Strategies in 'snake venomics' aiming at an integrative view of compositional, functional, and immunological characteristics of venoms.
This work offers a general overview on the evolving strategies for the proteomic analysis of snake venoms, and discusses how these may be combined through diverse experimental approaches with the goal of achieving a more comprehensive knowledge on the compositional, toxic, and immunological characteristics of venoms. Some recent developments in this field are summarized, highlighting how strategies have evolved from the mere cataloguing of venom components (proteomics/venomics), to a broader exploration of their immunological (antivenomics) and functional (toxicovenomics) characteristics. Altogether, the combination of these complementary strategies is helping to build a wider, more integrative view of the life-threatening protein cocktails produced by venomous snakes, responsible for thousands of deaths every year.


IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model.
The protection provided by smallpox vaccines when used after exposure to Orthopoxviruses is poorly understood. Postexposu re administration of 1st generation smallpox vaccines was effective during eradication. However, historical epidemiological reports and animal studies on postexposure vaccination are difficult to extrapolate to today's populations, and 2nd and 3rd generation vaccines, developed after eradication, have not been widely tested in postexposure vaccination scenarios. In addition to concerns about preparedness for a potential malevolent reintroduction of variola virus, humans are becoming increasingly exposed to naturally occurring zoonotic orthopoxviruses and, following these exposures, disease severity is worse in individuals who never received smallpox vaccination. This study investigated whether postexposure vaccination of prairie dogs with 2nd and 3rd generation smallpox vaccines was protective against monkeypox disease in four exposure scenarios. We infected animals with monkeypox virus at doses of 104 pfu (2× LD50) or 106 pfu (170× LD50) and vaccinated the animals with IMVAMUNE® or ACAM2000® either 1 or 3 days after challenge. Our results indicated that postexposure vaccination protected the animals to some degree from the 2× LD50, but not the 170× LD5 challenge. In the 2× LD50 challenge, we also observed that administration of vaccine at 1 day was more effective than administration at 3 days postexposure for IMVAMUNE®, but ACAM2000® was similarly effective at either postexposure vaccination time-point. The effects of postexposure vaccination and correlations with survival of total and neutralizing antibody responses, protein targets, take formation, weight loss, rash burden, and viral DNA are also presented.


Disrupting Mosquito Reproduction and Parasite Development for Malaria Control.
The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance.


Complex dynamics in recurrent cortical networks based on spatially realistic connectivities.
Most studies on the dynamics of recurrent cortical networks are either based on purely random wiring or neighborhood couplings. Neuronal cortical connectivity, however, shows a complex spatial pattern composed of local and remote patchy connections. We ask to what extent such geometric traits influence the "idle" dynamics of two-dimensional (2d) cortical network models composed of conductance-based integrate-and-fire (iaf) neurons. In contrast to the typical 1 mm(2) used in most studies, we employ an enlarged spatial set-up of 25 mm(2) to provide for long-range connections. Our models range from purely random to distance-dependent connectivities including patchy projections, i.e., spatially clustered synapses. Analyzing the characteristic measures for synchronicity and regularity in neuronal spiking, we explore and compare the phase spaces and activity patterns of our simulation results. Depending on the input parameters, different dynamical states appear, similar to the known synchronous regular "SR" or asynchronous irregular "AI" firing in random networks. Our structured networks, however, exhibit shifted and sharper transitions, as well as more complex activity patterns. Distance-dependent connectivity structures induce a spatio-temporal spread of activity, e.g., propagating waves, that random networks cannot account for. Spatially and temporally restricted activity injections reveal that a high amount of local coupling induces rather unstable AI dynamics. We find that the amount of local versus long-range connections is an important parameter, whereas the structurally advantageous wiring cost optimization of patchy networks has little bearing on the phase space.


Evolving treatment of advanced colorectal cancer.
Advances in colorectal cancer treatment have led to improved outcomes for patients. A number of cytotoxic agents, alone and in combination, have shown activity. The addition of the newer, so-called "targeted" agents to standard chemotherapy drugs and regimens has also modestly improved outcomes. Progress in our knowledge and understanding of molecular pathways has led to the identification of markers critical in determining response or nonresponse to some of the targeted agents. This review discusses the available therapies in metastatic colorectal cancer and describes some of the molecular markers implicated in activity and resistance to current targeted therapies.


Combined Treatment with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer-PPMO and AAV-U7 Rescues the Severe DMD Phenotype in Mice.
Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by an absence of the dystrophin protein, which is essential for muscle fiber integrity. Among the developed therapeutic strategies for DMD, the exon-skipping approach corrects the frameshift and partially restores dystrophin expression. It could be achieved through the use of antisense sequences, such as peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) or the small nuclear RNA-U7 carried by an adeno-associated virus (AAV) vector. AAV-based gene therapy approaches have potential for use in DMD treatment but are subject to a major limitation: loss of the AAV genome, necessitating readministration of the vector, which is not currently possible, due to the immunogenicity of the capsid. The PPMO approach requires repeated administrations and results in only weak cardiac dystrophin expression. Here, we evaluated a combination of PPMO- and AAV-based therapy in a mouse model of severe DMD. Striking benefits of this combined therapy were observed in striated muscles, with marked improvements in heart and diaphragm structure and function, with unrivalled extent of survival, opening novel therapeutic perspectives for patients.


A comparison of techniques for assessing farmland bumblebee populations.
Agri-environment schemes have been implemented across the European Union in order to reverse declines in farmland biodiversity. To assess the impact of these schemes for bumblebees, accurate measures of their populations are required. Here, we compared bumblebee population estimates on 16 farms using three commonly used techniques: standardised line transects, coloured pan traps and molecular estimates of nest abundance. There was no significant correlation between the estimates obtained by the three techniques, suggesting that each technique captured a different aspect of local bumblebee population size and distribution in the landscape. Bumblebee abundance as observed on the transects was positively influenced by the number of flowers present on the transect. The number of bumblebees caught in pan traps was positively influenced by the density of flowers surrounding the trapping location and negatively influenced by wider landscape heterogeneity. Molecular estimates of the number of nests of Bombus terrestris and B. hortorum were positively associated with the proportion of the landscape covered in oilseed rape and field beans. Both direct survey techniques are strongly affected by floral abundance immediately around the survey site, potentially leading to misleading results if attempting to infer overall abundance in an area or on a farm. In contrast, whilst the molecular method suffers from an inability to detect sister pairs at low sample sizes, it appears to be unaffected by the abundance of forage and thus is the preferred survey technique.


ICAM-1 interactions in the renal interstitium: a novel activator of fibroblasts during nephritis.
Chronic renal diseases often degenerate towards end-stage failure, requiring replacement renal therapy. The progressive decline of such diseases is a highly complex, multi-factorial process, which is poorly understood. Indeed, not all chronic conditions take on a progressive course, some may recover to regain normal function, while others may remain functionally impaired yet stable. The structural features of progressive decline, however, show common histological features, despite the diverse nature of the primary injury. These aberrant structural alterations are characterised essentially by a dramatic expansion of the tubulointerstitium, with accompanying tubular atrophy, resulting from interstitial fibrosis. These changes are thought to be a uniform response to prolonged inflammation which may originate in the glomerulus, the vasculature or the interstitial space (Strutz et al., 1995). A histomorphometric analysis of renal diseases, initially performed by Risdon et al. (1968), and supported by Bohle et al. (1987) and others (Eknoyan et al., 1990), revealed that the severity of abnormal glomerular pathology did not always correlate directly with impaired renal function. The extent of interstitial inflammation and the degree of interstitial fibrosis, however, were both shown to be more accurate predictors of renal function (Bohle et al., 1992). Furthermore there was a high probability of irreversible functional decline, in the presence of interstitial fibrotic lesions and tubular atrophy. Interstitial fibrosis is therefore considered an important histological marker for end stage renal failure, and is believed to be functionally more significant than primary changes within the glomerulus. In most tissues, resident fibroblasts are believed to be the cells principally responsible for the synthesis and breakdown of extracellular matrix (ECM) within connective tissues. Indeed in fibrotic diseases of lung and skin, the resident fibroblast has been identified as the most important cell responsible for the abnormal deposition of ECM components during the disease process (Phan et al., 1985). In the kidney, there are probably several sources of matrix components during fibrosis including tubular epithelial cells, inflammatory macrophages (Vaage and Linbland, 1990) as well as interstitial fibroblasts. Although the precise cellular source of the bulk of this matrix requires clarification, there is mounting evidence supporting a significant contribution from resident or infiltrating fibroblasts (Rodemann and Muller, 1990, 1991a,b; Strutz and Muller, 1995).


Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda.
A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.


The Impact of System Factors on Quality and Safety in Arterial Surgery: A Systematic Review.
A systems approach to patient safety proposes that a wide range of factors contribute to surgical outcome, yet the impact of team, work environment, and organisational factors, is not fully understood in arterial surgery. The aim of this systematic review is to summarize and discuss what is already known about the impact of system factors on quality and safety in arterial surgery. A systematic review of original research papers in English using MEDLINE, Embase, PsycINFO, and Cochrane databases, was performed according to PRISMA guidelines. Independent reviewers selected papers according to strict inclusion and exclusion criteria, and using predefined data fields, extracted relevant data on team, work environment, and organisational factors, and measures of quality and/or safety, in arterial procedures. Twelve papers met the selection criteria. Study endpoints were not consistent between papers, and most failed to report their clinical significance. A variety of tools were used to measure team skills in five papers; only one paper measured the relationship between team factors and patient outcomes. Two papers reported that equipment failures were common and had a significant impact on operating room efficiency. The influence of hospital characteristics on failure-to-rescue rates was tested in one large study, although their conclusions were limited to the American Medicare population. Five papers implemented changes in the patient pathway, but most studies failed to account for potential confounding variables. A small number of heterogenous studies have evaluated the relationship between system factors and quality or safety in arterial surgery. There is some evidence of an association between system factors and patient outcomes, but there is more work to be done to fully understand this relationship. Future research would benefit from consistency in definitions, the use of validated assessment tools, measurement of clinically relevant endpoints, and adherence to national reporting guidelines.


Engaging Learners in Health System Quality Improvement Efforts.
In 1999, an Institute of Medicine report spurred health care organizations to implement systems-based quality improve ment efforts and tackle patient safety. Simultaneously, the Accreditation Council for Graduate Medical Education asked residency programs to address Practice-Based Learning and Systems-Based Practice competencies. Medical educators now advocate incorporation of these competencies in undergraduate medical education.The authors examine the success of these efforts both from the health care delivery and systems perspective as well as from the perspective of educators as they aspire to engage medical students and residents in these domains. The authors argue that the missing element that prevents health care systems from the full realization of the promise of quality improvement is bidirectional alignment. Included are examples from the literature to demonstrate how medical educators are moving toward alignment of learners with health system quality improvement and safety needs. Finally, the authors explore business and information technology governance literature in support of the hypothesis that bidirectional alignment should be the next step in moving from reactive to proactive systems of care.


53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms.
The tumor suppressor protein 53BP1, a pivotal regulator of DNA double-strand break (DSB) repair, was first identified as a p53-interacting protein over two decades ago. However, its direct contributions to p53-dependent cellular activities remain undefined. Here, we reveal that 53BP1 stimulates genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. 53BP1-dependent p53 modulation requires both auto-oligomerization and tandem-BRCT domain-mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of these activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Furthermore, we demonstrate 53BP1-USP28 cooperation to be essential for normal p53-promoter element interactions and gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data provide a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell-fate decisions and reveal these activities to be distinct and separable from 53BP1's regulation of DNA double-strand break repair pathway choice.


Future scenarios and opportunities for interventional radiology in the post COVID-19 era.
Pandemic outbreak has led health systems worldwide into a rapid reorganization in response to coronavirus infections, forcing interventional radiology units to adapt. Interventional procedures have evolved in number, type and setting and have arguably been optimized as a direct consequence of this pandemic; a result that will undoubtedly lead to radical change within the specialty. This paper explores the future of interventional radiology from various perspectives, and forecasts the new opportunities that will be presented, from the adaptation of the interventional radiology staff and angiography suite, to the immunological environment, and through to digital medical education. We analyze the economic impact and the future relationship we can expect with the rest of the medical industry.


Two Stream Active Query Suggestion for Active Learning in Connectomics.
For large-scale vision tasks in biomedical images, the labeled data is often limited to train effective deep models. Active learning is a common solution, where a query suggestion method selects representative unlabeled samples for annotation, and the new labels are used to improve the base model. However, most query suggestion models optimize their learnable parameters only on the limited labeled data and consequently become less effective for the more challenging unlabeled data. To tackle this, we propose a two-stream active query suggestion approach. In addition to the supervised feature extractor, we introduce an unsupervised one optimized on all raw images to capture diverse image features, which can later be improved by fine-tuning on new labels. As a use case, we build an end-to-end active learning framework with our query suggestion method for 3D synapse detection and mitochondria segmentation in connectomics. With the framework, we curate, to our best knowledge, the largest connectomics dataset with dense synapses and mitochondria annotation. On this new dataset, our method outperforms previous state-of-the-art methods by 3.1% for synapse and 3.8% for mitochondria in terms of region-of-interest proposal accuracy. We also apply our method to image classification, where it outperforms previous approaches on CIFAR-10 under the same limited annotation budget. The project page is https://zudi-lin.github.io/projects/#two_stream_active.


Phosphorylation and regulation of CTP synthetase from Saccharomyces cerevisiae by protein kinase A.
The phosphorylation and regulation of the URA7-encoded CTP synthetase (EC 220.127.116.11, UTP:ammonia ligase (ADP-forming)) from Saccharomyces cerevisiae by cAMP-dependent protein kinase (protein kinase A) were examined. Protein kinase A is the principal mediator of signals transmitted through the RAS/cAMP pathway in S. cerevisiae. The results of labeling experiments indicated that the phosphorylation of CTP synthetase was mediated by the RAS/cAMP pathway in vivo. In vitro, protein kinase A phosphorylated CTP synthetase at a serine residue with a stoichiometry consistent with one phosphorylation site per CTP synthetase subunit. Protein kinase A activity was dose- and time-dependent using CTP synthetase as a substrate. The dependence of protein kinase A activity on CTP synthetase was cooperative (n = 1.8) and the Km value for CTP synthetase was 73 nM. Phosphorylation of CTP synthetase with protein kinase A resulted in the stimulation (190%) of activity. The mechanism of this stimulation included an increase in the Vmax of the reaction with respect to UTP and ATP, a decrease in the Km for ATP, and a decrease in the cooperative kinetic behavior of the enzyme. Phosphorylated CTP synthetase was less sensitive to product inhibition by CTP. Protein kinase C also phosphorylates and activates CTP synthetase. Phosphorylation of CTP synthetase with protein kinases A and C together resulted in an increase in CTP synthetase activity that was slightly greater than that obtained when the enzyme was phosphorylated with either protein kinase alone.


Palliative care in the community for cancer and end-stage cardiorespiratory disease: the views of patients, lay-carers and health care professionals.
Primary care plays an important role in delivering care to people who are dying. However, providing palliative care to people dying with conditions other than cancer may be more problematic, because it may be more difficult to establish an exact prognosis or to identify their needs. This article draws on qualitative research, which explored the views of health professionals, patients and their carers about care provided at the end of life. Differences between the care of people with cancer and those with end-stage cardiorespiratory disease were found in four main areas: management and progression of disease, communication and information, health care in the community and awareness of dying. The research shows that even in PHCTs (primary health care teams) committed to the delivery of palliative care, people dying with end-stage cardiorespiratory disease are less likely than those with cancer to receive full, and easily understood, information, to be aware that they are dying or to receive district nursing care. There is an increasing call for palliative care to be extended to all, but further work is needed to develop appropriate packages of care for those dying with conditions other than cancer.


Double constrained ordination for assessing biological trait responses to multiple stressors: A case study with benthic macroinvertebrate communities.
Benthic macroinvertebrate communities are used as indicators for anthropogenic stress in freshwater ecosystems. To better understand the relationship between anthropogenic stress and changes in macroinvertebrate community composition, it is important to understand how different stressors and species traits are associated, and how these associations influence variation in species occurrence and abundances. Here, we show the capacity of the multivariate technique of double constrained correspondence analysis (dc-CA) to analyse trait-environment relationships, and we compare it with the redundancy analysis method on community weighted mean values of traits (CWM-RDA), which is frequently used for this type of analysis. The analyses were based on available biomonitoring data for macroinvertebrate communities from the Danube River. Results from forward selection of traits and environmental variables using dc-CA analyses showed that aquatic stages, reproduction techniques, dispersal tactics, locomotion and substrate relations, altitude, longitudinal and transversal distribution, and substrate preferendum were significantly related to habitat characteristics, hydromorphological alterations and water quality measurements such as physico-chemical parameters, heavy metals, pesticides and pharmaceuticals. Environmental variables significantly associated with traits using the CWM-RDA method were generally consistent with those found in dc-CA analysis. However, the CWM-RDA does neither test nor explicitly select traits, while dc-CA tests and selects both traits and environmental variables. Moreover, the dc-CA analysis revealed that the set of environmental variables was much better in explaining the community data than the available trait set, a kind of information that can neither be obtained from CWM-RDA nor from RLQ (Environment, Link and Trait data), which is a close cousin of dc-CA but not regression-based. Our results suggest that trait-based analysis based on dc-CA may be useful to assess mechanistic links between multiple anthropogenic stressors and ecosystem health, but more data sets should be analysed in the same manner.


First-trimester pregnancy scanning as a screening tool for high-risk and abnormal pregnancies in a district general hospital setting.
This study set out to evaluate the feasibility and acceptability of routine early ultrasound (12-14 weeks) within a district general hospital (DGH) for identifying high-risk and abnormal pregnancies. This was a pilot study for screening by ultrasound examination all women who presented to their community midwife before 12 weeks' gestation. The study involved 991 women who presented clinically pregnant before 12 weeks' gestation between May 1998 and May 1999. Women were offered routinely two ultrasound examinations during their pregnancy, the first at 12-14 weeks' gestation and the second at 20-21 weeks' gestation. The main outcome measures were: range and number of abnormal/high-risk pregnancies identified during an ultrasound scan at 12-14 weeks' gestation; range and number of abnormalities diagnosed during scans at later gestations; outcomes of the pregnancies; questionnaires assessing how the women viewed early pregnancy ultrasound as a method of screening. Nine hundred and eighty-four (99%) women accepted the offer of an early ultrasound scan at 12-14 weeks' gestation; of these 840(85%) women accepted screening for trisomy 21 (T21) by fetal nuchal translucency thickness (NT) and maternal age (fetal medicine foundation risk assessment programme) and this was completed successfully in 797(80%) of cases. Twenty-four women (2%) had a failed pregnancy and where necessary an ERPC was performed following a planned admission. Thirty pregnancies (3%) were diagnosed as abnormal or having high risk of abnormality at the early scan. A major abnormality was confirmed before the expected anomaly scan at 20 weeks in five (17%) pregnancies; all of these patients opted for an elective termination. Twenty-six (3%) pregnancies had a diagnosis of abnormality at their anomaly scan. Of these, three pregnancies were diagnosed as major abnormalities with two resulting in termination of the affected pregnancy before 24 weeks' gestation. Eight hundred and thirty-seven women (85%) completed questionnaires, 833 women (84.5%) were satisfied with the counselling they received before the ultrasound scan and 827 women (84%) answered that they would accept an early pregnancy scan if offered during their next pregnancy. Early pregnancy ultrasound at 12-14 weeks' gestation can be used as an effective method of identifying and screening for major abnormalities of pregnancy within a DGH setting, but it is appropriate to use this in conjunction with an anomaly scan at around 20 weeks' gestation. Women found this method of screening acceptable.


Mexico's 2018 Report Card on Physical Activity for Children and Youth: Full report.
Mexico's 2018 Report Card evaluates the opportunities available for Mexican children and youth to reach healthy levels of physical activity, sleep, and sedentary behavior. The Report Card is a surveillance system that gathers data from national surveys, censuses, government documents, websites, grey literature, and published studies to evaluate 16 indicators in four categories: Daily Behaviors; Physical Fitness; Settings and Sources of Influence; and Strategies and Investments. Data were compared to established benchmarks. Each indicator was assigned a grade from 1 - 10 (< 6 is a failing grade) or "incomplete" if data was insufficient/unavailable. Daily Behavior grades were: Overall Physical Activity, 4; Organized Sport Participation, 5; Active Play, 3; Active Transportation, 5; Sleep, 7; and Sedentary Behavior, 3. Physical Fitness, received a 7. Settings and Sources of Influence grades were: Family and Peers, incomplete; School, 3; and Community and Environment, 4. Strategies and Investments were: Government Strategies, 6; and Non-Government Organizations, 2. Low grades in 11 of the 16 indicators indicate that schools, families, communities, and government need to work together to improve physical activity opportunities for children and youth in Mexico.


Genotype-temperature interaction in the regulation of development, growth, and morphometrics in wild-type, and growth-hormone transgenic coho salmon.
The neuroendocrine system is an important modulator of phenotype, directing cellular genetic responses to external cues such as temperature. Behavioural and physiological processes in poikilothermic organisms (e.g. most fishes), are particularly influenced by surrounding temperatures. By comparing the development and growth of two genotypes of coho salmon (wild-type and transgenic with greatly enhanced growth hormone production) at six different temperatures, ranging between 8 degrees and 18 degrees C, we observed a genotype-temperature interaction and possible trend in directed neuroendocrine selection. Differences in growth patterns of the two genotypes were compared by using mathematical models, and morphometric analyses of juvenile salmon were performed to detect differences in body shape. The maximum hatching and alevin survival rates of both genotypes occurred at 12 degrees C. At lower temperatures, eggs containing embryos with enhanced GH production hatched after a shorter incubation period than wild-type eggs, but this difference was not apparent at and above 16 degrees C. GH transgenesis led to lower body weights at the time when the yolk sack was completely absorbed compared to the wild genotype. The growth of juvenile GH-enhanced salmon was to a greater extent stimulated by higher temperatures than the growth of the wild-type. Increased GH production significantly influenced the shape of the salmon growth curves. Growth hormone overexpression by transgenesis is able to stimulate the growth of coho salmon over a wide range of temperatures. Temperature was found to affect growth rate, survival, and body morphology between GH transgenic and wild genotype coho salmon, and differential responses to temperature observed between the genotypes suggests they would experience different selective forces should they ever enter natural ecosystems. Thus, GH transgenic fish would be expected to differentially respond and adapt to shifts in environmental conditions compared with wild type, influencing their ability to survive and interact in ecosystems. Understanding these relationships would assist environmental risk assessments evaluating potential ecological effects.


Simultaneous estimation of thickness and refractive index of layered gradient refractive index optics using a hybrid confocal-scan swept-source optical coherence tomography system.
A hybrid confocal-scan swept-source optical coherence tomography metrology system was conceived for simultaneous measurements of the refractive index and thickness profiles of polymeric layered gradient refractive index (GRIN) optics. An uncertainty analysis predicts the metrology capability of the system and guides the selection of an optimum working numerical aperture. Experimental results on both a monolithic and a GRIN layered sheet are demonstrated to be in close agreement with theoretical predictions. Index measurement precision reached 0.0001 and 0.0008 for measuring 2.8 mm and ~300 µm thick layers, respectively. The thicknesses of these layers were simultaneously measured with a precision of 0.28 and 0.17 µm, respectively.


Phenotypic Characterization of Multifungicide Resistance in Botrytis cinerea Isolates from Strawberry Fields in Florida.
Chemical control has always been essential for the management of gray mold, caused by Botrytis cinerea, to ensure sustainable strawberry production. However, lack of knowledge about actual resistance development may have disastrous consequences and lead to severe epidemics such as the one that affected several strawberry fields in 2012 in Florida. In this study, we tested 392 isolates collected from Florida strawberry fields between 2010 and 2012 for their sensitivity to boscalid (Bosc), a succinate dehydrogenase inhibitor (SdhI); pyraclostrobin, a quinone outside inhibitor (QoI); boscalid + pyraclostrobin (Pristine); fenhexamid, a hydroxyanilide (Hyd); pyrimethanil and cyprodinil, anilinopyrimidines; fludioxonil, a phenylpyrrole; and fludioxonil + cyprodinil (Switch). The respective resistance frequencies for boscalid, pyraclostrobin, Pristine, fenhexamid, cyprodinil, and pyrimethanil were 85.4, 86.5, 86.0, 44.4, 52.7, and 59.5%. Overall, 17.8 and 19.8% of isolates showed reduced sensitivity to fludioxonil and Switch, respectively. All fungicides sprayed preventively on detached strawberry fruit failed to control isolates with high levels of resistance to each fungicide except for fludioxonil and Switch. Four phenotypes with multifungicide resistance (MFR) were detected in B. cinerea populations from Florida. Isolates resistant to one fungicide (FR1), two (MFR2), three (MFR3), and four (MFR4) fungicides from different chemical groups represented 5.9, 28.6, 41.8, and 23.7% of the total resistant population, respectively. The MFR3 isolates were predominant and contained two subpopulations, the Bosc-QoI-APR isolates (56.5%) and the Bosc-QoI-HydR isolates (40.6%). In addition to reporting on very highly resistant populations to boscalid and QoI fungicides, we show evidence for a widespread multifungicide resistance to B. cinerea that warrants immediate implementation of novel management strategies to impede the development of more resistant populations.


African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three U.S. population cohorts.
The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6 × 10(-6)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.


Preceding orbital granulocytic sarcoma in an adult patient with acute myelogenous leukemia with t(8;21): a case study and review of the literature.
A 25-year old man with a 30 month history of proptosis and pain of the right eye was referred to Severance Hospital of Yonsei University. Orbital computed tomography (CT) demonstrated a huge mass in the right retrobulbar orbit; an incisional biopsy and orbitotomy were performed for diagnosis and orbital soft tissue decompression. Subsequent histopathology disclosed sheets of mononuclear cells in the orbital mass, and immunohistochemical stains demonstrated positive results for myeloperoxidase and CD43, which supported the diagnosis of granulocytic sarcoma (GS). After his 1-year follow-up, the patient presented with pancytopenia, and an ensuing bone marrow aspiration revealed markedly hypercellular marrow replaced by many large abnormal myeloblasts. The patient was diagnosed with acute myelogenous leukemia with t(8;21) preceded by orbital GS. Orbital GS is primarily a disease of children, and extremely rare in adults. To the best of our knowledge, only four cases of this disease in adults have been reported in the literature. Our case is the first report of preceding orbital GS in an adult patient with a complex karyotype including t(8;21).


Combined effect of intercropping and turnip root fly (Delia floralis) larval feeding on the glucosinolate concentrations in cabbage roots and foliage.
The effects of plant competition and herbivory on glucosinolate concentrations in cabbage root and foliage were investigated in a cabbage-red clover intercropping system. Cabbage plants were grown under different competitive pressures and with varying degrees of attack by root-feeding Delia floralis larvae. Glucosinolate concentrations in cabbage were affected both by intercropping and by D. floralis density. Glucosinolate concentrations in foliage generally decreased as a response to intercropping, while the responses to insect root damage of individual glucosinolates were weaker. Root glucosinolates responded more strongly to both intercropping and egg density. Total root glucosinolate concentration decreased with clover density, but only at high egg densities. Increased egg density led to opposite reactions by the indole and aliphatic glucosinolates in roots. The responses of individual root glucosinolates to competition and root damage were complex and, on occasion, nonlinear. Reduced concentrations of several glucosinolates and the tendency towards a decrease in total concentration in cabbage foliage caused by intercropping and larval damage suggest that competing plants or plants with root herbivory do not allocate the same resources as unchallenged plants towards sustaining levels of leaf defensive compounds. This could also be true for root glucosinolate concentrations at high egg densities. In addition, the results suggest that changes occurring within a structural group of glucosinolates may be influenced by changes in a single compound, e.g., glucobrassicin (indol-3-ylmethyl) in foliage or sinigrin (2-propenyl) in roots.


Valtrex therapy for Epstein-Barr virus reactivation and upper respiratory symptoms in elite runners.
The aim of the study was to examine the effectiveness of prophylactic administration of the antiviral agent Valtrex for control of Epstein-Barr virus (EBV) reactivation and upper respiratory symptoms in elite distance runners. Twenty elite male distance runners were randomized into a 4-month double-blind, placebo-controlled cross-over trial. Saliva samples were collected weekly and mucosal immune status assessed by measurement of secretory IgA (SIgA) using an enzyme-linked immunosorbent assay (ELISA). EBV reactivation was monitored at the same time by detection of EBV in saliva using a quantitative real-time polymerase chain reaction. The initial EBV status of the runners was determined by detecting EBV antibodies in serum using an ELISA. Upper respiratory symptoms were recorded using self-reporting illness logs. There was no evidence of any marked change in maximal oxygen uptake (P = 0.86), training volume (P = 0.30), or mucosal immunity (P = 0.21) over the study period. Valtrex treatment resulted in an 82% reduction in the detectable EBV load in saliva for EBV seropositive runners compared with the placebo treatment (P = 0.04). The incidence of upper respiratory symptoms was not reduced by Valtrex treatment. The prophylactic administration of Valtrex reduced EBV reactivation but was not an effective intervention strategy for limiting upper respiratory symptoms in this cohort of elite distance runners. The upper respiratory symptoms in the distance runners could not be directly attributed to infection and may be of a noninfectious inflammatory nature.


Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1.
Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.


Hypocellular paratrabecular foci of treated small cleaved cell lymphoma in bone marrow biopsies.
Because of the new drug combinations being used to treat follicular lymphomas, the small cleaved cell lymphomatous foci in bone marrow biopsies appear to be altered. They become progressively hypocellular and contain a few and sometimes no small cleaved cells within oligocellular paratrabecular fibrous foci. These hypocellular paratrabecular foci (HPF) (a) are a clue that deeper sectioning is necessary to determine whether there are diagnostic foci of residual involvement by small cleaved cell lymphoma, (b) may indicate that other portions of the patient's bone marrow still contain viable foci of small cleaved cell lymphoma, and further, (c) should alert the clinician to the possibility of recurrence of small cleaved cell lymphoma in subsequent bone marrow biopsies. A comparison of patients who developed HPF in one or more of their bone marrow biopsy specimens with those who did not indicates that the changes are related to combinations of chemotherapy other than CHOP-Bleo (cyclophosphamide, adriamycin, vincristine, prednisone, bleomycin). Eighty-one percent of patients who developed HPF had received additional chemotherapeutic regimens, whereas 75% of patients whose bone marrows did not contain HPF had received only CHOP-B. The older age of the HPF-negative patients (median age 64 versus median age 43 for HPF-positive cases) may reflect more aggressive chemotherapy in the younger age group. While HPF appear to reflect some increased chemotherapeutic cytotoxicity affecting the lymphomatous foci in bone marrow, they do not appear to predict for a longer survival or cure.


Disruptions in functional network connectivity during alcohol intoxicated driving.
Driving while under the influence of alcohol is a major public health problem whose neural basis is not well understood. In a recently published functional magnetic resonance imaging (fMRI) study (Meda et al., 2009), our group identified 5, independent critical driving-associated brain circuits whose inter-regional connectivity was disrupted by alcohol intoxication. However, the functional connectivity between these circuits has not yet been explored in order to determine how these networks communicate with each other during sober and alcohol-intoxicated states. In the current study, we explored such differences in connections between the above brain circuits and driving behavior, under the influence of alcohol versus placebo. Forty social drinkers who drove regularly underwent fMRI scans during virtual reality driving simulations following 2 alcohol doses, placebo and an individualized dose producing blood alcohol concentrations (BACs) of 0.10%. At the active dose, we found specific disruptions of functional network connectivity between the frontal-temporal-basal ganglia and the cerebellar circuits. The temporal connectivity between these 2 circuits was found to be less correlated (p < 0.05) when driving under the influence of alcohol. This disconnection was also associated with an abnormal driving behavior (unstable motor vehicle steering). Connections between frontal-temporal-basal ganglia and cerebellum have recently been explored; these may be responsible in part for maintaining normal motor behavior by integrating their overlapping motor control functions. These connections appear to be disrupted by alcohol intoxication, in turn associated with an explicit type of impaired driving behavior.


The psychosocial impact of epilepsy on marriage: A narrative review.
There have been many studies exploring quality of life as well as the impact of epilepsy on the affected individual. However, epilepsy affects more than the patients themselves, and there seems to be a paucity of data regarding the impact of epilepsy beyond the person with epilepsy (PWE). In particular, it is uncertain what the impact of epilepsy on marriage may be. We therefore performed a narrative review to evaluate work measuring the psychosocial effect of epilepsy on marriage. We reviewed the literature on epilepsy and marriage by searching PubMed (Medline) and EMBASE and thoroughly examining relevant bibliographies. Forty-two papers were identified that addressed the issue of the psychosocial effect of epilepsy on marriage. The different approaches used to assess the impact of epilepsy on marriage can be broadly grouped into three categories: assessment of the social effect of living with epilepsy, which includes the marital prospects of PWEs and how changes in martial status associate with seizure frequency; assessment of quality of life (QOL) of PWEs; assessment of the association of social support with the disease burden of epilepsy. Within each of these approaches, different research methods have been employed including questionnaires, qualitative methods, and scales. The studies reviewed indicate that epilepsy has a severe impact on individuals and their families. While many quality-of-life surveys do comment on the marital status of the patient, there is little expansion beyond this. The impact that seizures may have on the partner of a patient with epilepsy is barely addressed. With increasing incidence of epilepsy in older populations, potential changes in the dynamic of a long-term marriage with the development of epilepsy in older age are not known. Similarly, the impact of marriage on concordance with medication or proceeding to, for example, surgical treatment for pharmacoresistant epilepsy has not been studied in detail. We suggest ways in which to address these aspects in order to better deliver holistic care to patients with epilepsy and their partners.


Iatrogenic Menopause After Treatment for Cervical Cancer.
The ever-improving prognosis of women diagnosed with cervical cancer has meant that survivorship and treatment-related sequelae are being brought more into the spotlight in an attempt to try to reduce morbidity and improve women's long-term health. However, there are many issues surrounding an iatrogenic menopause in cervical cancer, a variety of potential management options and barriers to treatment. Women who have become menopausal under the age of 45 years as a result of cervical cancer are significantly less likely to start hormone replacement therapy (HRT) or continue it long term as compared with those who have undergone a surgical menopause for a benign reason. High profile media reports raising concerns about the safety of HRT use have left many women reluctant to consider HRT as a therapeutic option for menopausal symptoms and many are seeking to use complementary/alternative medicine, including non-pharmacological interventions, to alleviate symptoms. The benefits of HRT in this population have been shown to reduce these effects, although adherence to treatment regimens is a challenge due to poor compliance, which is in part due to the fear of a second malignancy. The development of non-HRT-based interventions to ameliorate menopausal symptoms and reduce the long-term health consequences are needed for women who choose not to take HRT.


Multi-parametric neuroimaging reproducibility: a 3-T resource study.
Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan-rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22-61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1-5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols.


Treatment Progress and Behavior Following 2 Years of Inpatient Sex Offender Treatment.
Emerging research highlights the role of self-regulation in the treatment of sexual offenders. Safe Offender Strategies (SOS) is a manualized sex offender treatment program that emphasizes the role of self-regulation and self-regulatory skills development in sex offender treatment, particularly for offenders with serious mental illness and intellectual/developmental disabilities. The current study involves 156 adult male sexual offenders in an inpatient psychiatric setting who received SOS treatment for a period ranging from 6 months to 1 year. Participants' baseline and treatment data were obtained from archival medical records describing 1 year pre-treatment and up to 2 years of treatment participation. Dependent variables included monthly count rates of verbal and physical aggression and contact and noncontact sexual offending, as well as sexual deviancy attitudes, self-regulatory ability, and cooperation with treatment and supervision, as measured by the Sex Offender Treatment Intervention and Progress Scale (SOTIPS). Data were examined via paired-samples t tests, regression, and multilevel modeling, examining the impact of overall percentage of SOS groups attended over time, comparing participants' baseline measures to data from 2 years of treatment. The impact of predicted risk was also evaluated. Significant treatment dose effects were identified for improvements in aggression, sexual offending, and indicators of treatment compliance and change. These findings suggest that the skills-based, self-regulation approach utilized in SOS may be effective in improving clients' aggressive and sexual behaviors, attitudes toward their offenses and treatment, and self-regulatory ability over time. Implications for further research and treatment generalizability are discussed.


Lattice symmetries and the topologically protected transport of colloidal particles.
The topologically protected transport of colloidal particles on top of periodic magnetic patterns is studied experimentally, theoretically, and with computer simulations. To uncover the interplay between topology and symmetry we use patterns of all possible two dimensional magnetic point group symmetries with equal lengths lattice vectors. Transport of colloids is achieved by modulating the potential with external, homogeneous but time dependent magnetic fields. The modulation loops can be classified into topologically distinct classes. All loops falling into the same class cause motion in the same direction, making the transport robust against internal and external perturbations. We show that the lattice symmetry has a profound influence on the transport modes, the accessibility of transport networks, and the individual transport directions of paramagnetic and diamagnetic colloidal particles. We show how the transport of colloidal particles above a two fold symmetric stripe pattern changes from universal adiabatic transport at large elevations via a topologically protected ratchet motion at intermediate elevations toward a non-transport regime at low elevations. Transport above four-fold symmetric patterns is closely related to the two-fold symmetric case. The three-fold symmetric case however consists of a whole family of patterns that continuously vary with a phase variable. We show how this family can be divided into two topologically distinct classes supporting different transport modes and being protected by proper and improper six fold symmetries. We discuss and experimentally demonstrate the topological transition between both classes. All three-fold symmetric patterns support independent transport directions of paramagnetic and diamagnetic particles. The similarities and the differences in the lattice symmetry protected transport of classical over-damped colloidal particles versus the topologically protected transport in quantum mechanical systems are emphasized.


The 3-D prefrontal cortex: Hemispheric asymmetries in prefrontal activity and their relation to memory retrieval processes.
Neuroimaging results have raised interest in characterizing hemispheric asymmetries in prefrontal activity during different types of memory retrieval tasks. In this issue, Dobbins et al. and Mitchell et al. report results suggesting that the two hemispheres of the prefrontal cortex may indeed make different contributions to memory retrieval. Here, I discuss these findings within the context of studies characterizing more general processing differences between the cerebral hemispheres and studies characterizing prefrontal organization along the dorsal-ventral and anterior-posterior dimensions.


Oxidative stress in patients with Alzheimer's disease: effect of extracts of fermented papaya powder.
Brain tissue is particularly susceptible to oxidative stress (OS). Increased production of reactive oxygen species (ROS), reduced antioxidant systems, and decreased efficiency in repairing mechanisms have been linked to Alzheimer's disease (AD). Postmortem studies in AD patients' brains have shown oxidative damage markers (i.e., lipid peroxidation, protein oxidative damage, and glycoxidation). Fermented papaya (FPP, a product of Carica papaya Linn fermentation with yeast) is a nutraceutical supplement with favorable effects on immunological, hematological, inflammatory, and OS parameters in chronic/degenerative diseases. We studied 40 patients (age 78.2 ± 1.1 years), 28 AD patients, and 12 controls. Urinary 8-OHdG was measured to assess OS. Twenty AD patients were supplemented with FPP (Immunage, 4.5 grams/day) for 6 months, while controls did not receive any treatment. At baseline, 8-OHdG was significantly higher in patients with AD versus controls (13.7 ± 1.61 ng/mL versus 1.6 ± 0.12 ng/mL, P < 0.01). In AD patients FPP significantly decreased 8-OHdG (14.1 ± 1.7 ng/mL to 8.45 ± 1.1 ng/mL, P < 0.01), with no significant changes in controls. AD is associated with increased OS, and FPP may be helpful to counteract excessive ROS in AD patients.


Tyrosine improves appetite, cognition, and exercise tolerance in activity anorexia.
We have modified for mice the activity wheel model of Routtenberg to study the effects of tyrosine on exercise tolerance, behavior, and brain neurochemistry. Mice were fed for 2 h.d(-1) over a 2-wk period. During the second week, each group was injected daily with either saline or tyrosine (100 mg.kg(-1).d(-1)) and exercised on a running wheel. Controls were in cages with inactivated wheels and received the same treatment and feeding protocols as the experimental groups. Food consumption and cognitive function (eight-arm maze) were evaluated for 1 wk. Brains were then assayed for adrenergic and serotonergic metabolites. Activity together with a restricted diet caused extreme weight loss (27%) (P < 0.001) together with decreased food consumption (22%) (P < 0.001). Tyrosine restored food consumption to that of the controls (P < 0.001) with no effect on weight, since there was a 22% increase in activity (P < 0.001). Saline injections caused an 18% decrease in activity (P < 0.001). Both activity and tyrosine improved maze performance (P < 0.05). In the hypothalamus, activity caused a significant increase in 5-hydroxytryptamine (5-HT) (P < 0.001), 5-hydroxyindoleacetic acid (5-HIAA) (P < 0.01), and dopamine (P < 0.05); tyrosine prevented the increase in 5-HT (P < 0.05) and increased 5-HIAA in the controls (P < 0.01). With regard to hippocampal 5-HT, there was a significant increase in 5-HIAA following activity (P < 0.05), whereas tyrosine caused significant increase in 5-HIAA in the controls (P < 0.01). Activity significantly decreased the level of hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), whereas tyrosine decreased its level only in the controls (both at P < 0.0001). The level of tyrosine hydroxylase increased with activity (P < 0.05), and tyrosine decreased it significantly (P < 0.05). Activity anorexia is associated with increased hypothalamic 5-HT concentrations. Tyrosine administration reverses this, and significantly improves food consumption, cognitive behavior, and activity performance. Such nutritional modulations may have implications for the treatment of eating disorders and, in normal circumstances, tyrosine may improve exercise tolerance and delay fatigue.


Repeatability of measurement of fetal nuchal translucency thickness.
The aim of this prospective study was to assess the repeatability of measurement of fetal nuchal translucency thickness at 10-14 weeks' gestation. The nuchal translucency was measured by two of four operators in 200 pregnant women attending the Harris Birthright Research Centre for Fetal Medicine at 10-14 weeks' gestation. To assess repeatability of different components of variability, six measurements of nuchal translucency were made on each fetus, with a total of 1200 measurements. The data of this study demonstrate that 95% of the time the intraobserver, interobserver and caliper placement repeatability of measuring fetal nuchal translucency were less than 0.54 mm, 0.62 mm and 0.58 mm, respectively. In addition, the repeatability was unrelated to the size of the nuchal translucency. The findings of this study demonstrate that, when the nuchal translucency thickness is measured by well-trained operators, the measurement is highly reproducible.


Intraductal radiofrequency ablation of tumour ingrowth into an uncovered metal stent used for inoperable cholangiocarcinoma.
A 91-year-old woman diagnosed to have an inoperable cholangiocarcinoma had an uncovered metal stent inserted for palliative drainage. About 1.5 years later, tumour ingrowth into the metal stent caused cholangitis. Intraductal radiofrequency ablation was applied to create local coagulative tumour necrosis and the necrotic tissue was removed via a balloon catheter. A plastic stent was inserted to empirically treat any ensuing potential bile duct injury. The patient was discharged without complication with good palliative drainage. Intraductal radiofrequency ablation is a new technique for the treatment of metal stent occlusion due to tumour ingrowths. This is the first case report of this relatively safe and feasible new technique for the treatment of tumour ingrowth into a metal stent used as palliation for malignant biliary obstruction.


Predictors of patient satisfaction.
Correlates of patient satisfaction at varying points in time were assessed using a survey with 2-week and 3-month follow-up in a general medicine walk-in clinic, in USA. Five hundred adults presenting with a physical symptom, seen by one of 38 participating clinicians were surveyed and the following measurements were taken into account: patient symptom characteristics, symptom-related expectations, functional status (Medical Outcomes Study Short-Form Health Survey [SF-6]), mental disorders (PRIME-MD), symptom resolution, unmet expectations, satisfaction (RAND 9-item survey), visit costs and health utilization. Physician perception of difficulty (Difficult Doctor Patient Relationship Questionnaire), and Physician Belief Scale. Immediately after the visit, 260 (52%) patients were fully satisfied with their care, increasing to 59% at 2 weeks and 63% by 3 months. Patients older than 65 and those with better functional status were more likely to be satisfied. At all time points, the presence of unmet expectations markedly decreased satisfaction: immediately post-visit (OR: 0.14, 95% CI: 0.07-0.30), 2-week (OR: 0.07, 95% CI: 0.04-0.13) and 3-month (OR: 0.05, 95% CI: 0.03-0.09). Other independent variables predicting immediate after visit satisfaction included receiving an explanation of the likely cause as well as expected duration of the presenting symptom. At 2 weeks and 3 months, experiencing symptomatic improvement increased satisfaction while additional visits (actual or anticipated) for the same symptom decreased satisfaction. A lack of unmet expectations was a powerful predictor of satisfaction at all time-points. Immediately post-visit, other predictors of satisfaction reflected aspects of patient doctor communication (receiving an explanation of the symptom cause, likely duration, lack of unmet expectations), while 2-week and 3-month satisfaction reflected aspects of symptom outcome (symptom resolution, need for repeat visits, functional status). Patient satisfaction surveys need to carefully consider the sampling time frame as well as adjust for pertinent patient characteristics.


How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1)-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics) to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.


Fluorescence spectroscopy of single biomolecules.
Recent advances in single-molecule detection and single-molecule spectroscopy at room temperature by laser-induced fluorescence offer new tools for the study of individual macromolecules under physiological conditions. These tools relay conformational states, conformational dynamics, and activity of single biological molecules to physical observables, unmasked by ensemble averaging. Distributions and time trajectories of these observables can therefore be measured during a reaction without the impossible need to synchronize all the molecules in the ensemble. The progress in applying these tools to biological studies with the use of fluorophores that are site-specifically attached to macromolecules is reviewed.


Bicycle accidents in childhood.
The results of a 10 year study of bicycle fatalities and an eight year study of serious non-fatalities are reported for urban Brisbane (population 1,000,000). There were 845 serious non-fatal bicycle accidents and 46 fatalities during the study. Boys were involved in 86% of accidents. Boys have an accident rate of 134.21 per 100,000 population at risk and a fatality rate of 5.06 per 100,000 at risk. Serious bicycle accidents have increased by 50% in this decade; but considering fatal cases alone, no secular trend was evident over the 10 year period of the study. This suggests that an increase in the overall rate of bicycle accidents has been in part compensated by less serious injuries. In 70% of fatalities children had head injuries, and 87% of fatalities followed a collision between a cyclist and a motor vehicle or a train. Bicycle accidents on the roads most commonly occur to boys aged between 12 and 14 years on a straight road at "mid-block" between 3 and 5 pm in clear weather conditions and in daylight. It is concluded that injuries and fatalities after bicycle accidents can be reduced by protecting children's heads, separating child cyclists from other road traffic, or educating and training both cyclists and other road users in safe behaviour. The compulsory use of helmets and the restriction of access to the roads by child cyclists to reduce injuries are, however, still controversial in many areas.


Prediction of Cancer Incidence and Mortality in Korea, 2022.
This study aimed to report the projected cancer incidence and mortality for the year 2022 to estimate Korea's current cancer burden. Cancer incidence data from 1999 to 2019 were obtained from the Korea National Cancer Incidence Database, and cancer mortality data from 1993 to 2020 were acquired from Statistics Korea. Cancer incidence and mortality were projected by fitting a linear regression model to observed age-specific cancer rates against their respective years and then by multiplying the projected age-specific rates by the anticipated age-specific population for 2022. A joinpoint regression model was used to determine the year in which the linear trend changed significantly; we only used the data of the latest trend. In total, 274,488 new cancer cases and 81,277 cancer deaths are expected to occur in Korea in 2022. The most common cancer site is expected to be the thyroid, followed by the lung, colon and rectum, breast, and stomach. These five cancers are expected to represent half of the overall burden of cancer in Korea. The most common type of cancer leading to death is expected to be lung cancer, followed by liver, colorectal, pancreatic, and gallbladder cancers. The incidence rates for all types of cancer in Korea are estimated to gradually decrease. These up-to-date estimates of the cancer burden in Korea could be an important resource for planning and evaluating cancer-control programs.


The effect of hydroperiod and predation on the diversity of temporary pond zooplankton communities.
In temporary pond ecosystems, it is hypothesized that the two dominant structuring forces on zooplankton communities are predation and demographic constraints due to wetland drying. Both of these forces are deterministic processes that act most strongly at opposing ends of a hydroperiod gradient. Our objective was to test how these two processes affect α- and β-diversity of zooplankton communities derived from a diverse temporary pond system. We hypothesized that decreased hydroperiod length and the presence of salamander larvae as predators would decrease β-diversity and that intermediate hydroperiod communities would have the greatest species richness. Our 1-year mesocosm experiment (n = 36) consisted of two predation treatments (present/absent) and three hydroperiod treatments (short/medium/long) fully crossed, seeded from the resting egg bank of multiple temporary ponds. In total, we collected 37 species of microcrustacean zooplankton from our mesocosms. A reduction in hydroperiod length resulted in lower α-diversity, with short-hydroperiod treatments affected most strongly. Endpoint community dissimilarity (β-diversity) was greatest in the medium-hydroperiod treatment with regard to species presence/absence, but was greatest in the long-hydroperiod treatment when abundances were included. Predation by salamander larvae led to reduced β-diversity with respect to species presence/absence, but not among abundant species, and had no effect on α-diversity. Our results suggest that environmental changes that reduce hydroperiod length would result in reduced α-diversity; however, intermediate hydroperiod length appear to enhance β-diversity within a group of wetlands.


Continuous intravenous anakinra for treating severe secondary haemophagocytic lymphohistiocytosis/macrophage activation syndrome in critically ill children.
The cytokine storm of secondary haemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) can cause life-threatening multiorgan failure. Interleukin-1 (IL-1) receptor blockade with anakinra can be effective in the management of sHLH/MAS. Subcutaneous (SC) dosing regimens are widely described; however, intravenous (IV) dosing is advantageous where time-critical intervention is vital and where SC oedema and/or hypoperfusion limits absorption. We review three critically ill children (aged 9, 11 and 17) with sHLH and rapidly progressive multiorgan dysfunction, successfully treated with continuous IV anakinra infusion. This case series significantly enhances the incipient knowledge regarding the safety and efficacy of IV anakinra for life-threatening sHLH.


A minimally invasive technique for the detection and analysis of pulmonary fat embolism: a feasibility study.
We investigated the feasibility of postmortem percutaneous needle biopsy (PNB) for obtaining pulmonary samples adequate for the study of pulmonary fat embolism (PFE). Samples of both lungs were obtained from 26 cadavers via two different methods: (i) PNB and (ii) the double-edged knife technique, the gold standard at our institute. After water storage and Sudan III staining, six forensic pathologists independently examined all samples for the presence and severity of PFE. The results were compared and analyzed in each case regarding the vitality of the PFE and its relationship to the cause of death. The results showed that PFE was almost identically diagnosed and graded on the samples obtained via both methods. The discrepancies between the two techniques did not affect the diagnoses of vitality or cause of death related to PFE. This study demonstrates the feasibility of the PNB sampling method for the diagnosis and interpretation of PFE in the postmortem setting.


Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 3 Years of Follow-up.
To report 3-year results of the Primary Tube Versus Trabeculectomy (PTVT) Study. Unmasked multicenter randomized clinical trial. Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. Patients were enrolled at 16 clinical centers and were assigned randomly to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC; 0.4 mg/ml for 2 minutes). The primary outcome measure was the rate of surgical failure, defined as intraocular pressure (IOP) of more than 21 mmHg or reduced less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures included IOP, glaucoma medical therapy, visual acuity, and surgical complications. The cumulative probability of failure after 3 years of follow-up was 33% in the tube group and 28% in the trabeculectomy group (P = 0.17; hazard ratio, 1.39; 95% confidence interval, 0.9-2.2). Mean ± standard deviation IOP was 14.0±4.2 mmHg in the tube group and 12.1±4.8 mmHg in the trabeculectomy group at 3 years (P = 0.008), and the number of glaucoma medications was 2.1±1.4 in the tube group and 1.2±1.5 in the trabeculectomy group (P < 0.001). Serious complications requiring reoperation or producing loss of 2 or more Snellen lines developed in 3 patients (2%) in the tube group and 9 patients (8%) in the trabeculectomy group (P = 0.11). There was no significant difference in the rate of surgical failure between the 2 surgical procedures at 3 years. Trabeculectomy with MMC achieved lower IOP with use of fewer glaucoma medications compared with tube shunt surgery after 3 years of follow-up in the PTVT Study. Serious complications producing vision loss or requiring reoperation occurred with similar frequency after both surgical procedures.


B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance.
Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.


Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle.
Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.


Elimination and accumulation of polycyclic aromatic hydrocarbons in urban stormwater wet detention ponds.
The concentrations of polycyclic aromatic hydrocarbons (PAHS) in water and sediments of seven wet detention ponds receiving urban stormwater were investigated. The ponds comprised traditional wet detention ponds with a permanent wet volume and a storage volume as well as ponds that were expanded with sand filters and other means to improve the removal of micropollutants. The concentrations of sigmaPAH in the sediments varied between 6 +/- 5 and 2,222 +/- 603 ng g(-1) dry weight (mean +/- standard deviation), and were highest in the ponds with lower pond volume per catchment area and did not clearly reflect different activities in the catchments. In general, the concentrations of PAHS in the sediments decreased from inlet to outlet, especially in the systems with good conditions for sedimentation such as systems with flow perpendicular sand dikes and extensive submerged vegetation. High molecular weight PAHs were predominant in the sediments indicating the pyrogenic origin of the PAHS. There was no correlation between PAH species concentrations in water or sediments and their hydrophobicity (log K(ow)). PAH concentrations in water fluctuated in response to intensity and frequency of rain events, whereas concentrations in the sediments integrated the pollutant load over time. Pond systems expanded with sand filters and other technologies to enhance removal of micropollutants consistently had concentrations of PAHS in the effluents below the detection level.


β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.
Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.


Understanding the role of self-identity in habitual risky behaviours: pedestrian road-crossing decisions across the lifespan.
Self-identity as a careful pedestrian has not been fully considered in previous work on predicting intention to cross the road, or actual crossing behaviour, in non-optimal situations. Evidence suggests that self-identity may be a better predictor than attitudes in situations where decision-making styles have become habitual ways to respond. This study compared contributions of self-identity and attitudes to the prediction of intentions in two situations differing in level of habitual crossing expectation, and to crossing behaviour. Three hundred and sixty-two adults (17-92 years) completed a questionnaire measuring self-identity, attitudes, intentions, experience, social identity variables (e.g. age, gender) and personal limitations (mobility). Two hundred and five participants also completed a road-crossing simulation. Self-identity and attitude were both shown as significant independent predictors of intention in both situations. However, self-identity was less effective as a predictor in the higher risk scenario, where intention to perform the behaviour was lower, and for participants aged >75 years who had lower intention across scenarios. Self-identity strongly predicted intention to cross, which in turn predicted behaviour, but self-identity did not directly predict behaviour. Self-identity was strongly predicted by age. Implications for theories of compensation in older age and for design and targeting of pedestrian safety education are discussed.


A fully synthetic therapeutic vaccine candidate targeting carcinoma-associated Tn carbohydrate antigen induces tumor-specific antibodies in nonhuman primates.
We recently developed an efficient strategy based on a fully synthetic dendrimeric carbohydrate display (multiple antigenic glycopeptide; MAG) to induce anticarbohydrate antibody responses for therapeutic vaccination against cancer. Here, we show the superior efficacy of the MAG strategy over the traditional keyhole limpet hemocyanin glycoconjugate to elicit an anticarbohydrate IgG response against the tumor-associated Tn antigen. We highlight the influence of the aglyconic carrier elements of such a tumor antigen for their recognition by the immune system. Finally, we additionally developed the MAG system by introducing promiscuous HLA-restricted T-helper epitopes and performed its immunological evaluation in nonhuman primates. MAG:Tn vaccines induced in all of the animals strong tumor-specific anti-Tn antibodies that can mediate antibody-dependent cell cytotoxicity against human tumor. Therefore, the preclinical evaluation of the MAG:Tn vaccine demonstrates that it represents a safe and highly promising immunotherapeutic molecularly defined tool for targeting breast, colon, and prostate cancers that express the carbohydrate Tn antigen.


Dietary Intake, Body Composition, and Nutrition Knowledge of Australian Football and Soccer Players: Implications for Sports Nutrition Professionals in Practice.
Sports nutrition professionals aim to influence nutrition knowledge, dietary intake and body composition to improve athletic performance. Understanding the interrelationships between these factors and how they vary across sports has the potential to facilitate better-informed and targeted sports nutrition practice. This observational study assessed body composition (DXA), dietary intake (multiple-pass 24-hr recall) and nutrition knowledge (two previously validated tools) of elite and subelite male players involved in two team-based sports; Australian football (AF) and soccer. Differences in, and relationships between, nutrition knowledge, dietary intake and body composition between elite AF, subelite AF and elite soccer players were assessed. A total of 66 (23 ± 4 years, 82.0 ± 9.2 kg, 184.7 ± 7.7 cm) players participated. Areas of weaknesses in nutrition knowledge are evident (57% mean score obtained) yet nutrition knowledge was not different between elite and subelite AF and soccer players (58%, 57% and 56%, respectively, p > .05). Dietary intake was not consistent with recommendations in some areas; carbohydrate intake was lower (4.6 ± 1.5 g/kg/day, 4.5 ± 1.2 g/kg/day and 2.9 ± 1.1 g/kg/day for elite and subelite AF and elite soccer players, respectively) and protein intake was higher (3.4 ± 1.1 g/kg/day, 2.1 ± 0.7 g/kg/day and 1.9 ± 0.5 g/kg/day for elite and subelite AF and elite soccer players, respectively) than recommendations. Nutrition knowledge was positively correlated with fat-free soft tissue mass (n = 66; r2 = .051, p = .039). This insight into known modifiable factors may assist sports nutrition professionals to be more specific and targeted in their approach to supporting players to achieve enhanced performance.


Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study.
A lower retinal arteriolar-to-venular ratio (AVR) has been suggested to reflect generalized arteriolar narrowing and to predict the risk of cardiovascular diseases. The contribution of the separate arteriolar and venular diameters to this AVR is unknown. Thus, associations between retinal arteriolar and venular diameters, and the AVR on the one hand and blood pressure, atherosclerosis, inflammation markers, and cholesterol levels on the other were examined in the Rotterdam Study. In this cross-sectional population-based study, for one eye of each subject (> or =55 years; n = 5674), retinal arteriolar and venular diameters (in micrometers) of the blood columns were summed on digitized images. At baseline blood pressures, cholesterol levels, and markers of atherosclerosis and inflammation were also measured. With increasing blood and pulse pressures, retinal arteriolar and venular diameters and the AVR decreased significantly and linearly. Lower arteriolar diameters were associated with increased carotid intima-media thickness. Larger venular diameters were associated with higher carotid plaque score, more aortic calcifications, lower ankle-arm index, higher leukocyte count, higher erythrocyte sedimentation rate, higher total serum cholesterol, lower HDL, higher waist-to-hip ratio, and smoking. A lower AVR was related to increased carotid intima-media thickness, higher carotid plaque score, higher leukocyte count, lower HDL, higher body mass index, higher waist-to-hip ratio, and smoking. Because larger venular diameters are associated with atherosclerosis, inflammation, and cholesterol levels, the AVR does not depend only on generalized arteriolar narrowing due to the association between smaller arteriolar diameters and higher blood pressures. These data indicate that retinal venular diameters are variable and may play their own independent role in predicting cardiovascular disorders.


Poorly neutralizing cross-reactive antibodies against the fusion loop of West Nile virus envelope protein protect in vivo via Fcgamma receptor and complement-dependent effector mechanisms.
The human antibody response to flavivirus infection is dominantly directed against a cross-reactive epitope on the fusion loop of domain II (DII-FL) of the envelope (E) protein. Although antibodies against this epitope fail to recognize fully mature West Nile virus (WNV) virions and accordingly neutralize infection poorly in vitro, their functional properties in vivo remain less well understood. Here, we show that while passive transfer of poorly neutralizing monoclonal antibodies (MAb) and polyclonal antibodies against the DII-FL epitope protect against lethal WNV infection in wild-type mice, they fail to protect mice lacking activating Fcγ receptors (FcγR) and the complement opsonin C1q. Consistent with this, an aglycosyl chimeric mouse-human DII-FL MAb (E28) variant that lacks the ability to engage FcγR and C1q also did not protect against WNV infection in wild-type mice. Using a series of immunodeficient mice and antibody depletions of individual immune cell populations, we demonstrate that the nonneutralizing DII-FL MAb E28 does not require T, B, or NK cells, inflammatory monocytes, or neutrophils for protection. Rather, E28 treatment decreased viral load in the serum early in the course of infection, which resulted in blunted dissemination to the brain, an effect that required phagocytic cells, C1q, and FcγRIII (CD16). Overall, these studies enhance our understanding of the functional significance of immunodominant, poorly neutralizing antibodies in the polyclonal human anti-flavivirus response and highlight the limitations of current in vitro surrogate markers of protection, such as cell-based neutralization assays, which cannot account for the beneficial effects conferred by these antibodies.


[Mobility and balance].
Quality of life is strongly associated with the mobility of elderly people. Falls often cause restricted mobility, a decline in activities of daily living and an increased risk of institutionalisation. Frailty, commonly associated with aging, is a biologic syndrome of decreased resistance to stressors, resulting from declines across multiple physiological systems. Changes in mobility and gait constitute part of the frailty syndrome. Since more than one third of persons over the age of 65 fall each year, prevention of falls is very important. Already while taking the patients' history special emphasis should be laid on matters associated with an increased risk of falling, such as the use of more than four medications. To assess mobility several brief tests exist (i.e. Timed up & go [17], Walking while Talking [20]) which immediately yield information regarding mobility and falling risk. Patients with poor performance on such tests or those with a history of several falls should undergo a spatio-temporal gait analysis in order to determine a possible cause as well as suitable interventions. Additionally, the objective measurement of temporo-spatial gait parameters under dual task conditions may detect deficits in cognitive function. Several interventions have been shown to have favourable effects on gait stability and the occurrence of falls. Proprioceptive problems can be partially compensated for by wearing special shoes. Also, different movement exercises such as Tai Chi Chuan, Jaques-Dalcroze eurhythmics and social dancing are associated with better balance and gait safety, and a reduction of falls.


Response of pediatric malignant solid tumors following ifosfamide or ifosfamide/carboplatin/etoposide: a single hospital experience.
One hundred thirty-eight pediatric patients have received treatment for malignant solid tumors with ifosfamide with mesna, and 71 have received a combination with ifosfamide/carboplatin/etoposide (ICE). Responses were obtained in many types of pediatric tumors, yet comparison of responses was not possible because of inadequate numbers of tumors of differing histiotypes. Comparison of results between patients with all tumors treated with ifosfamide or ICE indicated that there was a higher response rate for patients treated with ICE, with an estimated odds ratio of 2.74 (95% C.I. 1.45-5.179). Excluding patients without prior chemotherapy and radiotherapy, the odds ratio for 2.801 (95% C.I. 1.45-5.4) suggests a similar result. There remain no guarantees that the more costly treatment with ICE, which requires cytokine support, will offer therapeutic benefits against resistant solid tumors.


Do Machines Replicate Humans? Toward a Unified Understanding of Radicalizing Content on the Open Social Web.
The advent of the Internet inadvertently augmented the functioning and success of violent extremist organizations. Terrorist organizations like the Islamic State in Iraq and Syria (ISIS) use the Internet to project their message to a global audience. The majority of research and practice on web-based terrorist propaganda uses human coders to classify content, raising serious concerns such as burnout, mental stress, and reliability of the coded data. More recently, technology platforms and researchers have started to examine the online content using automated classification procedures. However, there are questions about the robustness of automated procedures, given insufficient research comparing and contextualizing the difference between human and machine coding. This article compares output of three text analytics packages with that of human coders on a sample of one hundred nonindexed web pages associated with ISIS. We find that prevalent topics (e.g., holy war) are accurately detected by the three packages whereas nuanced concepts (Lone Wolf attacks) are generally missed. Our findings suggest that naïve approaches of standard applications do not approximate human understanding, and therefore consumption, of radicalizing content. Before radicalizing content can be automatically detected, we need a closer approximation to human understanding.