60+ B lineage, 5) 41H+, Ki-67+ B lineage, 6) loss of pan-B antigens, and 7) LFA-1-B lineage. Among T-cell populations outside the thymus, phenotypes associated with malignancy included 1) loss of pan-T antigens (including loss of the beta chain of the T-cell antigen receptor), 2) coexpression or loss of T-subset antigens, 3) Leu-6+ T-lineage, and 4) MB-1+ T lineage. Application of these criteria to a series of nearly 500 cases of lymphoma indicated that over 90% of B-lineage and about 80% of T-lineage neoplasms manifested immunophenotypic abnormalities that could distinguish them from benign, reactive lymphoid processes. It is concluded that immunophenotypic analysis of lymphoproliferative lesions is sufficiently sensitive and specific to confirm the histologic diagnosis of lymphoma in the vast majority of cases seen in clinical practice. Furthermore, in difficult cases or those with limited material or poor histology, immunophenotypic analysis may be the only means of making a definitive diagnosis.


Ripple Effects of Surface Acting: A Diary Study among Dual-Earner Couples.
This study among 80 dual-earner couples examines the ripple effects of emotional labour - on a daily basis. Specifically, we propose that employees who engage in surface acting at work drain their energetic resources, and undermine their own relationship satisfaction. Drawing upon conservation of resources (COR) theory, we predicted that work-related exhaustion would mediate the relationship between surface acting at work and at home. In addition, we hypothesized that employees' emotional energy in the evening would mediate the relationship between surface acting at home and (actor and partner) satisfaction with the relationship. Participants filled in a survey and a diary booklet during five consecutive working days (N = 80 couples, N = 160 participants x 5 days, N = 800 occasions). The hypotheses were tested with multilevel analyses, using the actor-partner interdependence model. Results showed that daily work-related exhaustion partially mediated the relationship between daily surface acting at work and at home. As hypothesized, daily surface acting at home influenced own and partner's daily relationship satisfaction through reduced daily emotional energy. These findings offer support for COR theory, and have important implications for organizations that encourage emotion regulation.


The relationship between distortion product otoacoustic emissions and extended high-frequency audiometry in tinnitus patients. Part 1: normally hearing patients with unilateral tinnitus.
The aim of this study was to evaluate distortion product otoacoustic emissions (DPOAEs) and extended high-frequency (EHF) thresholds in a control group and in patients with normal hearing sensitivity in the conventional frequency range and reporting unilateral tinnitus. Seventy patients were enrolled in the study: 47 patients with tinnitus in the left ear (Group 1) and 23 patients with tinnitus in the right ear (Group 2). The control group included 60 otologically normal subjects with no history of pathological tinnitus. Pure-tone thresholds were measured at all standard frequencies from 0.25 to 8 kHz, and at 10, 12.5, 14, and 16 kHz. The DPOAEs were measured in the frequency range from approximately 0.5 to 9 kHz using the primary tones presented at 65/55 dB SPL. The left ears of patients in Group 1 had higher median hearing thresholds than those in the control subjects at all 4 EHFs, and lower mean DPOAE levels than those in the controls for almost all primary frequencies, but significantly lower only in the 2-kHz region. Median hearing thresholds in the right ears of patients in Group 2 were higher than those in the right ears of the control subjects in the EHF range at 12.5, 14, and 16 kHz. The mean DPOAE levels in the right ears were lower in patients from Group 2 than those in the controls for the majority of primary frequencies, but only reached statistical significance in the 8-kHz region. Hearing thresholds in tinnitus ears with normal hearing sensitivity in the conventional range were higher in the EHF region than those in non-tinnitus control subjects, implying that cochlear damage in the basal region may result in the perception of tinnitus. In general, DPOAE levels in tinnitus ears were lower than those in ears of non-tinnitus subjects, suggesting that subclinical cochlear impairment in limited areas, which can be revealed by DPOAEs but not by conventional audiometry, may exist in tinnitus ears. For patients with tinnitus, DPOAE measures combined with behavioral EHF hearing thresholds may provide additional clinical information about the status of the peripheral hearing.


Efficacy and safety of oral lactoferrin supplementation in combination with rHuEPO-beta for the treatment of anemia in advanced cancer patients undergoing chemotherapy: open-label, randomized controlled study.
Advanced-stage cancer patients often suffer from anemia that closely resembles the anemia of chronic inflammatory diseases characterized by specific changes in iron homeostasis and absorption. i.v. iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. We report the results of an open-label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with rHuEPO, for the treatment of anemia in a population of 148 advanced cancer patients undergoing chemotherapy. All patients received s.c. rHuEPO-beta, 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg i.v. weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C-reactive protein, or erythrocyte sedimentation rate were observed between arms. In contrast, ferritin decreased in the lactoferrin arm whereas it increased in the i.v. iron arm. In conclusion, these results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy.


Multiwatt-power highly-coherent compact single-frequency tunable vertical-external-cavity-surface-emitting-semiconductor-laser.
We demonstrate high power (2.1W) low noise single frequency operation of a tunable compact verical-external-cavity surface-emitting- laser exhibiting a high beam quality. We took advantage of thermal lens-based stability to develop a short (3-10 mm) plano-plano external cavity without any intracavity filter. The semiconductor structure emitting at 1microm is optically pumped by a 8W commercial 808 nm multimode diode laser at large incidence angle. For heat management purpose the GaAs-based VECSEL membrane was bonded on a SiC substrate. We measured a low divergence quasi-circular TEM00 beam (M2 = 1.2) close to diffraction limit, with a linear light polarization (>30 dB).We simulated the steady state laser beam of this unstable cavity using Fresnel diffraction. The side mode suppression ratio is > 45 dB. The free running laser linewidth is 37 kHz limited by pump induced thermal fluctuations. Thanks to this high-Q external cavity approach, the frequency noise is low and the dynamics is in the relaxation-oscillation-free regime, exhibiting low intensity noise (< 0.1%), with a cutoff frequency approximately 41MHz above which the shot noise level is reached. The key parameters limiting the laser power and coherence are studied. This design/properties can be extended to other wavelengths.


Applications of isoelectric focusing in forensic serology.
The typing of certain polymorphic proteins present in human body fluids is an important aspect of the analysis of serological evidence. This is particularly true when dealing with evidence related to violent criminal activity such as homocide, assault, or rape. Until recently, the routine analysis of the genetic polymorphisms of interest relied upon conventional electrophoretic techniques such as horizontal starch or agarose slab gel or both, cellulose acetate, and vertical polyacrylamide gradient gel methods. These techniques adequately separate a limited number of common variants. In some cases, these methods are still those of choice. However, as a result of the nature of the conventional approach, problems with time required for analysis, resolution, diffusion of bands, sensitivity of protein detection, and cost are often encountered. Isoelectric focusing (IEF) offers an effective alternative to conventional electrophoresis for genetic marker typing. This method exploits the isoelectric point of allelic products rather than charge-to-mass ratio in a particular pH environment. The advantages of employing IEF include: reduction of time of analysis, increased resolution of protein bands, the possibility of subtyping existing phenotypes, increased sensitivity of detection, the counteraction of diffusion effects, and reduced cost per sample.


Extensions to In Silico Bioactivity Predictions Using Pathway Annotations and Differential Pharmacology Analysis: Application to Xenopus laevis Phenotypic Readouts.
The simultaneous increase of computational power and the availability of chemical and biological data have contributed to the recent popularity of in silico bioactivity prediction algorithms. Such methods are commonly used to infer the 'Mechanism of Action' of small molecules and they can also be employed in cases where full bioactivity profiles have not been established experimentally. However, protein target predictions by themselves do not necessarily capture information about the effect of a compound on a biological system, and hence merging their output with a systems biology approach can help to better understand the complex network modulation which leads to a particular phenotype. In this work, we review approaches and applications of target prediction, as well as their shortcomings, and demonstrate two extensions of this concept which are exemplified using phenotypic readouts from a chemical genetic screen in Xenopus laevis. In particular, the experimental observations are linked to their predicted bioactivity profiles. Predicted targets are annotated with pathways, which lead to further biological insight. Moreover, we subject the prediction to further machine learning algorithms, namely decision trees, to capture the differential pharmacology of ligand-target interactions in biological systems. Both methodologies hence provide new insight into understanding the Mechanism of Action of compound activities from phenotypic screens.


DNA repair and crossing over favor similar chromosome regions as discovered in radiation hybrid of Triticum.
The uneven distribution of recombination across the length of chromosomes results in inaccurate estimates of genetic to physical distances. In wheat (Triticum aestivum L.) chromosome 3B, it has been estimated that 90% of the cross over events occur in distal sub-telomeric regions representing 40% of the chromosome. Radiation hybrid (RH) mapping which does not rely on recombination is a strategy to map genomes and has been widely employed in animal species and more recently in some plants. RH maps have been proposed to provide i) higher and ii) more uniform resolution than genetic maps, and iii) to be independent of the distribution patterns observed for meiotic recombination. An in vivo RH panel was generated for mapping chromosome 3B of wheat in an attempt to provide a complete scaffold for this ~1 Gb segment of the genome and compare the resolution to previous genetic maps. A high density RH map with 541 marker loci anchored to chromosome 3B spanning a total distance of 1871.9 cR was generated. Detailed comparisons with a genetic map of similar quality confirmed that i) the overall resolution of the RH map was 10.5 fold higher and ii) six fold more uniform. A significant interaction (r = 0.879 at p = 0.01) was observed between the DNA repair mechanism and the distribution of crossing-over events. This observation could be explained by accepting the possibility that the DNA repair mechanism in somatic cells is affected by the chromatin state in a way similar to the effect that chromatin state has on recombination frequencies in gametic cells. The RH data presented here support for the first time in vivo the hypothesis of non-casual interaction between recombination hot-spots and DNA repair. Further, two major hypotheses are presented on how chromatin compactness could affect the DNA repair mechanism. Since the initial RH application 37 years ago, we were able to show for the first time that the iii) third hypothesis of RH mapping might not be entirely correct.