The mystery of intracellular developmental programmes and timers.
There has been a revolution in understanding animal development in the last 25 years or so, but there is at least one area of development that has been relatively neglected and therefore remains largely mysterious. This is the intracellular programmes and timers that run in developing precursor cells and change the cells over time. The molecular mechanisms underlying these programmes are largely unknown. My colleagues and I have studied such programmes in two types of rodent neural precursor cells: those that give rise to oligodendrocytes, which make myelin in the CNS (central nervous system), and those that give rise to the various cell types in the retina.


Central afferents to the nucleus of the solitary tract in rats and mice.
The nucleus of the solitary tract (NTS) regulates life-sustaining functions ranging from appetite and digestion to heart rate and breathing. It is also the brain's primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders. To better understand which neurons may exert top-down control over the NTS, here we provide a brain-wide map of all neurons that project axons directly to the caudal, viscerosensory NTS, focusing on a medial subregion with aldosterone-sensitive HSD2 neurons. Injecting an axonal tracer (cholera toxin b) into the NTS produces a similar pattern of retrograde labeling in rats and mice. The paraventricular hypothalamic nucleus (PVH), lateral hypothalamic area, and central nucleus of the amygdala (CeA) contain the densest concentrations of NTS-projecting neurons. PVH afferents are glutamatergic (express Slc17a6/Vglut2) and are distinct from neuroendocrine PVH neurons. CeA afferents are GABAergic (express Slc32a1/Vgat) and are distributed largely in the medial CeA subdivision. Other retrogradely labeled neurons are located in a variety of brain regions, including the cerebral cortex (insular and infralimbic areas), bed nucleus of the stria terminalis, periaqueductal gray, Barrington's nucleus, Kölliker-Fuse nucleus, hindbrain reticular formation, and rostral NTS. Similar patterns of retrograde labeling result from tracer injections into different NTS subdivisions, with dual retrograde tracing revealing that many afferent neurons project axon collaterals to both the lateral and medial NTS subdivisions. This information provides a roadmap for studying descending axonal projections that may influence visceromotor systems and visceral "mind-body" symptoms.


Epigenetic influence of social experiences across the lifespan.
The critical role of social interactions in driving phenotypic variation has long been inferred from the association between early social deprivation and adverse neurodevelopmental outcomes. Recent evidence has implicated molecular pathways involved in the regulation of gene expression as one possible route through which these long-term outcomes are achieved. These epigenetic effects, though not exclusive to social experiences, may be a mechanism through which the quality of the social environment becomes embedded at a biological level. Moreover, there is increasing evidence for the transgenerational impact of these early experiences mediated through changes in social and reproductive behavior exhibited in adulthood. In this review, recent studies which highlight the epigenetic effects of parent-offspring, peer and adult social interactions both with and across generations will be discussed and the implications of this research for understanding the developmental origins of individual differences in brain and behavior will be explored.


Research review: The relationship between childhood violence exposure and juvenile antisocial behavior: a meta-analytic review.
The connection between childhood violence exposure and antisocial behavior in adolescence has received much attention and has important implications for understanding and preventing criminal behavior. However, there are a limited number of well-designed prospective studies that can suggest a causal relationship, and little is known about the magnitude of the relationship. This meta-analysis provides a quantitative comparison of 18 studies (N = 18,245) assessing the relationship between childhood (before age 12) violence exposure and adolescent antisocial behavior. An overall effect size (Cohen's d) was calculated for each study, an average for the 18 studies, and averages for subsets of analyses within studies. Results indicated a small effect from prospective studies (d = .31) and a large effect from cross-sectional studies (d = .88). The effect for victimization (d = .61) was larger than for witnessing violence (d = .15). Effect size varied across studies employing different methodologies, populations, and conceptualizations of violence exposure and antisocial behavior. These findings do not support a simple, direct link from early violence exposure to antisocial behavior but suggest that many factors influence this relationship.


Retaining clinician-scientists: nature versus nurture.
In their IOVS article "Rejuvenating Clinician-Scientist Training" (published March 28, 2014), Balamurali Ambati and Judd Cahoon rightly point out the dearth of new clinician-scientists in ophthalmology. Within the context of their suggestions for increasing the number of successful clinician-scientists, they claim that the traditional MD-PhD training programs and K awards have failed to produce individuals who will carry on the important work of clinically relevant research that will improve patients' lives and sight. In this response we present data, including information on the career paths of graduates of the Washington University ophthalmology residency, that call into question the presumed failure of MD-PhD and K award programs and show that, in fact, graduates of these programs are more likely to succeed as clinician-scientists than are their peers who have not trained in such scientifically rigorous environments. We propose that, rather than a failure of early training programs, it may be obstacles that arise later in training and among junior faculty that prevent promising careers from reaching maturity. Funding, one rather large obstacle, takes the form of imbalanced start-up monies, less National Institutes of Health (NIH) funding awarded to young investigators, and study section composition that may work against those with clinically driven questions. We also explore the challenges faced in the culture surrounding residency and fellowship training. We agree with Ambati and Cahoon that there needs to be more innovation in the way training programs are structured, but we believe that the evidence supports supplementing the current model rather than scrapping it and starting over with unproven initiatives. The data on training programs supports the contention that those who have already made substantial investment and commitment to the clinician-scientist pathway through participation in MSTP or K training programs are the most likely to succeed on this career trajectory. To muffle the siren song of private practice and retain those best prepared for the clinician-scientist pathway requires additional investment as their careers mature through protected research time, mentorship, and advocacy.


[Objective evaluation of selective peripheral denervation for spasmodic torticollis].
The authors evaluated the results of selective peripheral denervation (SPD) of posterior rami of the cervical spinal nerves and/or the accessory nerve for spasmodic torticollis. Five patients underwent seven operations in total and the results were evaluated with the modified Tsui's score which was used in the clinical trial of botulinum toxin (BTX) for torticollis in Japan. The preoperative score was 10.8 +/- 2.2 (mean +/- S.D.) and the postoperative score was 1.4 +/- 1.7. The score changes indicated the effects of the operation as "excellent" in four cases and "good" in one case. These results indicate that SPD is superior to BTX in terms of control of symptoms in spasmodic torticollis. After the initial operation, however, two patients showed the so-called "mole-hitting game phenomenon" in which normal muscles develop abnormal contraction after denervation of abnormal muscles. This forced us to perform the second operations. Although this phenomenon was first described in botulinum toxin treatment, this is probably the first report in surgically denervated cases.


The effect of layout and pacing on learning from diagrams with unnecessary text.
Although the presentation of extraneous (i.e., irrelevant or unnecessary) information hinders learning, it is unclear whether and how layout and pacing influence this effect. In two experiments, participants learned how the heart functions using four different layouts: a diagram presented without unnecessary text (diagram only), with unnecessary text separated from the diagram (separated) or integrated into the diagram (integrated), or with separated unnecessary text and the instruction to integrate (integration instruction). In Experiment 1, study time was self-paced for half of the participants and system paced for the other half. There were no effects of layout and of pacing on learning, although system pacing was more effortful than self-pacing. In Experiment 2, which was system paced and employed eye tracking, the integrated condition showed worse learning outcomes than the separated condition. Moreover, in the integrated condition, participants made more integration attempts between the unnecessary text and the diagram than in the separated condition.


Tissue carcinoembryonic antigen, calcium, copper and iron levels in cancerous lung patients.
The expression of various trace elements and markers in lung cancer is controversial. The aim of this study is to evaluate the presence of calcium (Ca), copper (Cu), iron (Fe) and carcinoembryonic antigen (CEA) in cancerous untreated lung tissues and to determine a possible association between these markers and lung cancer. Fourty-eight cancerous lung tissue blocks, from Sultan Qaboos University Hospital, Sultanate of Oman, were studied. Fe, Ca, Cu, and CEA were demonstrated in the tissue blocks using Perl's Prussian blue, Von Kossa's, modified rhodanine and immunohistochemical staining methods, respectively. Twenty-three of 48 specimens showed positive Fe staining, 2 showed positive Ca staining and Cu was absent in all specimens. 93.7% expressed CEA in varying degree of positivity. 81.25% of these sections showed high expression of CEA. Tissue concentrations of trace elements were not elevated in lung cancer and therefore cannot be considered as a potential marker. Despite the low sensitivity and specificity of CEA as previously reported, tissue CEA should be considered as a potential marker in the evaluation of lung cancer.


Risk Factors for Childhood Stunting in 137 Developing Countries: A Comparative Risk Assessment Analysis at Global, Regional, and Country Levels.
Stunting affects one-third of children under 5 y old in developing countries, and 14% of childhood deaths are attributable to it. A large number of risk factors for stunting have been identified in epidemiological studies. However, the relative contribution of these risk factors to stunting has not been examined across countries. We estimated the number of stunting cases among children aged 24-35 mo (i.e., at the end of the 1,000 days' period of vulnerability) that are attributable to 18 risk factors in 137 developing countries. We classified risk factors into five clusters: maternal nutrition and infection, teenage motherhood and short birth intervals, fetal growth restriction (FGR) and preterm birth, child nutrition and infection, and environmental factors. We combined published estimates and individual-level data from population-based surveys to derive risk factor prevalence in each country in 2010 and identified the most recent meta-analysis or conducted de novo reviews to derive effect sizes. We estimated the prevalence of stunting and the number of stunting cases that were attributable to each risk factor and cluster of risk factors by country and region. The leading risk worldwide was FGR, defined as being term and small for gestational age, and 10.8 million cases (95% CI 9.1 million-12.6 million) of stunting (out of 44.1 million) were attributable to it, followed by unimproved sanitation, with 7.2 million (95% CI 6.3 million-8.2 million), and diarrhea with 5.8 million (95% CI 2.4 million-9.2 million). FGR and preterm birth was the leading risk factor cluster in all regions. Environmental risks had the second largest estimated impact on stunting globally and in the South Asia, sub-Saharan Africa, and East Asia and Pacific regions, whereas child nutrition and infection was the second leading cluster of risk factors in other regions. Although extensive, our analysis is limited to risk factors for which effect sizes and country-level exposure data were available. The global nature of the study required approximations (e.g., using exposures estimated among women of reproductive age as a proxy for maternal exposures, or estimating the impact of risk factors on stunting through a mediator rather than directly on stunting). Finally, as is standard in global risk factor analyses, we used the effect size of risk factors on stunting from meta-analyses of epidemiological studies and assumed that proportional effects were fairly similar across countries. FGR and unimproved sanitation are the leading risk factors for stunting in developing countries. Reducing the burden of stunting requires a paradigm shift from interventions focusing solely on children and infants to those that reach mothers and families and improve their living environment and nutrition.


Minimally invasive valve sparing mitral valve repair-the loop technique-how we do it.
Mitral valve insufficiency is the second most common heart valve disease, with untreated regurgitation leading to enlargement of the left atrium (LA), atrial fibrillation and heart failure. Besides functional regurgitation, the main cause is degenerative valve disease with elongation of the chordae tendineae and prolapsing of the leaflets. Surgical repair is the gold standard therapy for mitral valve insufficiency today. Recently, the implantation of neochordae (the "loop-technique") has been established and is the preferred technique in many centres including ours. Results of surgical mitral valve repair are good with low rates of re-intervention and mortality. With minimally invasive techniques, patient satisfaction is high and hospital stay is short. In conclusion, mitral valve repair should be the preferred strategy in patients with symptomatic mitral valve insufficiency or with asymptomatic mitral valve insufficiency in accordance with the guidelines. Modern repair techniques like neo-chord implantation with the loop-technique combined with minimally invasive access routes result in low mortality and morbidity and short hospital stay as well as high patient satisfaction.


Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia.
Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia. Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions. No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied. These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.


Automated multistructure atlas-assisted detection of lymph nodes using pelvic MR lymphography in prostate cancer patients.
To investigate whether atlas-based anatomical information can improve a fully automated lymph node detection system for pelvic MR lymphography (MRL) images of patients with prostate cancer. Their data set contained MRL images of 240 prostate cancer patients who had an MRL as part of their clinical work-up between January 2008 and April 2010, with ferumoxtran-10 as contrast agent. Each MRL consisted of at least a 3D T1-weighted sequence, a 3D T2*-weighted sequence, and a FLASH-3D sequence. The reference standard was created by two expert readers, reading in consensus, who annotated and interactively segmented the lymph nodes in all MRL studies. A total of 5089 lymph nodes were annotated. A fully automated computer-aided detection (CAD) system was developed to find lymph nodes in the MRL studies. The system incorporates voxel features based on image intensities, the Hessian matrix, and spatial position. After feature calculation, a GentleBoost-classifier in combination with local maxima detection was used to identify lymph node candidates. Multiatlas based anatomical information was added to the CAD system to assess whether this could improve performance. Using histogram analysis and free-receiver operating characteristic analysis, this was compared to a strategy where relative position features were used to encode anatomical information. Adding atlas-based anatomical information to the CAD system reduced false positive detections both visually and quantitatively. Median likelihood values of false positives decreased significantly in all annotated anatomical structures. The sensitivity increased from 53% to 70% at 10 false positives per lymph node. Adding anatomical information through atlas registration significantly improves an automated lymph node detection system for MRL images.


Sensing Urban Patterns with Antenna Mappings: The Case of Santiago, Chile.
Mobile data has allowed us to sense urban dynamics at scales and granularities not known before, helping urban planners to cope with urban growth. A frequently used kind of dataset are Call Detail Records (CDR), used by telecommunication operators for billing purposes. Being an already extracted and processed dataset, it is inexpensive and reliable. A common assumption with respect to geography when working with CDR data is that the position of a device is the same as the Base Transceiver Station (BTS) it is connected to. Because the city is divided into a square grid, or by coverage zones approximated by Voronoi tessellations, CDR network events are assigned to corresponding areas according to BTS position. This geolocation may suffer from non negligible error in almost all cases. In this paper we propose "Antenna Virtual Placement" (AVP), a method to geolocate mobile devices according to their connections to BTS, based on decoupling antennas from its corresponding BTS according to its physical configuration (height, downtilt, and azimuth). We use AVP applied to CDR data as input for two different tasks: first, from an individual perspective, what places are meaningful for them? And second, from a global perspective, how to cluster city areas to understand land use using floating population flows? For both tasks we propose methods that complement or improve prior work in the literature. Our proposed methods are simple, yet not trivial, and work with daily CDR data from the biggest telecommunication operator in Chile. We evaluate them in Santiago, the capital of Chile, with data from working days from June 2015. We find that: (1) AVP improves city coverage of CDR data by geolocating devices to more city areas than using standard methods; (2) we find important places (home and work) for a 10% of the sample using just daily information, and recreate the population distribution as well as commuting trips; (3) the daily rhythms of floating population allow to cluster areas of the city, and explain them from a land use perspective by finding signature points of interest from crowdsourced geographical information. These results have implications for the design of applications based on CDR data like recommendation of places and routes, retail store placement, and estimation of transport effects from pollution alerts.


Reversal of Growth of Utilization of Interventional Techniques in Managing Chronic Pain in Medicare Population Post Affordable Care Act.
Over the past 2 decades, the increase in the utilization of interventional techniques has been a cause for concern. Despite multiple regulations to reduce utilization of interventional techniques, growth patterns continued through 2009. A declining trend was observed in a previous evaluation; however, a comparative analysis of utilization patterns of interventional techniques has not been performed showing utilization before and after the enactment of the Affordable Care Act (ACA). Our aim is to assess patterns of utilization and variables of interventional techniques in chronic pain management in the fee-for-service (FFS) Medicare population, with a comparative analysis of pre- and post-ACA. Utilization patterns and variables of interventional techniques were assessed from 2000 to 2009 and from 2009 to 2016 in the FFS Medicare population of the United States in managing chronic pain. The master data from the Centers for Medicare & Medicaid Services (CMS) physician/supplier procedure summary from 2000 to 2016 was utilized to assess overall utilization and comparative utilization at various time periods. The analysis of Medicare data from 2000 to 2016 showed an overall decrease in utilization of interventional techniques 0.6% per year from 2009 to 2016, whereas from 2000 to 2009, there was an increase of 11.8% per year per 100,000 individuals of the Medicare population. In addition, the United States experienced an increase of 0.7% per year of population growth, 3.2% of those 65 years or older and a 3% annual increase in Medicare participation from 2009 to 2016. Further analysis also showed a 1.7% annual decrease in the rate of utilization of epidural and adhesiolysis procedures per 100,000 individuals of the Medicare population, with a 2.2% decrease for disc procedures and other types of nerve blocks, whereas there was an increase of 0.8% annually for facet joint interventions and sacroiliac joint blocks from 2009 to 2016. Epidural and adhesiolysis procedures showed an 8.9% annual increase, facet joint interventions and sacroiliac joint blocks showed a 17.6% increase, and disc procedures and other types of nerve blocks showed a 7.2% increase annually per 100,000 individuals of the Medicare population from 2000 to 2009. The limitations of this assessment include lack of analysis of individual procedures. Additional limitations include lack of inclusion of patients from Medicare Advantage plans and lack of complete and accurate data for statewide utilization. From 2009 to 2016, interventional techniques decreased at an annual rate of 0.6% with an overall decrease of 3.9%, compared to an overall increase of 173.6% from 2000 to 2009 with an annual increase of 11.8%. An additional analysis of data with individual procedures is essential to gain further insights into utilization patterns. Interventional pain management, chronic spinal pain, interventional techniques, epidural injections, adhesiolysis, facet joint interventions, sacroiliac joint injections, disc procedures, other types of nerve blocks.


A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming.
Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.


Genetic Mapping of Resistance in Hexaploid Wheat for a Quarantine Disease: Karnal Bunt.
Karnal bunt (KB) of wheat, caused by Tilletia indica, is one of the greatest challenges to grain industry, not because of yield loss, but quarantine regulations that restrict international movement and trade of affected stocks. Genetic resistance is the best way to manage this disease. Although several different sources of resistance have been identified to date, very few of those have been subjected to genetic analyses. Understanding the genetics of resistance, characterization and mapping of new resistance loci can help in development of improved germplasm. The objective of this study was to identify and characterize resistance loci (QTL) in two independent recombinant inbred lines (RILs) populations utilizing different wheat lines as resistance donors. Elite CIMMYT wheat lines Blouk#1 and Huirivis#1 were used as susceptible female parents and WHEAR/KUKUNA/3/C80.1/3∗BATAVIA//2∗WBLL1 (WKCBW) and Mutus as moderately resistant male parents in Pop1 and Pop2 populations, respectively. Populations were evaluated for KB resistance in 2015-16 and 2016-17 cropping seasons at two seeding dates (total four environments) in Cd. Obregon, Mexico. Two stable QTL from each population were identified in each environment: QKb.cim-2B and QKb.cim-3D (Pop1), QKb.cim-3B1 and QKb.cim-5B2 (Pop2). Other than those four QTL, other QTL were detected in each population which were specific to environments: QKb.cim-5B1, QKb.cim-6A, and QKb.cim-7A (Pop1), QKb.cim-3B2, QKb.cim-4A1, QKb.cim-4A2, QKb.cim-4B, QKb.cim-5A1, QKb.cim-5A2, and QKb.cim-7A2 (Pop2). Among the four stable QTL, all but QKb.cim-3B1 were derived from the resistant parent. QKb.cim-2B and QKb.cim-3D in Pop1 and QKb.cim-3B1 and QKb.cim-5B2 in Pop2 explained 5.0-11.4% and 3.3-7.1% phenotypic variance, respectively. A combination of two stable QTL in each population reduced KB infection by 24-33%, respectively. Transgressive resistant segregants lines derived with resistance alleles from both parents in each population were identified. Single nucleotide polymorphism (SNP) markers flanking these QTL regions may be amenable to marker-assisted selection. The best lines from both populations (in agronomy, end-use quality and KB resistance) carrying resistance alleles at all identified loci, may be used for inter-crossing and selection of improved germplasm in future. Markers flanking these QTL may assist in selection of such lines.


Real-time segmentation of multiple implanted cylindrical liver markers in kilovoltage and megavoltage x-ray images.
Gold markers implanted in or near a tumor can be used as x-ray visible landmarks for image based tumor localization. The aim of this study was to develop and demonstrate fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in cone-beam CT (CBCT) projections, for real-time motion management. Thirteen patients treated with conformal stereotactic body radiation therapy in three fractions had 2-3 cylindrical gold markers implanted in the liver prior to treatment. At each fraction, the projection images of a pre-treatment CBCT scan were used for automatic generation of a 3D marker model that consisted of the size, orientation, and estimated 3D trajectory of each marker during the CBCT scan. The 3D marker model was used for real-time template based segmentation in subsequent x-ray images by projecting each marker's 3D shape and likely 3D motion range onto the imager plane. The segmentation was performed in intra-treatment kV images (526 marker traces, 92,097 marker projections) and MV images (88 marker traces, 22,382 marker projections), and in post-treatment CBCT projections (42 CBCT scans, 71,381 marker projections). 227 kV marker traces with low mean contrast-to-noise ratio were excluded as markers were not visible due to MV scatter. Online segmentation times measured for a limited dataset were used for estimating real-time segmentation times for all images. The percentage of detected markers was 94.8% (kV), 96.1% (MV), and 98.6% (CBCT). For the detected markers, the real-time segmentation was erroneous in 0.2-0.31% of the cases. The mean segmentation time per marker was 5.6 ms [2.1-12 ms] (kV), 5.5 ms [1.6-13 ms] (MV), and 6.5 ms [1.8-15 ms] (CBCT). Fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in CBCT projections was demonstrated for a large dataset.


Burden of disease associated with a COPD eosinophilic phenotype.
Based on blood and sputum samples, up to 40% of patients with COPD have eosinophilic inflammation; however, there is little epidemiology data characterizing the health care burden within this sub-population. Given that COPD-attributable medical costs in the USA are predicted to approach $50 billion by 2020, we analyzed the effect of blood eosinophil counts and exacerbations on health care resource utilization and costs. This cross-sectional study used electronic medical records and insurance claims data from the Reliant Medical Group (January 2011-December 2015). Eligible patients were ≥40 years of age, continuously enrolled during the year of interest (2012, 2013, 2014, or 2015), had ≥1 COPD-related code in the preceding year, and documented maintenance therapy use. Patients with ≥1 blood eosinophil count recorded were stratified into 2 cohorts: <150 cells/µL and ≥150 cells/µL. Endpoints included demographics, clinical characteristics, health care resource utilization, and costs. The impact of blood eosinophil count and exacerbation patterns on health care resource utilization and costs was assessed with multivariate analyses. On average, 2,832 eligible patients were enrolled annually, of whom ~28% had ≥1 eosinophil count recorded during the year. The ≥150 cells/µL cohort had numerically higher all-cause and COPD-related health care resource utilization and cost each year compared with the <150 cells/µL cohort, but varied by service and year. Among patients with exacerbations, the ≥150 cells/µL cohort exhibited significantly higher COPD-related costs compared with the <150 cells/µL cohort. Blood eosinophil counts may be a useful biomarker for burden of disease in a subgroup of patients with COPD.


In vivo degradation of magnesium alloy LA63 scaffolds for temporary stabilization of biological myocardial grafts in a swine model.
Synthetic or biological patch materials used for surgical myocardial reconstruction are often fragile. Therefore, a transient support by degradable magnesium scaffolds can reduce the risk of dilation or rupture of the patch until physiological remodeling has led to a sufficient mechanical durability. However, there is evidence that magnesium implants can influence the growth and physiological behavior of the host's cells and tissue. Hence, we epicardially implanted scaffolds of the magnesium fluoride-coated magnesium alloy LA63 in a swine model to assess biocompatibility and degradation kinetics. Chemical analysis of the pigs' organs revealed no toxic accumulation of magnesium ions in the skeletal muscle, myocardium, liver, kidney, and bone of the pigs 1, 3, and 6 months postimplantation. The implants were surrounded by a fibrous granulation tissue, but no signs of necrosis were histologically evaluable. A sufficiently slow degradation rate of the magnesium alloy scaffold can be demonstrated via micro-computed tomography investigation. We conclude that stabilizing scaffolds of the magnesium fluoride-coated magnesium alloy LA63 can be used for epicardial application because no significant adverse effects to myocardial tissue were noted. Thus, degradable stabilizing scaffolds of this magnesium alloy with a slow degradation rate can extend the indication of innovative biological and synthetic patch materials.


The Mycoplasma hyorhinis genome displays differential chromatin accessibility.
Whilst the regulation of chromatin accessibility and its effect on gene expression have been well studied in eukaryotic species, the role of chromatin dynamics and 3D organisation in genome reduced bacteria remains poorly understood [1,2]. In this study we profiled the accessibility of the Mycoplasma hyorhinis genome, these data were collected fortuitously as part of an experiment where ATAC-Seq was conducted on mycoplasma, contaminated mammalian cells. We found a differential and highly reproducible chromatin accessibility landscape, with regions of increased accessibility corresponding to genes important for the bacteria's life cycle and infectivity. Furthermore, accessibility in general correlated with transcriptionally active genes as profiled by RNA-Seq, but peaks of high accessibility were also seen in non-coding and intergenic regions, which could contribute to the topological organisation of the genome. However, changes in transcription induced by starvation or application of the RNA polymerase inhibitor rifampicin did not themselves change the accessibility profile, which confirms that the differential accessibility is inherently a property of the genome, and not a consequence of its function. These results together show that differential chromatin accessibility is a key feature of the regulation of gene expression in bacteria.


Great balls of fire and the vicious cycle: a study of the effects of cycling on male fertility.
Over the past few years we have been bombarded with publicity telling us to do more exercise in order to reduce our risk of developing heart disease. Also, as commuter traffic increases and petrol prices rise, workers are constantly looking for quicker, cheaper and greener ways of travelling short distances. As a result of this, bicycle sales have risen exponentially. However, as the popularity of cycling increases, so do the fears that spending hours in the saddle every day may not be as beneficial as first thought. For many years now reports in the literature have suggested that exercise in general, and cycling specifically, may actually increase an individual's risk of developing problems in the male reproductive system. In this report I will review the evidence available in the literature, paying special attention to cycling and the risks of developing testicular cancer, secondary impotence and, most importantly, the effects on male fertility.


Prognostic value of Morise clinical score, calcium score and computed tomography coronary angiography in patients with suspected or known coronary artery disease.
Our aim was to determine the prognostic value of computed tomography coronary angiography (CTCA), coronary artery calcium scoring (CACS) and Morise clinical score in patients with known or suspected coronary artery disease (CAD). A total of 722 patients (480 men; 62.7±10.9 years) who were referred for further cardiac evaluation underwent CACS and contrast-enhanced CTCA to evaluate the presence and severity of CAD. Of these, 511 (71%) patients were without previous history of CAD. Patients were stratified according to the Morise clinical score (low, intermediate, high), to CACS (0-10, 11-100, 101-400, 401-1,000, >1,000) and to CTCA (absence of CAD, nonsignificant CAD, obstructive CAD). Patients were followed up for the occurrence of major events: cardiac death, nonfatal myocardial infarction, unstable angina and revascularisation. Significant CAD (>50% luminal narrowing) was detected in 260 (36%) patients; nonsignificant CAD (<50% luminal narrowing) in 250 (35%) and absence of CAD in 212 (29%). During a mean follow-up of 20±4 months, 116 events (21 hard) occurred. In patients with normal coronary arteries on CTCA, the major event rate was 0% vs. 1.7% in patients with nonsignificant CAD and 7.3% in patients with significant CAD (p<0.0001). Three hard events (14%) occurred in patients with CACS≤100 and two (9.5%) in patients with intermediate Morise score; one revascularisation was observed in a patient with low Morise score. At multivariate analysis, diabetes, obstructive CAD and CACS >1,000 were significant predictors of events (p<0.05). An excellent prognosis was noted in patients with a normal CTCA (0% event rate). CACS ≤100 and low-intermediate Morise score did not exclude the possibility of events at follow-up.


Characterization of monoclonal and polyclonal antibodies to human tissue kallikrein.
Monoclonal antibodies to purified human urinary kallikrein have been developed. Selection of antibody producing clones was based on 125I-kallikrein binding activity of hybridoma media in both radioimmunoassay and enzyme-linked immunosorbent assay. Three clones (2 IgG1, 1 IgG2b) were subcloned, characterized, and compared with the polyclonal antiserum generated in rabbits immunized with the purified kallikrein. With radioimmunoassay, mouse ascitic fluids or rabbit antisera dilutions showing 50% binding to 125I-kallikrein were 1:1.2 X 10(6) (E7A9), 1:1.2 X 10(5) (H6A6), 1:8.0 X 10(4) (E12H1), and 1:1.4 X 10(6) (the rabbit antisera). With enzyme-linked immunosorbent assay, mouse ascitic fluids from clones E7A9 and H6A6 showed half-maximal absorbance at dilutions of 1:2.1 X 10(5) and 1:1.0 X 10(5) respectively, and the polyclonal antiserum showed half-maximal absorbance at a dilution of 1:2.0 X 10(4). These monoclonal antibodies showed no cross-reactivity with rat tissue kallikrein, rat urinary plasminogen activator, or dog pancreatic kallikrein, while the polyclonal antiserum showed some cross-reactivity. The binding of monoclonal or polyclonal antibodies to 125I-human urinary kallikrein was not affected by human plasma kallikrein, thrombin, or urokinase in a competitive radioimmunoassay. By using purified human urinary kallikrein immobilized to agarose, antibodies produced by clones E7A9 and H6A6 and in the rabbit antisera were purified to homogeneity. Each of these affinity-purified antibodies inhibited the esterase activity, and two of the three inhibited the kininogenase activity, of human urinary kallikrein. A sandwich immunosorbent assay was developed to measure this kallikrein using monoclonal antibody from the clone E7A9 in conjunction with the polyclonal antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)


Cholestasis in infants with immune hydrops fetalis.
Rhesus (Rh) hemolytic disease of the newborn represents a broad spectrum of symptoms in the fetus and newborn, ranging from mild to severe hemolytic anemia and hydrops fetalis. Cholestasis is a common problem in infants with immune hydrops fetalis (IHF). The aim of this study was to evaluate the incidence and course of cholestasis in infants with IHF due to Rh alloimmunization. Infants with IHF during the 10-year follow-up were retrospectively included in the study. Demographics, laboratory parameters, and prenatal and postnatal interventions were recorded. The incidence of cholestasis and certain risk factors were investigated. A total of 30 infants with IHF with a mean gestational age 33 ± 2.6 weeks were included. Of these, 15 infants (50%) survived to discharge. The incidence of cholestasis was 60% (18/30). Cholestasis was diagnosed within a median 3 (0-7) days. All cholestatic infants who survived recovered within three months. In conclusion, cholestasis in IHF is frequent, transient and has an early onset.


Efficacy of mitoxantrone and intrathecal triamcinolone acetonide treatment in chronic progressive multiple sclerosis patients.
Treatment approaches are rare for chronic progressive patients with multiple sclerosis (MS). Objective was to evaluate the clinical benefit of repeated intrathecal application of the sustained release steroid triamcinolone acetonide or the administration of mitoxantrone (MIX) in 2 similar cohorts of chronic progressive patients with MS in an open-label fashion. Expanded Disability Status Scale scores significantly decreased after the first 6 intraspinal triamcinolone acetonide injections, which were performed every third day, and then remained stable. Walking distance significantly increased and did not reduce until the end of the 1-year-long trial period. Mitoxantrone treatment did not improve the Expanded Disability Status Scale score; however, no further significant deterioration appeared. Walking distance did not significantly decrease. Both treatment regimens were safe; the patients experienced nearly no adverse effects. Triamcinolone acetonide application provided a clinical benefit, whereas MIX administration prevented further worsening of MS symptoms. We stress that only specialists with a broad experience in intraspinal triamcinolone acetonide application and MIX administration should perform both kinds of therapy only after a careful information and risk-benefit evaluation in cooperation with the patient. Future trials will show the efficacy of combination of both treatment approaches in chronic progressive patients with MS.


Impact of PCB on resistance to Flavobacterium psychrophilum after experimental infection of rainbow trout Oncorhynchus mykiss eggs by nanoinjection.
The effects of sublethal exposure of a commercial blend of polychlorinated biphenyls (PCB), i.e. Clophen A50, on disease resistance to the aetiological agent of rainbow trout fry syndrome, Flavobacterium psychrophilum, were investigated. Newly fertilised rainbow trout Oncorhynchus mykiss eggs were nanoinjected with 2 doses of Clophen A50 (0.4 or 2 microg egg(-1)) and/or 100 colony forming units of F. psychrophilum. The mean cumulative mortality in control groups, and groups exposed to the lower dose of Clophen A50 (0.4 microg egg(-1)) was below 5.0%. The mean cumulative mortality in groups exposed to the higher dose of Clophen A50 (2.0 microg egg(-1)) was 5.8%, which was not significantly different from the control groups. In all groups infected with F. psychrophilum, with or without exposure to Clophen A50, significantly higher cumulative mortalities compared with control groups were recorded. No differences in mortality were recorded between groups exposed to bacteria alone or bacteria in combination with the higher dose of Clophen A50 (21.6 and 20.4%, respectively). Decreased disease resistance was recorded in groups exposed to F. psychrophilum and the lower dose of Clophen A50, with a mean cumulative mortality of 56.0%. These results could be due to non dose-dependent effects on the immune system, or toxic effects of PCB or their metabolites on the bacteria in groups exposed to the higher dose of Clophen A50. The present study indicates that maternal transfer of PCB might affect disease resistance to vertically transmitted F. psychrophilum.


A high resolution genetic map anchoring scaffolds of the sequenced watermelon genome.
As part of our ongoing efforts to sequence and map the watermelon (Citrullus spp.) genome, we have constructed a high density genetic linkage map. The map positioned 234 watermelon genome sequence scaffolds (an average size of 1.41 Mb) that cover about 330 Mb and account for 93.5% of the 353 Mb of the assembled genomic sequences of the elite Chinese watermelon line 97103 (Citrullus lanatus var. lanatus). The genetic map was constructed using an F(8) population of 103 recombinant inbred lines (RILs). The RILs are derived from a cross between the line 97103 and the United States Plant Introduction (PI) 296341-FR (C. lanatus var. citroides) that contains resistance to fusarium wilt (races 0, 1, and 2). The genetic map consists of eleven linkage groups that include 698 simple sequence repeat (SSR), 219 insertion-deletion (InDel) and 36 structure variation (SV) markers and spans ∼800 cM with a mean marker interval of 0.8 cM. Using fluorescent in situ hybridization (FISH) with 11 BACs that produced chromosome-specifc signals, we have depicted watermelon chromosomes that correspond to the eleven linkage groups constructed in this study. The high resolution genetic map developed here should be a useful platform for the assembly of the watermelon genome, for the development of sequence-based markers used in breeding programs, and for the identification of genes associated with important agricultural traits.


Improving predictions of tropical forest response to climate change through integration of field studies and ecosystem modeling.
Tropical forests play a critical role in carbon and water cycles at a global scale. Rapid climate change is anticipated in tropical regions over the coming decades and, under a warmer and drier climate, tropical forests are likely to be net sources of carbon rather than sinks. However, our understanding of tropical forest response and feedback to climate change is very limited. Efforts to model climate change impacts on carbon fluxes in tropical forests have not reached a consensus. Here, we use the Ecosystem Demography model (ED2) to predict carbon fluxes of a Puerto Rican tropical forest under realistic climate change scenarios. We parameterized ED2 with species-specific tree physiological data using the Predictive Ecosystem Analyzer workflow and projected the fate of this ecosystem under five future climate scenarios. The model successfully captured interannual variability in the dynamics of this tropical forest. Model predictions closely followed observed values across a wide range of metrics including aboveground biomass, tree diameter growth, tree size class distributions, and leaf area index. Under a future warming and drying climate scenario, the model predicted reductions in carbon storage and tree growth, together with large shifts in forest community composition and structure. Such rapid changes in climate led the forest to transition from a sink to a source of carbon. Growth respiration and root allocation parameters were responsible for the highest fraction of predictive uncertainty in modeled biomass, highlighting the need to target these processes in future data collection. Our study is the first effort to rely on Bayesian model calibration and synthesis to elucidate the key physiological parameters that drive uncertainty in tropical forests responses to climatic change. We propose a new path forward for model-data synthesis that can substantially reduce uncertainty in our ability to model tropical forest responses to future climate.


Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus.
Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus. Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age +/-1 SD 33+/-8 years) and 26 age-, sex-, and body mass index-matched healthy control subjects (32+/-8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [<5 years] and longer-duration [>10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/gamma-ATP ratio was reduced significantly both in subjects with longer-term (2.1+/-0.5 versus 1.5+/-0.4, P<0.000) and newly diagnosed (2.1+/-0.5 versus 1.6+/-0.2, P<0.000) diabetes. The phosphocreatine/gamma-ATP ratio was similar in newly diagnosed diabetes subjects and those with longer-term disease (1.6+/-0.2 versus 1.5+/-0.4, P=0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7+/-0.6 versus 2.3+/-0.4, P=0.005). On univariate analysis, there was no significant correlation of phosphocreatine/gamma-ATP ratio with myocardial perfusion reserve index (r=0.21, P=0.26). We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment.


Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.
Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).


[Inhibitor of the extrinsic pathway of coagulation and cytokines in patients with sepsis].
To analyse the possible correlation between the plasma levels of the extrinsic pathway inhibitor (TFPI) in patients with infection along with two cytokines mediating in the action of bacterial endotoxin on the vascular endothelium, namely, tumour factor (TNF) and interleukin-1 (IL-1). Twenty-five patients with infection, none of them showing septic shock or disseminated intravascular coagulation, were studied. Plasma TFPI concentration was assessed by a chromogenic substrate technique; TNF was determined with immunoradiometric methods and IL-1 was estimated with ELISA. The results were compared with those of a group of 25 healthy subjects matched for age and sex. Positive blood cultures were found in 15 of the 25 patients (60%), 12 due to gram-negative and 3 to gram-positive germs. A significant increase of TFPI (p < 0.004), TNF and IL-1 (p < 0.001) was found in infection patients with respect to the control subjects. No significant correlation between TFPI and TNF or IL-1 was found. Increased TFPI, unrelated to cytokines, is present in patients with sepsis.


Update on geographic atrophy in age-related macular degeneration.
Age-related macular degeneration (AMD) is the main cause of legal blindness in older patients in developed countries, and geographic atrophy (GA) represents the advanced form of dry AMD. Although it accounts for one third of the cases of late AMD and is responsible for 20% of the cases of severe visual loss due to the disorder. GA currently lacks effective treatment, whereas antiangiogenic therapies have been shown to be successful in managing choroidal neovascularization, the other form of late AMD. Recent advances in GA epidemiology, etiology, genetics, and imaging techniques have renewed the interest in this entity, which is a cause of progressive visual loss even in treated patients with neovascular AMD. This knowledge has triggered many clinical trials targeting different molecules shown to be associated with the disease, and it is hoped that this research will translate into effective drugs for GA in the near future.


Evaluation of the Benefits of De-Escalation for Patients with Sepsis in the Emergency Intensive Care Unit.
Although the 2016 Japanese guidelines for the management of sepsis recommend de-escalation of treatment after identification of the causative pathogen, adherence to this practice remain unknown. The objective of this study was to evaluate the benefits of de-escalating treatment for sepsis patients at an advanced critical care and emergency medical centre. Based on electronic patient information, 85 patients who were transported to the centre by ambulance, and diagnosed with sepsis between January 2008 and September 2013 were enrolled and evaluated. Patients were divided into two groups with and without de-escalation, and comparisons were conducted for several variables, including length of hospital stay, and length of antibiotic administration. Two types of subgroup analysis were conducted between patients with septic shock or positive blood cultures. Statistical analysis was conducted using chi-square and Mann-Whitney U tests. The length of hospital stay after diagnosis was significantly shorter for the de-escalation group than for the non-de-escalation group. In the subgroup analysis, de-escalation for blood culture-positive patients was beneficial in terms of the length of hospital stay and length of antibiotic administration. The findings of this study suggest that sepsis treatment de-escalation is beneficial for treatment efficacy and appropriate use of antibiotics. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Attitudes to patient safety amongst medical students and tutors: Developing a reliable and valid measure.
Patient safety education is an increasingly important component of the medical school curricula. This study reports on the development of a valid and reliable patient safety attitude measure targeted at medical students, which could be used to compare the effectiveness of different forms of patient safety education delivery. The Attitudes to Patient Safety Questionnaire (APSQ) was developed as a 45-item measure of attitudes towards five patient safety themes. In Study 1, factor analysis conducted on the responses of 420 medical students and tutors, revealed nine interpretable factors. The revised 37-item APSQ-II was then administered to 301 students and their tutors at two further medical schools. Good stability of factor structure was revealed with reliability coefficients ranging from 0.64 to 0.82 for the nine factors. The questionnaire also demonstrated good criterion validity, being able to distinguish between tutors and students across a range of domains. This article reports on the first attempt to develop a valid and reliable measure of patient safety attitudes which can distinguish responses between different groups. The predictive validity of the measure is yet to be assessed. The APSQ could be used to measure patient safety attitudes in other healthcare contexts in addition to evaluating changes in undergraduate curricula.


HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.
Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.


The role of leptin in diencephalic syndrome.
Diencephalic syndrome is a rare condition associated with central nervous system tumors. The most common presentation is secondary failure to thrive with proper caloric intake and no statural impairment. Despite the importance of this syndrome, little is known of its pathophysiology. Some reports have documented changes in human growth hormone and insulin levels at the onset, whereas others have described endocrine disorders of hypothalamic insufficiency resulting from surgery of the tumor. It has been suggested that the hormonal changes described, such as increased human growth hormone and ghrelin or decreased insulin and leptin levels, are related to a patient's BMI. These findings support the role of these 4 hormones as indicators of the patient's nutritional status but not as mediators or potential therapeutic targets of the disease. We report the case of an infant who initially presented with tumor progression and, after chemotherapy, progressive weight gain and reduced tumor size. Because he presented no hormonal deficiencies or obesity after therapy, we were able to analyze his hormonal status uninfluenced by effects of metabolic treatment or excess weight. Although ghrelin and leptin levels have been related to nutritional status, our patient's leptin levels fell when tumor size decreased and weight increased: an extraordinary finding because leptin concentration is expected to increase with weight gain. This paradoxical response suggests that leptin may be dysregulated in diencephalic syndrome or that the diencephalic astrocytoma may have had an effect on leptin secretion.


Comparative in vitro activities of trovafloxacin (CP-99,219) against 221 aerobic and 217 anaerobic bacteria isolated from patients with intra-abdominal infections.
Four hundred thirty-eight bacteria cultured from specimens of patients with serious intra-abdominal infections were tested by agar dilution against trovafloxacin and other quinolones and antimicrobial agents. Trovafloxacin inhibited 435 strains (99.3%) at < or =2 microg/ml. All the quinolones had similar activities against Enterobacteriaceae and Pseudomonas sp., but trovafloxacin showed superior activities against streptococci, enterococci, and anaerobic organisms. Because of its excellent in vitro activities against diverse bacteria, trovafloxacin has potential use as a single agent for polymicrobial infections.


Validity of the coupled-oscillator model for laser-array dynamics.
We show that the coupled-oscillator model accurately describes the dynamics of laser arrays. Excellent qualitative and quantitative agreement is obtained between this model and the results of experiments on Nd:YAG laser arrays. Recent claims of instantaneous phase locking are shown to be in error.


Hepatic glucose sensing and integrative pathways in the liver.
The hepatic glucose-sensing system is a functional network of enzymes and transcription factors that is critical for the maintenance of energy homeostasis and systemic glycemia. Here we review the recent literature on its components and metabolic actions. Glucokinase (GCK) is generally considered as the initial postprandial glucose-sensing component, which acts as the gatekeeper for hepatic glucose metabolism and provides metabolites that activate the transcription factor carbohydrate response element binding protein (ChREBP). Recently, liver receptor homolog 1 (LRH-1) has emerged as an upstream regulator of the central GCK-ChREBP axis, with a critical role in the integration of hepatic intermediary metabolism in response to glucose. Evidence is also accumulating that O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and acetylation can act as glucose-sensitive modifications that may contribute to hepatic glucose sensing by targeting regulatory proteins and the epigenome. Further elucidation of the components and functional roles of the hepatic glucose-sensing system may contribute to the future treatment of liver diseases associated with deregulated glucose sensors.


How to evaluate the effect of seven years of the Norwegian School Fruit Scheme (2007-2014) on fruit, vegetable and snack consumption and weight status: A natural experiment.
Aim: From August 2007 to June 2014, the Norwegian School Fruit Scheme (NSFS) legally established that all pupils in junior high and combined schools (275,000 pupils every year), but not those in primary schools (343,000 pupils every year), were entitled to a free piece of fruit or vegetable every school day. The NSFS is a natural experiment, unique in terms of scope and lengthiness. Such governmental efforts to improve the diet of the public are rarely evaluated. Thus, an evaluation of the comprehensive, well-designed NSFS is warranted. The aim was to describe how the NSFS can be evaluated using existing data sets. Methods: Four data sets have been identified for the evaluation of the NSFS: (a) the Nord-Trøndelag Health Study, (b) the Norwegian Mother and Child Cohort Study, (c) the Norwegian Child Growth Study/Growth in Teenagers and (d) Health Behaviour in School Aged Children. These comprehensive studies have collected cross-sectional or longitudinal data providing information about children's dietary consumption and/or weight status, which can be utilised in the evaluation of the NSFS. Both short- and long-term effects of the NSFS related to dietary habits and weight status and the potential effect of moderators such as socio-economic status, sex, ethnicity and the age of children and adolescents can be studied. Conclusions: Worldwide, there is a lack of well-designed, long-term studies evaluating the impact of governmental efforts to improve public diet. The present study describes how the NSFS can be evaluated using data from four large data sets on eating habits and weight status.


Differentially expressed genes in the cuticle and hemolymph of the silkworm, Bombyx mori, injected with the fungus Beauveria bassiana.
The most important pathogenic fungus of the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), is Beauveria bassiana (Balsamo-Crivelli ) Vuillemin (Hypocreales: Clavicipitaceae), which causes significant damage to sericulture production. Therefore, diagnosing fungal disease and developing new control measures are crucial to silk production. To better understand the responsive and interactive mechanisms between the host silkworm and this fungus, variations in silkworm gene expression were investigated using the suppression subtractive hybridization method following the injection of B. bassiana conidia. Two cDNA libraries were constructed, and 140 cDNA clones were isolated. Of the 50 differentially expressed genes identified, 45 (112 clones) were identified in the forward library, and 5 (28 clones) were identified in the reverse library. Expression profiling of six of these genes by quantitative polymerase chain reaction (qPCR) verified that they were induced by the fungal challenge. The present study provides insight into the interaction between lepidopteran insects and pathogenic fungi.


Internet-Delivered Disease Management for Recurrent Depression: A Multicenter Randomized Controlled Trial.
Strategies to improve the life of patients suffering from recurrent major depression have a high relevance. This study examined the efficacy of 2 Internet-delivered augmentation strategies that aim to prolong symptom-free intervals. Efficacy was tested in a 3-arm, multicenter, open-label, evaluator-blind, randomized controlled trial. Upon discharge from inpatient mental health care, 232 adults with 3 or more major depressive episodes were randomized to 1 of 2 intervention groups (SUMMIT or SUMMIT-PERSON) or to treatment as usual (TAU) alone. Over 12 months, participants in both intervention arms received, in addition to TAU, intense monitoring via e-mail or a smartphone, including signaling of upcoming crises, assistance with personal crisis management, and facilitation of early intervention. SUMMIT-PERSON additionally offered regular expert chats. The primary outcome was 'well weeks', i.e. weeks with at most mild symptoms assessed by the Longitudinal Interval Follow-Up Evaluation, during 24 months after the index treatment. SUMMIT compared to TAU reduced the time with an unwell status (OR 0.48; 95% CI 0.23-0.98) through faster transitions from unwell to well (OR 1.44; 95% CI 0.83-2.50) and slower transitions from well to unwell (OR 0.69; 95% CI 0.44-1.09). Contrary to the hypothesis, SUMMIT-PERSON was not superior to either SUMMIT (OR 0.77; 95% CI 0.38-1.56) or TAU (OR 0.62; 95% CI 0.31-1.24). The efficacy of SUMMIT was strongest 8 months after the intervention. The fully automated Internet-delivered augmentation strategy SUMMIT has the potential to improve TAU by reducing the lifelong burden of patients with recurrent depression. The fact that the effects wear off suggests a time-unlimited extension.


Functional Index-3: A Valid and Reliable Functional Outcome Assessment Measure in Patients With Dermatomyositis and Polymyositis.
Patients with dermatomyositis (DM) and polymyositis (PM) have reduced muscle endurance.The aim of this study was to streamline the Functional Index-2 (FI-2) by developing the Functional Index-3 (FI-3) and to evaluate its measurement properties, content and construct validity, and intra- and interrater reliability. A dataset of the previously performed and validated FI-2 (n = 63) was analyzed for internal redundancy, floor, and ceiling effects. The content of the FI-2 was revised into the FI-3. Construct validity and intrarater reliability of FI-3 were tested on 43 DM and PM patients at 2 rheumatology centers. Interrater reliability was tested in 25 patients. The construct validity was compared with the Myositis Activities Profile (MAP), Health Assessment Questionnaire (HAQ), and Borg CR-10 using Spearman correlation coefficient. Spearman correlation coefficients of 63 patients performing FI-3 revealed moderate to high correlations between shoulder flexion and hip flexion tasks and similar correlations with MAP and HAQ scores; there were lower correlations for neck flexion task. All FI-3 tasks had very low to moderate correlations with the Borg scale. Intraclass correlation coefficients (ICC) of FI-3 tasks for intrarater reliability (n = 25) were moderate to good (0.88-0.98). ICC of FI-3 tasks for interrater reliability (n = 17) were fair to good (range 0.83-0.96). The FI-3 is an efficient and valid method for clinically assessing muscle endurance in DM and PM patients. FI-3 construct validity is supported by the significant correlations between functional tasks and the MAP, HAQ, and Borg CR-10 scores.


Explicit instruction of rules interferes with visuomotor skill transfer.
In the present study, we examined the effects of explicit knowledge, obtained through instruction or spontaneous detection, on the transfer of visuomotor sequence learning. In the learning session, participants learned a visuomotor sequence, via trial and error. In the transfer session, the order of the sequence was reversed from that of the learning session. Before the commencement of the transfer session, some participants received explicit instruction regarding the reversal rule (i.e., Instruction group), while the others did not receive any information and were sorted into either an Aware or Unaware group, as assessed by interview conducted after the transfer session. Participants in the Instruction and Aware groups performed with fewer errors than the Unaware group in the transfer session. The participants in the Instruction group showed slower speed than the Aware and Unaware groups in the transfer session, and the sluggishness likely persisted even in late learning. These results suggest that explicit knowledge reduces errors in visuomotor skill transfer, but may interfere with performance speed, particularly when explicit knowledge is provided, as opposed to being spontaneously discovered.


Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy.
Lactulose is effective in secondary prophylaxis of hepatic encephalopathy (HE). Probiotics improves minimal hepatic encephalopathy (MHE), which predisposes to HE. No study has been conducted on the secondary prophylaxis of HE using probiotics. Our objective was to study the effects of lactulose and probiotics for secondary prophylaxis of HE. Consecutive cirrhotic patients who had recovered from HE were randomized to receive lactulose (Gp-L, 30 ml three times per day), three capsules of probiotics (Gp-P) per day containing 112.5 billion viable lyophilized bacteria per capsule, or no therapy (Gp-N). All patients were assessed by psychometry (number connection test (NCT-A, B), figure connection test if illiterate (FCT-A, B), digit symbol test (DST), and block design test (BDT)), critical flicker frequency (CFF) test, and arterial ammonia at inclusion. The patients were followed up monthly. The primary end point was development of overt HE according to West Haven criteria or a follow-up of 12 months. Of 360 patients who recovered, 235 (65.2%) met the inclusion criteria (Gp-L, n=80; Gp-P, n=77; and Gp-N, n=78). In all, 38 patients (16.1%) were lost to follow-up and 77 patients developed HE (Gp-L, n=18; Gp-P, n=22; and Gp-N, n=37). There was a significant difference between Gp-L and Gp-N (P=0.001) and between Gp-P and Gp-N (P=0.02) but no difference between the Gp-L and Gp-P groups (P=0.349). The rate of readmission for causes other than HE (Gp-L, Gp-P, and Gp-N, 19:21:28; P=0.134) and deaths (Gp-L:Gp-P:Gp-N=13:11:16; P=0.56) in all three groups were similar. There was a high prevalence of abnormal psychometry test results (NCT-A, 71.5%; NCT-B, 69.2%; DST, 76.9%; and BDT, 85.2%), and FCT-A and -B were abnormal in 35 of 48 patients (72.7%). CFF was <38 Hz in 118 patients (50.2%). Upon multivariate analysis, recurrence of overt HE was significantly associated with two or more abnormal psychometric tests and arterial ammonia after the recovery of an episode of HE. Lactulose and probiotics are effective for secondary prophylaxis of HE in patients with cirrhosis.


Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy.
Multiorgan dysfunction (MOD) is one of four consensus based criteria for the diagnosis of intrapartum asphyxia. The theoretical concept behind MOD is the diving reflex (conservation of blood flow to vital organs at the cost of non-vital organs). To assess the patterns of involvement of each major organ/system and combinations of involvement in infants with post-asphyxial hypoxic-ischaemic encephalopathy (HIE), and to describe this in relation to long term outcome. Retrospective cohort study. Regional tertiary neonatal intensive care unit at the Hospital for Sick Children, Toronto, Canada. Term neonates with post-intrapartal asphyxial HIE assessed for kidney, cardiovascular system, lung, and liver function. Death and presence or absence of severe neurodevelopmental disability. Out of 130 of 144 eligible infants with outcome data, 80 (62%) had severe adverse outcome and 50 (38%) had good outcome. All infants had evidence of MOD (at least one organ dysfunction in addition to HIE). Renal, cardiovascular, pulmonary, and hepatic dysfunction was present in 58-88% of infants with good outcome and 64-86% of infants with adverse outcome. MOD was present in all the infants with severe post-asphyxial HIE. However, there was no association between MOD and outcome in these infants. No relation between individual or combinations of organ involvements and long term outcomes was observed.


Brief mindfulness meditation training alters psychological and neuroendocrine responses to social evaluative stress.
To test whether a brief mindfulness meditation training intervention buffers self-reported psychological and neuroendocrine responses to the Trier Social Stress Test (TSST) in young adult volunteers. A second objective evaluates whether pre-existing levels of dispositional mindfulness moderate the effects of brief mindfulness meditation training on stress reactivity. Sixty-six (N=66) participants were randomly assigned to either a brief 3-day (25-min per day) mindfulness meditation training or an analytic cognitive training control program. All participants completed a standardized laboratory social-evaluative stress challenge task (the TSST) following the third mindfulness meditation or cognitive training session. Measures of psychological (stress perceptions) and biological (salivary cortisol, blood pressure) stress reactivity were collected during the social evaluative stress-challenge session. Brief mindfulness meditation training reduced self-reported psychological stress reactivity but increased salivary cortisol reactivity to the TSST, relative to the cognitive training comparison program. Participants who were low in pre-existing levels of dispositional mindfulness and then received mindfulness meditation training had the greatest cortisol reactivity to the TSST. No significant main or interactive effects were observed for systolic or diastolic blood pressure reactivity to the TSST. The present study provides an initial indication that brief mindfulness meditation training buffers self-reported psychological stress reactivity, but also increases cortisol reactivity to social evaluative stress. This pattern may indicate that initially brief mindfulness meditation training fosters greater active coping efforts, resulting in reduced psychological stress appraisals and greater cortisol reactivity during social evaluative stressors.


Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study.
Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without.


Longitudinal Associations Between Observed and Perceived Neighborhood Food Availability and Body Mass Index in a Multiethnic Urban Sample.
Blacks, Hispanics, and women of lower socioeconomic status tend to have a higher risk of obesity. Numerous studies over the past decade examined the role of the neighborhood food environment in body weight. However, few were longitudinal. This longitudinal study examined whether multiple measures of neighborhood food availability were associated with body mass index (BMI) in a predominately Black and Hispanic adult sample living in low- to moderate-income urban neighborhoods. This longitudinal study used two waves of data (2002, 2008), including interviewer-measured height and weight, from a community survey of adults ( n = 219). In both 2002 and 2008, multiple measures characterized neighborhood food availability: GIS-derived availability of retail food outlets (large grocery store, small grocery store, convenience store, liquor stores), observed fruit and vegetable availability (count of stores selling 10 or more fresh fruit or vegetable varieties), and perceived fruit and vegetable access. Random intercept models estimated multivariable associations, controlling for individual-level demographics and neighborhood median household income. Small grocery store availability was associated with 1.22-unit increase in BMI ( p = .047), while each unit increase in perceived fruit and vegetable access was associated with a 0.69-unit decrease in BMI ( p = .055). BMI was not associated with large grocery store, convenience store, or liquor store availability, or with observed fruit and vegetable availability. Findings suggest that improving the neighborhood food environment, particularly at small grocery stores, may help urban residents living in low- to moderate-income neighborhoods achieve healthier body weights over time.


A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies.
Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.


CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model.
CD46, a membrane cofactor expressed on all nucleated human cells, plays an essential role in suppressing autoimmune reactions and protecting host cells from complement-mediated attack. Human transgenic CD46 homozygous mice (CD46+/+ ) are prone to lethal sepsis upon infection with Neisseria meningitidis (N. meningitidis). However, the underlying mechanisms are poorly understood. Here, we determined thatCD46+/+ mice produce large numbers of M1 type macrophages with enhanced surface expression of MHC II and production of pro-inflammatory mediators such as IL-6, TNF, IL-12, and IL-1β In the presence of M-CSF or GM-CSF, CD46 signaling enhances monocyte-macrophage differentiation. Additionally, CD46+/+ macrophages rapidly undergo apoptosis upon LPS challenge or meningococcal infection, which could contribute to uncontrolled bacterial dissemination in vivo. Adoptive transfer of CD46+/+ peritoneal macrophages aggravated septic responses in wild-type mice, but the depletion of macrophages partially alleviated septic reactions in CD46+/+ mice after N. meningitidis infection. Our findings reveal a novel role of CD46 in accelerating inflammatory responses upon meningococcal infection or LPS stimulation by regulating the functional polarization and survival of macrophages.


Additive host genetic factors influence fecal egg excretion rates during Schistosoma mansoni infection in a rural area in Brazil.
This study quantifies the influence of shared household and kinship on egg counts during Schistosoma mansoni infection in a sample from rural Brazil. Detailed genealogic information allowed assignment of 597 individuals to 6 multihousehold pedigrees residing in 145 households. A variance component method was used to partition egg counts into shared household, additive genetic, and individual-specific environmental effects. Host additive genetic effects consistently accounted for a large proportion of the variation in egg counts: 43% in an unadjusted model and 40% in model adjusted for covariates. In a model that examined the confounding of shared household with kinship, additive genetic effects still accounted for 27% of the variation in egg counts and shared household only 12%. The consistently important role for host additive genetic factors on the variation in egg counts points to new ways of modeling and understanding the mechanisms that contribute to trait variation during infection with S. mansoni.


Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs.
Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.


The accuracy of antenatal ultrasonography in identifying renal abnormalities.
To determine the accuracy of measuring antenatal renal pelvic diameter for prediction of renal abnormalities. Prospective evaluation of all pregnant women undergoing ultrasonography. A teaching hospital providing primary and referral maternity care. Fifty-six pregnant women with suspected fetal hydronephrosis or cystic lesions identified from 7500 ultrasonograms over 3 years. Antenatal renal pelvic diameter was measured in the anteroposterior dimension. Neonates underwent postnatal ultrasonography after day 3 of life; if the results were abnormal, a cystogram and renal diuretic scan were obtained. None of 50 kidneys 15 mm or smaller in anteroposterior pelvic diameter had obstruction; 11 (79%) of 14 kidneys larger than 15 mm were obstructed or demonstrated vesicoureteral reflux. Of 12 kidneys believed to be multicystic before birth, five (42%) proved to have hydronephrosis. Since the majority of fetuses with suspected hydronephrosis proved to be normal, parents should not be unduly alarmed by the physician. Renal pelvic diameter of more than 15 mm is strongly predictive of hydronephrosis. Since severe hydronephrosis is treatable and can be mistaken for a multicystic kidney antenatally, full radiologic evaluation is needed soon after birth.


Human pentraxin 3 (PTX3) as a novel biomarker for the diagnosis of pulmonary arterial hypertension.
Although inflammation is an important feature of pulmonary arterial hypertension (PAH), the usefulness of local inflammatory markers as biomarkers for PAH is unknown. In this study, we tested whether plasma concentrations of human pentraxin 3 (PTX3), a local inflammatory marker, would be a useful biomarker for detecting PAH. Plasma PTX3 concentrations were evaluated in 50 PAH patients (27 with idiopathic PAH, 17 with PAH associated with connective tissue disease (CTD-PAH), and six with congenital heart disease), 100 age and sex-matched healthy controls, and 34 disease-matched CTD patients without PAH. Plasma concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) were also determined. Mean PTX3 levels were significantly higher in all PAH patients than in the healthy controls (4.40±0.37 vs. 1.94±0.09 ng/mL, respectively; P<0.001). Using a threshold level of 2.84 ng/mL, PTX3 yielded a sensitivity of 74.0% and a specificity of 84.0% for the detection of PAH. In CTD-PAH patients, mean PTX3 concentrations were significantly higher than in CTD patients without PAH (5.02±0.69 vs. 2.40±0.14 ng/mL, respectively; P<0.001). There was no significant correlation between plasma levels of PTX3 and BNP or CRP. Receiver operating characteristic (ROC) curves for screening PAH in patients with CTD revealed that PTX3 (area under the ROC curve 0.866) is superior to BNP. Using a PTX3 threshold of 2.85 ng/mL maximized true-positive and false-negative results (sensitivity 94.1%, specificity 73.5%). Plasma concentrations of PTX3 may be a better biomarker of PAH than BNP, especially in patients with CTD.


The D-chiro-inositol paradox in the ovary.
The D-chiro-inositol-to-myo-inositol ratio is regulated by an insulin-dependent epimerase. Enzyme activity varies among tissues, likely owing to the specific needs of the two different molecules. We hypothesize that in the ovaries of polycystic ovary syndrome patients, epimerase activity is enhanced, leading to a local myo-inositol deficiency which in turn is responsible for the poor oocyte quality.


Flavonoid antioxidants.
In order to ascertain the role of dietary flavonoids as antioxidants in vivo it is necessary to understand the chemical nature of the absorbed forms in the circulation in vivo and how the multiplicity of research findings in vitro reflect the bioactivity of flavonoids in vivo. Only when we gain adequate information on the circulating forms can we begin to understand the targeting to the tissues, whether flavonoids cross the blood-brain barrier, for example, and in what forms. Flavonoids are powerful antioxidants in vitro, but their overall function in vivo has yet to be clarified, whether antioxidant, anti-inflammatory, enzyme inhibitor, enzyme inducer, inhibitor of cell division, or some other role. It should also be emphasised that the reducing properties of flavonoids might contribute to redox regulation in cells, independently of their antioxidant properties, and thus might protect against cell ageing, for example, by working together with the intracellular reductant network. To gain understanding of these issues the factors influencing the absorption of flavonoids in the gastrointestinal tract needs to be established, namely the questions of: de-glycosylation before absorption, conjugation in the small intestine through glucuronidation, sulphation or methylation etc, metabolism and degradation in the colon to smaller phenolic molecules. The forms in which they circulate in vivo will influence their polarity and, thus, their localization and bioactivities in vivo. Finally if antioxidant activities are important, the elucidation of how such properties in vitro relate to the potential for conjugates and metabolites in vivo to act as antioxidants is required. The absorbed flavonoid components might function in the aqueous phase (like vitamin C) or in the lipophilic milieu (as vitamin E) in vivo. This will depend on their polarity properties on uptake, how they are metabolised on absorption, and their resulting structural forms in the circulation.


Loss of native rocky reef biodiversity in Australian metropolitan embayments.
Urbanisation of the coastal zone represents a key threat to marine biodiversity, including rocky reef communities which often possess disproportionate ecological, recreational and commercial importance. The nature and magnitude of local urban impacts on reef biodiversity near three Australian capital cities were quantified using visual census methods. The most impacted reefs in urbanised embayments were consistently characterised by smaller, faster growing species, reduced fish biomass and richness, and reduced mobile invertebrate abundance and richness. Reef faunal distribution varied significantly with heavy metals, local population density, and proximity to city ports, while native fish and invertebrate communities were most depauperate in locations where invasive species were abundant. Our study adds impetus for improved urban planning and pollution management practises, while also highlighting the potential for skilled volunteers to improve the tracking of changes in marine biodiversity values and the effectiveness of management intervention.


The role of anthracyclines in second-line therapy of ovarian cancer.
Anthracyclines (ANTs) have been in clinical practice since the 1960s and represent one of the most commonly used classes of anticancer drugs. In the 1990s, meta-analyses showed a favorable impact of doxorubicin (DOX/A) on the survival of patients with advanced ovarian cancer, when it was combined with cyclophosphamide and cisplatin (CAP) and compared to CP alone. With the acceptance of paclitaxel-carboplatin (TCb) as the new reference arm for first-line treatment, testing the addition of ANTs to TCb seems a logic next step. Trials presently testing this, make use of either epirubicin (EPI) or pegylated liposomal doxorubicin (PLD: Doxil(R)/Caelyx(R)). These are the two most favorable ANTs, based on data obtained with various ANTs in ovarian cancer failing platinum-based chemotherapy. EPI has not been evaluated in direct comparison with other antineoplastic agents. PLD has been compared with both paclitaxel and topotecan. No difference in efficacy parameters could be observed, but the toxicity profile of PLD scored favorably against those of the comparator in both trials, despite the fact that palmar-plantar erythrodysesthesia can be troublesome, and sometimes lead to treatment discontinuation. Data from four randomized trials evaluating the role of ANT combinations in patients with relapsed ovarian cancer suggest that the addition of EPI or DOX to paclitaxel does not lead to better outcomes in patients with platinum- refractory or resistant disease. In platinum-sensitive disease, any benefit of EPI-platinum or DOX-platinum combinations over platinum alone is uncertain. There are no randomized trials with PLD combinations in the second-line setting. It is concluded that both EPI and PLD can be recommended as a reasonable single-agent treatment option for relapsed patients, with a preference for PLD taking into account its more favorable toxicity profile.


Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling.
The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-κB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-κB and tumor suppressor gene CYLD regulates the pool of CD5+ B cells through sustained canonical NF-κB signaling. Reinforced canonical NF-κB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5+ B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-κB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-κB-driven clonal CD5+ B-cell expansion and ultimately CLL-like disease.


Dual Catalytic Activity of a Cytochrome P450 Controls Bifurcation at a Metabolic Branch Point of Alkaloid Biosynthesis in Rauwolfia serpentina.
Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant-derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti-arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report the discovery and characterization of vinorine hydroxylase, a cytochrome P450 enzyme that hydroxylates vinorine to form vomilenine, which was found to exist as a mixture of rapidly interconverting epimers. Surprisingly, this cytochrome P450 also catalyzes the non-oxidative isomerization of the ajmaline precursor vomilenine to perakine. This unusual dual catalytic activity of vinorine hydroxylase thereby provides a control mechanism for the bifurcation of these alkaloid pathway branches. This discovery highlights the unusual catalytic functionality that has evolved in plant pathways.


Development of a spatially dispersed short-coherence interferometry sensor using diffraction grating orders.
Modern manufacturing processes can achieve good throughput by requiring that manufactured products be screened by better quality control exercised at a quicker rate. This trend in the quality control of manufactured products increases the need for process-oriented precision metrology capable of performing faster inspections and yielding valuable feedback to the manufacturing system. This paper presents a spatially dispersed short-coherence interferometry sensor using diffraction orders of the zeroth and first order for a diffraction grating introduced as a new compact system configuration for surface profile measurement. In this modified design, the diffraction grating acts as the beam splitter/combiner. Diffractions for the zeroth and first orders are represented by the reference and measurement arms, respectively, of a Michelson interferometer, which reduces the optical path length. This innovative design has been proven effective for determining the step-height repeatability in the sensor range from 27 nm to 22 nm for profiles spanning the step heights of the tested specimens.


Association of radiographic findings in hand X-ray with clinical features and autoantibodies in patients with systemic sclerosis.
Musculoskeletal involvement is one of the major causes of impairment in daily life of patients with systemic sclerosis (SSc). Several hand radiographic findings can be seen in SSc patients; however, their association with clinical features and autoantibodies remains unclear. Here, we analyzed 124 SSc patients with their hand X-rays and clinical and serological features. Abnormal findings in hand X-rays including acro-osteolysis, calcinosis, flexion contracture, erosive change, joint space narrowing, and subluxation were observed in 110 patients (68%). These X-ray findings were more prevalent in patients with longer disease duration and digital ischemic changes. The majority of erosions were typical for erosive hand osteoarthritis, which was seen in 19% of patients. Hand X-ray findings were associated with involved organs; acro-osteolysis with interstitial lung disease, calcinosis with pulmonary arterial hypertension and gastrointestinal tract involvement, and flexion contracture with gastrointestinal tract involvement. Those findings were also relevant to autoantibodies; acro-osteolysis was more common in SSc patients with anti-Scl70 antibody but less in patients with anticentromere antibody. Calcinosis was more prevalent in patient with anticentromere antibody. In our study, organ involvements and SSc-associated autoantibodies showed associations with hand radiographic abnormalities. Hand X-ray findings might reflect underlying pathogenesis and autoantibody profiles in SSc patients.Key Points• Hand X-ray abnormalities were observed in approximately two-thirds of patients with SSc.• Erosive osteoarthritis was more prevalent in SSc patients than general population.• Hand X-ray findings were associated with disease duration, organ involvements, and SSc-associated autoantibodies, reflecting underlying pathogenesis.