Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways.
The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.


Mass spectrometric analysis of HOCl- and free-radical-induced damage to lipids and proteins.
In inflammatory diseases, release of oxidants leads to oxidative damage to biomolecules. HOCl (hypochlorous acid), released by the myeloperoxidase/H2O2/Cl- system, can cause formation of phospholipid chlorohydrins, or alpha-chloro-fatty aldehydes from plasmalogens. It can attack several amino acid residues in proteins, causing post-translational oxidative modifications of proteins, but the formation of 3-chlorotyrosine is one of the most stable markers of HOCl-induced damage. Soft-ionization MS has proved invaluable for detecting the occurrence of oxidative modifications to both phospholipids and proteins, and characterizing the products generated by HOCl-induced attack. For both phospholipids and proteins, the application of advanced mass spectrometric methods such as product or precursor ion scanning and neutral loss analysis can yield information both about the specific nature of the oxidative modification and the biomolecule modified. The ideal is to be able to apply these methods to complex biological or clinical samples, to determine the site-specific modifications of particular cellular components. This is important for understanding disease mechanisms and offers potential for development of novel biomarkers of inflammatory diseases. In the present paper, we review some of the progress that has been made towards this goal.


A Systematic Review of Cost-Effectiveness Models in Type 1 Diabetes Mellitus.
Critiques of cost-effectiveness modelling in type 1 diabetes mellitus (T1DM) are scarce and are often undertaken in combination with type 2 diabetes mellitus (T2DM) models. However, T1DM is a separate disease, and it is therefore important to appraise modelling methods in T1DM. This review identified published economic models in T1DM and provided an overview of the characteristics and capabilities of available models, thus enabling a discussion of best-practice modelling approaches in T1DM. A systematic review of Embase(®), MEDLINE(®), MEDLINE(®) In-Process, and NHS EED was conducted to identify available models in T1DM. Key conferences and health technology assessment (HTA) websites were also reviewed. The characteristics of each model (e.g. model structure, simulation method, handling of uncertainty, incorporation of treatment effect, data for risk equations, and validation procedures, based on information in the primary publication) were extracted, with a focus on model capabilities. We identified 13 unique models. Overall, the included studies varied greatly in scope as well as in the quality and quantity of information reported, but six of the models (Archimedes, CDM [Core Diabetes Model], CRC DES [Cardiff Research Consortium Discrete Event Simulation], DCCT [Diabetes Control and Complications Trial], Sheffield, and EAGLE [Economic Assessment of Glycaemic control and Long-term Effects of diabetes]) were the most rigorous and thoroughly reported. Most models were Markov based, and cohort and microsimulation methods were equally common. All of the more comprehensive models employed microsimulation methods. Model structure varied widely, with the more holistic models providing a comprehensive approach to microvascular and macrovascular events, as well as including adverse events. The majority of studies reported a lifetime horizon, used a payer perspective, and had the capability for sensitivity analysis. Several models have been developed that provide useful insight into T1DM modelling. Based on a review of the models identified in this study, we identified a set of 'best in class' methods for the different technical aspects of T1DM modelling.


Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion.
Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.


Evaluation of clomipramine as an adjunct to behavioural therapy in the treatment of separation-related problems in dogs.
Forty-nine dogs showing signs of separation-related problems were randomly assigned to one of three groups: group A (15 dogs) received a placebo twice daily; group B (17 dogs) received clomipramine at 0.5 to 1.0 mg/kg twice daily; and group C (17 dogs) received clomipramine at 1.0 to 2.0 mg/kg twice daily. All the dogs also received behavioural therapy. Their owners were required to complete questionnaires about their dog's behaviour initially, and one, four and eight weeks after the treatment with clomipramine began. Bipolar ratings scales were used to monitor the frequencies of 'general', 'attachment-related' and 'separation-related' behaviours. Kruskal-Wallis tests and Kendall Rank correlations were used to determine any initial differences between the treatment groups, and the association between the initial scores and behavioural changes after one week of treatment with clomipramine. Extended Mantel-Haenszel statistics were used to evaluate the effects of clomipramine treatment versus the placebo, and Page's test was used to assess the effectiveness of behavioural therapy on its own. There were no significant differences in the demographic characteristics of the owners of the dogs assigned to the three groups. The dogs differed slightly in age between groups, and the dogs in the two clomipramine-treated groups were reported as showing problems at a significantly earlier age than those in the placebo group. Clomipramine treatment had a sustained suppressive effect on the dogs' general activity levels, and a more modest suppressive effect on their attachment-related tendency to want much physical contact with their owners. The typical signs of separation-related behaviour problems were not significantly affected by treatment with clomipramine, but behavioural therapy on its own was highly effective in reducing behavioural problems.


Cytomegalovirus infections in pediatric liver transplantation.
From 1986 to 1989, 26 consecutive pediatric liver transplant recipients were followed up at The Hospital for Sick Children, Toronto, Canada. The patients were reviewed to assess the incidence of infection with cytomegalovirus, the severity of disease, and the relationship of recipient and donor serostatus to cytomegalovirus disease. Overall, the incidence of infection was 54% (14/26). Over 90% of patients who were seropositive or whose donors were seropositive developed evidence of cytomegalovirus infection after transplantation. Forty-three percent (6/14) of those with cytomegalovirus infections developed severe, fatal cytomegalovirus disease, despite treatment with immunoglobulins and ganciclovir (Syntex Laboratories Inc, Palo Alto, Calif) or foscarnet sodium (Astra, Pharmaceutical Products Inc, Westborough, Mass). Of all posttransplant deaths, two thirds were associated with severe cytomegalovirus infection. Cytomegalovirus-related deaths occurred in three of four seronegative patients with seropositive donors and three of six seropositive patients with seropositive donors. Therefore, a seropositive donor appeared to be a major risk factor for severe cytomegalovirus disease.


Motoric impairment following manganese exposure in asteroid echinoderms.
In the oceans, naturally occurring manganese (Mn) is released from the sediments during events of hypoxia. While neuro- and immuno-toxic effects of bioavailable manganese are well documented for crustaceans, studies of similar effects of manganese on other marine invertebrates are comparatively few. Here, we developed a new functional test "the repeated turning assay" to investigate if manganese exposure at ∼12 mg L(-1) affected motoric behaviour of two asteroid echinoderms, the Common sea star, Asterias rubens, and the Black brittle star, Ophiocomina nigra. By measuring of the turning-over capacity, from dorsal to ventral position, after one and two weeks of manganese exposure, we showed that for both species Mn exposure significantly delayed the ability to turn. After a recovery period of two weeks, the capacity of turning-over was not restored to that of unexposed animals neither for A. rubens nor for O. nigra. Further investigation of sea stars showed that Mn accumulated ∼5 fold in the tube feet, organs involved in their turning-over activity, and the high concentration remained after the recovery period. In the tube feet we also recorded an increased activity of acetylcholinesterase (AChE), here used as a proxy for neuromuscular disturbances. The results indicated that Mn induces neuromuscular disturbance in echinoderms which is important news, given that previous studies have concluded that adult echinoderms are relatively tolerant to Mn.


Destructive impact of imperfect beam collimation in extraordinary optical transmission.
We investigate the difference between analytic predictions, numerical simulations, and experiments measuring the transmission of energy through subwavelength, periodically arranged holes in a metal film. At normal incidence, theory predicts a sharp transmission minimum when the wavelength is equal to the periodicity, and sharp transmission maxima at one or more nearby wavelengths. In experiments, the sharpest maximum from the theory is not observed, while the others appear less sharp. In numerical simulations using commercial electromagnetic field solvers, we find that the sharpest maximum appears and approaches our predictions as the computational resources are increased. To determine possible origins of the destruction of the sharp maximum, we incorporate additional features in our model. Incorporating imperfect conductivity and imperfect periodicity in our model leaves the sharp maximum intact. Imperfect collimation, on the other hand, incorporated into the model causes the destruction of the sharp maximum as happens in experiments. We provide analytic support through an asymptotic calculation for both the existence of the sharp maximum and the destructive impact of imperfect collimation.


Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes.
To determine whether exposure to repetitive head impacts over a single season affects white matter diffusion measures in collegiate contact sport athletes. A prospective cohort study at a Division I NCAA athletic program of 80 nonconcussed varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 79 non-contact sport athletes. Assessment occurred preseason and shortly after the season with diffusion tensor imaging and neurocognitive measures. There was a significant (p = 0.011) athlete-group difference for mean diffusivity (MD) in the corpus callosum. Postseason fractional anisotropy (FA) differed (p = 0.001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions, including the corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. The magnitude of change in corpus callosum MD postseason was associated with poorer performance on a measure of verbal learning and memory. This study suggests a relationship between head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion, in a cohort of college athletes. Further work is needed to assess whether such effects are short term or persistent.


Human hippocampus represents space and time during retrieval of real-world memories.
Memory stretches over a lifetime. In controlled laboratory settings, the hippocampus and other medial temporal lobe brain structures have been shown to represent space and time on the scale of meters and seconds. It remains unclear whether the hippocampus also represents space and time over the longer scales necessary for human episodic memory. We recorded neural activity while participants relived their own experiences, cued by photographs taken with a custom lifelogging device. We found that the left anterior hippocampus represents space and time for a month of remembered events occurring over distances of up to 30 km. Although previous studies have identified similar drifts in representational similarity across space or time over the relatively brief time scales (seconds to minutes) that characterize individual episodic memories, our results provide compelling evidence that a similar pattern of spatiotemporal organization also exists for organizing distinct memories that are distant in space and time. These results further support the emerging view that the anterior, as opposed to posterior, hippocampus integrates distinct experiences, thereby providing a scaffold for encoding and retrieval of autobiographical memories on the scale of our lives.


RADPRE: a computational program for identification of differential mRNA processing including alternative polyadenylation.
Genome-wide studies revealed the prevalence of multiple transcripts resulting from alternative polyadenylation (APA) of a single given gene in higher eukaryotes. Several studies in the past few years attempted to address how those APA events are regulated and what the biological consequences of those regulations are. Common to these efforts is the comparison of unbiased transcriptome data, either derived from whole-genome tiling array or next generation sequencing, to identify the specific APA events in a given condition. RADPRE (Ratio-based Analysis of Differential mRNA Processing and Expression) is an R program, developed to serve such a purpose using data from the whole-genome tilling array. RADPRE took a set of tilling array data as input, performed a series of calculation including a correction of the probe affinity variation, a hierarchy of statistical tests and an estimation of the false discovery rate (FDR) of the differentially processed genes (DPG). The result was an output of a few tabular files including DPG and their corresponding FDR. This chapter is written for scientists with limited programming experiences.


An integrated framework for high angular resolution diffusion imaging-based investigation of structural connectivity.
Structural connectivity models hold great promise for expanding what is known about the ways information travels throughout the brain. The physiologic interpretability of structural connectivity models depends heavily on how the connections between regions are quantified. This article presents an integrated structural connectivity framework designed around such an interpretation. The framework provides three measures to characterize the structural connectivity of a subject: (1) the structural connectivity matrix describing the proportion of connections between pairs of nodes, (2) the nodal connection distribution (nCD) characterizing the proportion of connections that terminate in each node, and (3) the connection density image, which presents the density of connections as they traverse through white matter (WM). Individually, each possesses different information concerning the structural connectivity of the individual and could potentially be useful for a variety of tasks, ranging from characterizing and localizing group differences to identifying novel parcellations of the cortex. The efficiency of the proposed framework allows the determination of large structural connectivity networks, consisting of many small nodal regions, providing a more detailed description of a subject's connectivity. The nCD provides a gray matter contrast that can potentially aid in investigating local cytoarchitecture and connectivity. Similarly, the connection density images offer insight into the WM pathways, potentially identifying focal differences that affect a number of pathways. The reliability of these measures was established through a test/retest paradigm performed on nine subjects, while the utility of the method was evaluated through its applications to 20 diffusion datasets acquired from typically developing adolescents.


Efficacy and Safety of Ultrasound-Guided Radiofrequency Ablation for Primary Hyperparathyroidism: A Prospective Study.
To assess the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) in patients with primary hyperparathyroidism (PHPT). This prospective study enrolled 39 participants (14 male, 25 female; mean age, 59.5 ± 15.3 [range, 18-87] years) between September 1, 2018, and January 31, 2021. All participants had parathyroid lesions causing PHPT, proven biochemically and through imaging. The imaging features of the PHPT nodules, including the shape, margin, size, composition, and location, were evaluated before treatment. Serum intact parathyroid hormone, calcium, and phosphorus levels; parathyroid nodule volume; and PHPT-related symptoms were recorded before and after treatment. We calculated the technical success, biochemical cure, and clinical cure rates for these patients. Complications were evaluated during and after the ablation. Complete ablation was achieved in 38 of the 39 nodules in the 39 enrolled participants. All the patients were treated in one session. The technical success rate was 97.4% (38/39). The mean follow-up duration was 13.2 ± 4.6 (range, 6.0-24.9) months. At 6 and 12 months post-RFA, the biochemical cure rates were 82.1% (32/39) and 84.4% (27/32), respectively, and the clinical cure rates were 100% (39/39) and 96.9% (31/32), respectively. Only 2.6% (1/39) of the patients had recurrent PHPT. At 1, 3, 6, and 12 months after technically successful RFA, 44.7% (17/38), 34.3% (12/35), 15.8% (6/38), and 12.5% (4/32) of participants, respectively, had elevated eucalcemic parathyroid hormone levels. Recurrent laryngeal nerve paralysis occurred in 5.1% (2/39) of the patients, who recovered spontaneously within 1-3 months. US-guided RFA was effective and safe for PHPT patients. RFA may be an alternative treatment tool for patients who cannot tolerate or refuse to undergo surgery.


Accounting for consumers' preferences in the analysis of dietary recommendations.
The goal of this article is to present and demonstrate the applicability of an original method to assess the economic and health impacts of compliance with food-based recommendations. The method takes account of consumers' preferences and the associated adoption cost in the assessment of various recommendations. We combine an economic model of diet choice with an epidemiological model to compute the health impacts of dietary changes. To demonstrate the use of the method, we analyse the impacts of a 5% variation in the consumption of seven food groups taken separately: a 5% increase in consumption of fruits and vegetables (F&V) and milk products; and a 5% decrease in consumption of red meat, all meats, salty/sweet products, ready meals and butter/cream/cheese. A recommendation, when adopted by consumers, generates important changes in the whole diet due to substitutions and complementarities among foods. All simulated recommendations have a positive impact on health. The F&V recommendation has the largest impact on the number of DALYs averted, but the highest adoption cost for consumers, especially for low-income consumers. Alone, the change in energy intake explains from 71% to 98% of the DALYs averted induced by a recommendation. Small increases in recommended foods have the potential of generating relatively significant health gains. Preference-driven substitutions among foods have a major effect on simulated health outcomes and should be included in the assessment of dietary recommendations, together with the adoption cost borne by consumers.


Filling the interspace-restoring arid land mosses: source populations, organic matter, and overwintering govern success.
Biological soil crusts contribute to ecosystem functions and occupy space that could be available to invasive annual grasses. Given disturbances in the semiarid shrub steppe communities, we embarked on a set of studies to investigate restoration potential of mosses in sagebrush steppe ecosystems. We examined establishment and growth of two moss species common to the Great Basin, USA: Bryum argenteum and Syntrichia ruralis from two environmental settings (warm dry vs. cool moist). Moss fragments were inoculated into a third warm dry setting, on bare soil in spring and fall, both with and without a jute net and with and without spring irrigation. Moss cover was monitored in spring seasons of three consecutive years. Both moss species increased in cover over the winter. When Bryum received spring irrigation that was out of sync with natural precipitation patterns, moss cover increased and then crashed, taking two seasons to recover. Syntrichia did not respond to the irrigation treatment. The addition of jute net increased moss cover under all conditions, except Syntrichia following fall inoculation, which required a second winter to increase in cover. The warm dry population of Bryum combined with jute achieved on average 60% cover compared to the cool moist population that achieved only 28% cover by the end of the study. Differences were less pronounced for Syntrichia where moss from the warm dry population with jute achieved on average 51% cover compared to the cool moist population that achieved 43% cover by the end of the study. Restoration of arid land mosses may quickly protect soils from erosion while occupying sites before invasive plants. We show that higher moss cover will be achieved quickly with the addition of organic matter and when moss fragments originate from sites with a climate that is similar to that of the restoration site.


Predicting deer-vehicle collisions in an urban area.
Collisions with deer and other large animals are increasing, and the resulting economic costs and risks to public safety have made mitigation measures a priority for both city and wildlife managers. We created landscape models to describe and predict deer-vehicle collision (DVCs) within the City of Edmonton, Alberta. Models based on roadside characteristics revealed that DVCs occurred frequently where roadside vegetation was both denser and more diverse, and that DVCs were more likely to occur when the groomed width of roadside right-of-ways was smaller. No DVCs occurred where the width of the vegetation-free or manicured roadside buffer was greater than 40 m. Landscape-based models showed that DVCs were more likely in more heterogeneous landscapes where road densities were lower and speed limits were higher, and where non-forested vegetation such as farmland was in closer proximity to larger tracts of forest. These models can help wildlife and transportation managers to identify locations of high collision frequency for mitigation. Modifying certain landscape and roadside habitats can be an effective way to reduce deer-vehicle collisions.


The C-terminal region affects the activity of photoactivated adenylyl cyclase from Oscillatoria acuminata.
Photoactivated adenylyl cyclase (PAC) is a unique protein that, upon blue light exposure, catalyzes cAMP production. The crystal structures of two PACs, from Oscillatoria acuminata (OaPAC) and Beggiatoa sp. (bPAC), have been solved, and they show a high degree of similarity. However, the photoactivity of OaPAC is much lower than that of bPAC, and the regulatory mechanism of PAC photoactivity, which induces the difference in activity between OaPAC and bPAC, has not yet been clarified. Here, we investigated the role of the C-terminal region in OaPAC, the length of which is the only notable difference from bPAC. We found that the photoactivity of OaPAC was inversely proportional to the C-terminal length. However, the deletion of more than nine amino acids did not further increase the activity, indicating that the nine amino acids at the C-terminal critically affect the photoactivity. Besides, absorption spectral features of light-sensing domains (BLUF domains) of the C-terminal deletion mutants showed similar light-dependent spectral shifts as in WT, indicating that the C-terminal region influences the activity without interacting with the BLUF domain. The study characterizes new PAC mutants with modified photoactivities, which could be useful as optogenetics tools.


Nitric oxide production as an indication of Mycobacterium bovis infection in white-tailed deer (Odocoileus virginianus).
White-tailed deer (Odocoileus virginianus) are reservoirs for Mycobacterium bovis in northeast Michigan, USA. Production of nitric oxide (NO) by activated macrophages is a potent mechanism of mycobacterial killing. The capacity of macrophages to produce NO, however, varies among mammalian species. The objective of this study was to determine if mononuclear cells from white-tailed deer produce nitrite as an indication of NO production and, if so, is NO produced in response to stimulation with M. bovis antigens. Supernatants were harvested from adherent peripheral blood mononuclear cell (PBMC) cultures that had been stimulated with either Mannheimia haemolytica lipopolysaccharide (LPS) or media alone (i.e., no stimulation). Nitrite levels within M. haemolytica LPS-stimulated culture supernatants exceeded (P < 0.05) those detected within supernatants from non-stimulated cultures as well as those detected within supernatants from cultures receiving an inhibitor of NO synthase in addition to M. haemolytica LPS. In response to stimulation with M. bovis antigens, nitrite production by PBMC from M. bovis-infected deer exceeded (P < 0.05) the production by PBMC from non-infected deer. The response of PBMC from infected deer to M. bovis antigens exceeded (P < 0.05) the response of parallel cultures from the same deer receiving no stimulation. The response of PBMC from M. bovis-infected deer to M. avium antigens did not differ from that of PBMC from M. bovis-infected deer to no stimulation or from that of PBMC from non-infected deer to M. avium antigens. These findings indicate that adherent PBMC from white-tailed deer are capable of NO production and that mononuclear cells isolated from M. bovis-infected white-tailed deer produce NO in an antigen-specific recall response.


Strong artificial selection in domestic mammals did not result in an increased recombination rate.
Recombination rates vary in intensity and location at the species, individual, sex and chromosome levels. Despite the fundamental biological importance of this process, the selective forces that operate to shape recombination rate and patterns are unclear. Domestication offers a unique opportunity to study the interplay between recombination and selection. In domesticates, intense selection for particular traits is imposed on small populations over many generations, resulting in organisms that differ, sometimes dramatically, in morphology and physiology from their wild ancestor. Although earlier studies suggested increased recombination rate in domesticates, a formal comparison of recombination rates between domestic mammals and their wild congeners was missing. In order to determine broad-scale recombination rate, we used immunolabeling detection of MLH1 foci as crossover markers in spermatocytes in three pairs of closely related wild and domestic species (dog and wolf, goat and ibex, and sheep and mouflon). In the three pairs, and contrary to previous suggestions, our data show that contemporary recombination rate is higher in the wild species. Subsequently, we inferred recombination breakpoints in sequence data for 16 genomic regions in dogs and wolves, each containing a locus associated with a dog phenotype potentially under selection during domestication. No difference in the number and distribution of recombination breakpoints was found between dogs and wolves. We conclude that our data indicate that strong directional selection did not result in changes in recombination in domestic mammals, and that both upper and lower bounds for crossover rates may be tightly regulated.


Cancer Screening Among U.S. Medicaid Enrollees with Chronic Comorbidities or Residing in Long-Term Care Facilities.
Ensuring appropriate cancer screenings among low-income persons with chronic conditions and persons residing in long-term care (LTC) facilities presents special challenges. This study examines the impact of having chronic diseases and of LTC residency status on cancer screening among adults enrolled in Medicaid, a joint state-federal government program providing health insurance for certain low-income individuals in the U.S. We used 2000-2003 Medicaid data for Medicaid-only beneficiaries and merged 2003 Medicare-Medicaid data for dually-eligible beneficiaries from four states to estimate the likelihood of cancer screening tests during a 12-month period. Multivariate regression models assessed the association of chronic conditions and LTC residency status with each type of cancer screening. LTC residency was associated with significant reductions in screening tests for both Medicaid-only and Medicare-Medicaid enrollees; particularly large reductions were observed for receipt of mammograms. Enrollees with multiple chronic comorbidities were more likely to receive colorectal and prostate cancer screenings and less likely to receive Papanicolaou (Pap) tests than were those without chronic conditions. LTC residents have substantial risks of not receiving cancer screening tests. Not performing appropriate screenings may increase the risk of delayed/missed diagnoses and could increase disparities; however, it is also important to consider recommendations to appropriately discontinue screening and decrease the risk of overdiagnosis. Although anecdotal reports suggest that patients with serious comorbidities may not receive regular cancer screening, we found that having chronic conditions increases the likelihood of certain screening tests. More work is needed to better understand these issues and to facilitate referrals for appropriate cancer screenings.


Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.
Modafinil has recently been approved for the treatment of shift work sleep disorder, making it potentially available for shift-working emergency physicians. The authors' objectives were to determine whether modafinil improved cognitive performance of emergency physicians following overnight shifts and to record symptoms and subjective evaluations of the effect of modafinil on the participants. This was a randomized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines. Participants were assigned to one of two study groups, with study sessions occurring at least seven weeks apart, and received either modafinil or placebo depending on their random allocation. Testing after night shifts included a coding task and an AX version of the Continuous Performance Task, both of which test cognitive function. Participants also completed visual analog scales for three subjective outcomes, and symptoms were elicited. Modafinil facilitated performance on long interstimulus-interval AX trials (F [1, 23] = 6.65, p = 0.1) and marginally reduced errors on AY trials in the Continuous Performance Task (F [1, 23] = 3.59, p = 0.07), suggesting facilitation of sustained attention, cognitive control, and working memory. Additionally, modafinil, compared with placebo, facilitated performance on the coding task at the first session. Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose. Modafinil increased certain aspects of cognitive function and subjectively improved participants' ability to attend post-night-shift didactic sessions but made it more difficult for participants to fall asleep when opportunities for sleep arose.


The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue.
The X-ray crystal structure of the complex between the Ras-related protein Rap1A in the GTP-analogue (GppNHp) form and the Ras-binding domain (RBD) of the Ras effector molecule c-Raf1, a Ser/Thr-specific protein kinase, has been solved to a resolution of 2.2 A. It shows that RBD has the ubiquitin superfold and that the structure of Rap1A is very similar to that of Ras. The interaction between the two proteins is mediated by an apparent central antiparallel beta-sheet formed by strands B1-B2 from RBD and strands beta 2-beta 3 from Rap1A. Complex formation is mediated by main-chain and side-chain interactions of the so-called effector residues in the switch I region of Rap1A.


Manipulation of the Reconstruction of the Au(111) Surface with the STM.
Modification of the reconstruction of an Au(111) surface with a scanning tunneling microscope (STM) is demonstrated. This modification is accomplished by transferring a number of surface atoms to the STM tip to generate a surface multivacancy (hole), which modifies the stress distribution at the surface. The structural changes that follow the tip-induced surface perturbation are imaged in a time-resolved manner. The structural modification is the result of both short-range interactions, which lead to local atomic relaxation, and long-range elastic interactions, which produce large-scale rearrangements.


Managing patient dose in digital radiology. A report of the International Commission on Radiological Protection.
Digital techniques have the potential to improve the practice of radiology but they also risk the overuse of radiation. The main advantages of digital imaging, i.e. wide dynamic range, post processing, multiple viewing options, and electronic transfer and archiving possibilities, are clear but overexposures can occur without an adverse impact on image quality. In conventional radiography, excessive exposure produces a 'black' film. In digital systems, good images are obtained for a large range of doses. It is very easy to obtain (and delete) images with digital fluoroscopy systems, and there may be a tendency to obtain more images than necessary. In digital radiology, higher patient dose usually means improved image quality, so a tendency to use higher patient doses than necessary could occur. Different medical imaging tasks require different levels of image quality, and doses that have no additional benefit for the clinical purpose should be avoided. Image quality can be compromised by inappropriate levels of data compression and/or postprocessing techniques. All these new challenges should be part of the optimisation process and should be included in clinical and technical protocols. Local diagnostic reference levels should be re-evaluated for digital imaging, and patient dose parameters should be displayed at the operator console. Frequent patient dose audits should occur when digital techniques are introduced. Training in the management of image quality and patient dose in digital radiology is necessary. Digital radiology will involve new regulations and invoke new challenges for practitioners. As digital images are easier to obtain and transmit, the justification criteria should be reinforced. Commissioning of digital systems should involve clinical specialists, medical physicists, and radiographers to ensure that imaging capability and radiation dose management are integrated. Quality control requires new procedures and protocols (visualisation, transmission, and archiving of the images).


The use of complementary and alternative medical providers by insured cancer patients in Washington State.
Insurance coverage of complementary and alternative medicine (CAM) is expanding. However, to the authors' knowledge, little is know concerning CAM utilization among cancer patients under the insurance model of financing. In this study, the authors evaluated CAM provider utilization by cancer patients in a state that requires the inclusion of alternative practitioners in private, commercial insurance products. An analysis was carried out of year 2000 claims data from two large Washington State insurance companies. Of 357,709 claimants, 7915 claimants (2.3%) had a cancer diagnosis. Among cancer patients, 7.1% had a claim for naturopathy, acupuncture, or massage; and 11.6% had a claim for chiropractic during the study year. The use of naturopathy (odds ratio [OR], 2.0; P<0.001) and acupuncture (OR, 1.4; P<0.001) were more common, and the use of chiropractic was less common (OR, 0.9; P<0.001) for cancer patients compared with those without cancer. No significant differences were noted in the use of massage between the two groups. Except in 2 individuals (0.03%), cancer patients also had at least 1 conventional provider claim during the year. Factors associated with nonchiropractic alternative provider use were female gender, the presence of metastatic cancer, hematologic malignancy, and the use of chemotherapy. Increased use of naturopathic physicians accounted for much of this trend. Musculoskeletal pain was the most common diagnosis at the CAM provider visit. Billed amounts for alternative services were <2% of the overall medical bills for cancer patients. A substantial number of insured cancer patients will use alternative providers if they are given the choice. The cost of this treatment is modest compared with conventional care charges. For individuals with cancer, CAM providers do not appear to be replacing conventional providers but instead are integrated into overall care.


Dosimetric comparison of Gamma Knife® IconTM and linear accelerator-based fractionated stereotactic radiotherapy (FSRT) plans for the re-irradiation of large (>14 cm3) recurrent glioblastomas.
Our objective is to investigate dosimetric differences between clinically deliverable Gamma Knife® (GK) Icon™ and linac-based FSRT plans on the basis of normal brain dose sparing for large (>14 cm3) recurrent glioblastomas (GBM). Sixteen patients with large, recurrent GBM were treated using re-irradiation via linac-based FSRT, 35 Gy in 10 fractions. For each patient, a new GK FSRT plan was created in Leksell GammaPlan® V11 (LGP). To maintain clinical deliverability, the LGP optimization included a planning goal of treatment time <20 minutes per fraction. Dosimetric comparison of coverage and normal brain dose between the linac and GK treatment plans was performed in MIM. The GK FSRT plans had significantly (p < 0.05) lower mean normal brain dose values (-8.85%), mean values of normal brain V20 (-32.4%) and V12 (-25.9%), and a lower mean V4 (-10.0%). GK FSRT plans have the potential to reduce the risk of radiation-related toxicities.


The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans.
Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging1. Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.


Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(-) cancer cells.
Although CD133 has been reported to be a promising colon cancer stem cell marker, the biological functions of CD133+ colon cancer cells remain controversial. In the present study, we investigated the biological differences between CD133+ and CD133- colon cancer cells, with a particular focus on their interactions with cancer-associated fibroblasts, especially CD10+ fibroblasts. We used 19 primary colon cancer tissues, 30 primary cultures of fibroblasts derived from colon cancer tissues and 6 colon cancer cell lines. We isolated CD133+ and CD133- subpopulations from the colon cancer tissues and cultured cells. In vitro analyses revealed that the two populations showed similar biological behaviors in their proliferation and chemosensitivity. In vivo analyses revealed that CD133+ cells showed significantly greater tumor growth than CD133- cells (P=0.007). Moreover, in cocultures with primary fibroblasts derived from colon cancer tissues, CD133+ cells exhibited significantly more invasive behaviors than CD133- cells (P<0.001), especially in cocultures with CD10+ fibroblasts (P<0.0001). Further in vivo analyses revealed that CD10+ fibroblasts enhanced the tumor growth of CD133+ cells significantly more than CD10- fibroblasts (P<0.05). These data demonstrate that the in vitro invasive properties and in vivo tumor growth of CD133+ colon cancer cells are enhanced in the presence of specific cancer-associated fibroblasts, CD10+ fibroblasts, suggesting that the interactions between these specific cell populations have important roles in cancer progression. Therefore, these specific interactions may be promising targets for new colon cancer therapies.


Tissue- and species-dependent expression of sheep lung microsomal cytochrome P4502B(LgM2).
Expression of sheep lung microsomal cytochrome P4502B(LgM2) isozyme was determined in lung and liver preparations from rabbits, rats, sheep, cows and humans. Several tissues of sheep such as lung, liver, adrenal, kidney, ovary, intestine, muscle, spleen, pancreas and brain were also examined. Tissue homogenates were analyzed by Western-blotting with an antibody raised against purified sheep lung P4502B(LgM2) isozyme in rabbits. This isozyme was detected in lung samples from every species examined. Homologues of cytochrome P4502B(LgM2) were expressed in livers of sheep and rabbits but not in those of humans and cows. Although homologous forms of P4502B(LgM2) were not expressed in sheep brain, ovary, pancreas, spleen and muscle tissues, they were expressed in sheep adrenal, intestine and kidney.


Gastrointestinal autonomic nerve tumors in the pediatric population: a report of four cases and a review of the literature.
Gastrointestinal autonomic nerve tumors (GANTs) are a subpopulation of gastrointestinal stromal tumors (GISTs) that are characterized by ultrastructural features resembling enteric autonomic nerve cells, without epithelial, Schwannian, or smooth muscle differentiation. Delineation of the clinicopathologic features of GANT in the pediatric population is lacking. The clinicopathologic and outcome data for four pediatric patients with GANT are presented. The data from these patients and four previously reported pediatric patients are summarized and compared with data for GANT in adults. All four cases occurred in females at a mean age of 12.5 years. The primary tumor site was the stomach in all cases, and the mean tumor size was 6.3 cm. Immunocytochemical and ultrastructural examination were essential in distinguishing GANT from GIST in all cases by identifying features of neural origin (neuron specific enolase in all four cases, NFP in three cases, S-100 in two cases, dense core neurosecretory granules in all four cases, and neuritelike processes in all four cases), while failing to identify features of myogenic origin (no desmin, smooth muscle actin, myofilaments, or dense bodies were found in any of the cases). Primary treatment was surgical, with chemotherapy administered to 1 patient at the time of recurrence. All patients are alive after a mean follow-up of 60 months (range, 8 months to 9 years). Similarities of pediatric GANT to GANT in adults include the need for a high index of suspicion for diagnosis; comparable histopathologic, immunohistochemical, and ultrastructural features; and surgery as the primary therapy. Distinguishing features in children may be a prevalence among females in the second decade, a predominance of smaller gastric tumors, and a positive prognostic value of younger age.


Ultra-wide range field-dependent measurements of the relaxivity of Gd1-xEuxVO4 nanoparticle contrast agents using a mechanical sample-shuttling relaxometer.
The current trend for Magnetic Resonance Imaging points towards higher magnetic fields. Even though sensitivity and resolution are increased in stronger fields, T1 contrast is often reduced, and this represents a challenge for contrast agent design. Field-dependent measurements of relaxivity are thus important to characterize contrast agents. At present, the field-dependent curves of relaxivity are usually carried out in the field range of 0 T to 2 T, using fast field cycling relaxometers. Here, we employ a high-speed sample shuttling device to switch the magnetic fields experienced by the nuclei between virtually zero field, and the center of any commercial spectrometer. We apply this approach on rare-earth (mixed Gadolinium-Europium) vanadate nanoparticles, and obtain the dispersion curves from very low magnetic field up to 11.7 T. In contrast to the relaxivity profiles of Gd chelates, commonly used for clinical applications, which display a plateau and then a decrease for increasing magnetic fields, these nanoparticles provide maximum contrast enhancement for magnetic fields around 1-1.5 T. These field-dependent curves are fitted using the so-called Magnetic Particle (MP) model and the extracted parameters discussed as a function of particle size and composition. We finally comment on the new possibilities offered by this approach.


Reducing selection bias in case-control studies from rare disease registries.
In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example. A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching. The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias. We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.


Nitrogen balance and delta15N: why you're not what you eat during nutritional stress.
While past experiments on animals, birds, fish, and insects have shown changes in stable isotope ratios due to nutritional stress, there has been little research on this topic in humans. To address this issue, a small pilot study was conducted. Hair samples from eight pregnant women who experienced nutritional stress associated with the nausea and vomiting of morning sickness (hyperemesis gravidarum) were measured for carbon (delta13C) and nitrogen (delta15N) stable isotope ratios. The delta13C results showed no change during morning sickness or pregnancy when compared with pre-pregnancy values. In contrast, the delta15N values generally increased during periods of weight loss and/or restricted weight gain associated with morning sickness. With weight gain and recovery from nutritional stress, the hair delta15N values displayed a decreasing trend over the course of gestation towards birth. This study illustrates how delta15N values are not only affected by diet, but also by the nitrogen balance of an individual. Potential applications of this research include the development of diagnostic techniques for tracking eating disorders, disease states, and nitrogen balance in archaeological, medical, and forensic cases.


Google searches for suicide and suicide risk factors in the early stages of the COVID-19 pandemic.
A novel coronavirus (SARS-CoV-2), which causes the COVID-19 respiratory illness, emerged in December of 2019 and has since spread globally. The dramatic lifestyle changes and stressors associated with this pandemic pose a threat to mental health and have the potential to exacerbate risk factors for suicide. We used autoregressive integrated moving average (ARIMA) models to assess Google Trends data representing searches in the United States for 18 terms related to suicide and known suicide risk factors following the emergence of COVID-19. Although the relative proportion of Google searches for suicide-related queries was lower than predicted during the early pandemic period, searches for the following queries representative of financial difficulty were dramatically elevated: "I lost my job" (226%; 95%CI, 120%-333%), "laid off" (1164%; 95%CI, 395%-1932%), "unemployment" (1238%; 95%CI, 560%-1915%), and "furlough" (5717%; 95%CI, 2769%-8665%). Searches for the Disaster Distress Helpline, which was promoted as a source of help for those impacted by COVID-19, were also remarkably elevated (3021%; 95%CI, 873%-5169%). Google searches for other queries representative of help-seeking and general mental health concerns were moderately elevated. It appears that some indices of suicidality have fallen in the United States in this early stage of the pandemic, but that COVID-19 may have caused an increase in suicide risk factors that could yield long-term increases in suicidality and suicide rates.


The relationship between body composition, anaerobic performance and sprint ability of amputee soccer players.
The purpose of the present study was to investigate the relationship between body composition, anaerobic performance and sprint performance of amputee soccer players. Fifteen amputee soccer players participated in this study voluntarily. Subjects' height, body weight, body mass index, body fat percentage (Jackson and Pollock formula) and somatotype characteristics (Heath-Carter system) were determined. The sprint performance at 10m, 20m and 30m was evaluated, whereas the counter movement jump (CMJ), relative CMJ (RCMJ), squat jump (SJ) and relative SJ (RSJ) tests were used for the determination of anaerobic performance. The results of the Pearson Product Moment correlation analysis indicated that body composition was significantly correlated with CMJ and SJ (p < 0.01), on the other hand, no measure of body composition was significantly related to the other component (p > 0.05). A significant correlation was found between CMJ, RCMJ, SJ, 10 m, 20 m and 30 m sprint performance (p < 0.05); whereas, in contrast, no measure of body composition was significantly related to the 10 m, 20 m and 30 m sprint performance (p > 0.05). In conclusion, the findings of the present study indicated that sprint performance was described as an essential factor in anaerobic performance whereas body composition and somatotype play a determinant role in anaerobic and sprint performance in amputee soccer players.


Solar Availability for Winter Space Heating: An Analysis of SOLMET Data, 1953 to 1975.
Solar availability for space heating on coldest-weather days has been determined from an analysis of SOLMET data tapes. The tapes contain hourly readings of insolation and ambient temperature over the period from 1953 through 1975. Scatter diagrams of insolation versus heating degree-days, compiled on a daily basis, indicate a wide variation in the insolation level, even during coldest-weather periods. For all but one of the eight sites studied, the peak-day backup energy requirement of the solar system was in excess of 85 percent of the peak-day energy requirement of the conventional (nonsolar) heating system.


Non-p.V600E BRAF Mutations Are Common Using a More Sensitive and Broad Detection Tool.
To assess the performance of a next-generation sequencing (NGS) platform for the clinical detection of BRAF mutations. In this retrospective quality assessment of an NGS assay, we analyzed BRAF mutations within parts of exons 11 and 15 in 835 neoplastic tissues submitted to our molecular diagnostics laboratory. The NGS assays detected a BRAF mutation in 5.9% of lung adenocarcinomas, 13% of colorectal cancers, and 44% of melanomas. Mutant allele frequencies were less than 20% in 28% of 88 BRAF-mutated specimens. Two lymph node specimens with subcapsular or infiltrative metastasis showed 1% to 2% mutant alleles. There were 26 unique BRAF mutations in exons 11 and 15, including three novel mutations. Mutations were located outside codon 600 in 39% of BRAF-mutated tumors. Lung adenocarcinomas showed significantly higher non-p.V600E mutations (86%) than did colorectal cancers (23%) and melanomas (34%). The three most common BRAF mutations in lung cancers accounted for only 41% of the observed BRAF mutations (p.D594G [18%], p.V600E [14%], and p.G469A [9%]). The NGS assay demonstrated a high analytic sensitivity and a broad reportable range for clinical detection of BRAF mutations. Elucidating the spectrum of non-p. V600E BRAF mutations in different malignancies is a first step toward understanding their clinical significance.


Rearrangement of the (6S,8R,11S) and (6R,8S,11R) exocyclic 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal to N2-deoxyguanosine cyclic hemiacetal adducts when placed complementary to cytosine in duplex DNA.
trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. The Michael addition of deoxyguanosine to HNE yields four diastereomeric exocyclic 1,N(2)-dG adducts. The corresponding acrolein- and crotonaldehyde-derived exocyclic 1,N(2)-dG adducts undergo ring-opening to N(2)-dG aldehydes, placing the aldehyde functionalities into the minor groove of DNA. The acrolein- and the 6R-crotonaldehyde-derived exocyclic 1,N(2)-dG adducts form interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Only the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Moreover, as compared to the exocyclic 1,N(2)-dG adducts of acrolein and crotonaldehyde, the cross-linking reaction is slow (Wang, H.; Kozekov, I. D.; Harris, T. M.; Rizzo, C. J. J. Am. Chem. Soc. 2003, 125, 5687-5700). Accordingly, the chemistry of the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry has been compared with that of the (6R,8S,11R) adduct, when incorporated into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). When placed complementary to dC in this duplex, both adducts open to the corresponding N(2)-dG aldehydic rearrangement products, suggesting that the formation of the interstrand cross-link by the exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry, and the lack of cross-link formation by the exocyclic 1,N(2)-dG adduct of (6R,8S,11R) stereochemistry, is not attributable to inability to undergo ring-opening to the aldehydes in duplex DNA. Instead, these aldehydic rearrangement products exist in equilibrium with stereoisomeric cyclic hemiacetals. The latter are the predominant species present at equilibrium. The trans configuration of the HNE H6 and H8 protons is preferred. The presence of these cyclic hemiacetals in duplex DNA is significant as they mask the aldehyde species necessary for interstrand cross-link formation.


Entrapped Styrene Butadiene Polymer Chains by Sol-Gel-Derived Silica Nanoparticles with Hierarchical Raspberry Structures.
A sol-gel transformation of liquid silica precursor to solid silica particles was carried out in a one-pot synthesis way, where a solution of styrene butadiene elastomer was present. The composites, thus produced, offered remarkable improvements of mechanical and dynamic mechanical performances compared to precipitated silica. The morphological analysis reveals that the alkoxy-based silica particles resemble a raspberry structure when the synthesis of the silica was carried out in the presence of polymer molecules and represent a much more open silica-network structure. However, in the absence of the polymer, the morphology of the silica particles is found to be different. It is envisaged that the special morphology of the in situ synthesized silica particles contributes to the superior reinforcement effects, which are associated with a strong silica-rubber interaction by rubber chains trapped inside the raspberry-like silica aggregates. Therefore, the interfaces are characterized in detail by low-field solid-state 1H NMR spectroscopy, 29Si solid-state NMR spectroscopy, and energy-dispersive X-ray spectroscopy. Low-field 1H NMR-based double-quantum experiments provide a quantitative information about the cross-link density of the silica-filled rubber composites and about the influence of silane coupling agent on the chemical cross-link density of the network and correlates well with equilibrium swelling measurements. The special microstructure of the alkoxy-based silica was found to be associated with the interaction between alkoxy-based silica and rubber chains as a consequence of particle growth in the presence of rubber chains.


Eriodictyol alleviates lipopolysaccharide-triggered oxidative stress and synaptic dysfunctions in BV-2 microglial cells and mouse brain.
Oxidative stress takes part in the development of the neurodegenerative disease. Eriodictyol, a flavonoid, commonly presents in citrus fruits, which was well-known for its various bioactivities. The purpose of this study was to investigate the neuroprotective effects of eriodictyol on lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress, synaptic dysfunctions, and the potential mechanisms involved. We found that eriodictyol explicitly restored LPS-triggered the decrease of cell viability and the mitochondrial potential as well as inflammation responses via mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) pathways regulated by reactive oxygen species (ROS). Besides, eriodictyol alleviated LPS-induced oxidative stress via NF-E2-Related factor2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway in vivo and in vitro. Furthermore, eriodictyol reduced LPS-elicited synaptic dysfunctions via increasing the expression of silent information regulator 1 (Sirt1). Overall, eriodictyol protects LPS-triggered oxidative stress, neuroinflammation, and synaptic dysfunctions partially through MAPKs, NF-κB mediated by ROS, Sirt1, and Nrf2/Keap1 signal pathways, which further supports that eriodictyol is a potentially nutritional preventive strategy for oxidative stress-related neurodegenerative diseases.


Effect of almonds on insulin secretion and insulin resistance in nondiabetic hyperlipidemic subjects: a randomized controlled crossover trial.
Nuts appear to have a marked effect in cohort studies in reducing the risk of coronary heart disease (CHD), but their demonstrated ability to lower cholesterol can only explain a proportion of the reduction in risk. Our aim was to assess whether improvement in carbohydrate metabolism provides a further explanation for the effect of nuts in reducing CHD. The effects of whole almonds, taken as snacks, were compared with the effects of low saturated fat (<5% energy) whole-wheat muffins (control) in the therapeutic diets of hyperlipidemic subjects. In a randomized crossover study, 27 hyperlipidemic men and women consumed 3 isoenergetic (mean, 423 kcal/d) supplements each for 1 month. Supplements provided 22.2% of energy and consisted of full-dose almonds (73 +/- 3 g/d), half-dose almonds plus half-dose muffins, and full-dose muffins. Subjects were assessed at weeks 0, 2, and 4 and fasting blood samples were obtained. Twenty-four-hour urinary output was collected at the end of week 4 on each treatment. Mean body weights differed by less than 300 g between treatments. No differences were seen in baseline or treatment values for fasting glucose, insulin, C-peptide, or insulin resistance as measured by homeostasis model assessment of insulin resistance. However, 24-hour urinary C-peptide output as a marker of 24-hour insulin secretion was significantly reduced on the half-and full-dose almonds by comparison to the control after adjustment for urinary creatinine output (P = .002 and P = .004, respectively). We conclude that reductions in 24-hour insulin secretion appear to be a further metabolic advantage of nuts that in the longer term may help to explain the association of nut consumption with reduced CHD risk.


BIL&GIN: A neuroimaging, cognitive, behavioral, and genetic database for the study of human brain lateralization.
We report on a database, named BIL&GIN, designed for investigating the cognitive, behavioral, genetic, and brain morphological/functional correlates of hemispheric specialization. The database contains records from a sample of 453 adult participants enriched in left-handers (45%, N=205) as compared to the general population. For each subject, socio-demographic data, hand and eye laterality, family handedness, and cognitive abilities in the language, motor, visuo-spatial, and numerical domains have been recorded. T1-MRI and DTI data were also acquired, as well as resting-state functional MRI. Task-evoked functional MRI was performed in a sub-sample of 303 subjects (157 left-handers) using a customized functional battery of 16 cognitive tasks exploring the same three cognitive domains. Performances at the tasks executed in the magnet as well as post-acquisition debriefing were recorded. A saliva sample was obtained from the subjects of this sub-sample from which DNA was extracted. The BIL&GIN contains results of imaging data processing for each subject, namely maps of tissue (GM, WM, CSF) probability, cortical thickness, cortical surface, and diffusion parameters as well as regional values of these phenotypes for regions of both AAL and FreeSurfer parcellations. For the subjects who underwent FMRI, individual SPM contrast maps for each of the 8 runs were also calculated and included in the database, as well as corresponding BOLD variations in ROIs of the AAL and AICHA atlases, and Wilke's hemispheric functional lateralization index. The BIL&GIN data sharing is based on a collaborative model.


Antimicrobial Activity of New Materials Based on Lavender and Basil Essential Oils and Hydroxyapatite.
This study presents, for the first-time, the results of a study on the hydrodynamic diameter of essential oils (EOs) of basil and lavender in water, and solutions of EOs of basil (B) and lavender (L) and hydroxyapatite (HAp). The possible influence of basil and lavender EOs on the size of hydroxyapatite nanoparticles was analyzed by Scanning Electron Microscopy (SEM). We also investigated the in vitro antimicrobial activity of plant EOs and plant EOs hydroxyapatite respectively, against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus1144 (MRSA 1144) and S. aureus 1426) and Gram-negative bacteria (Escherichia coli ATCC 25922 and Escherichia coli ESBL 4493). From the autocorrelation function, obtained by Dynamic Light Scattering (DLS) measurements it was observed that basil yielded one peak at an average hydrodynamic diameter of 354.16 nm, while lavender yielded one peak at an average hydrodynamic diameter of 259.76 nm. In the case of HAp nanoparticles coated with basil (HApB) and lavender (HApL) essential oil, the aggregation was minimal. We found that the lavender EO exhibited a very good inhibitory growth activity (MIC values ranging from <0.1% for E. coli reference strain to 0.78% for S. aureus strains). The biological studies indicated that HapL material displayed an enhanced antimicrobial activity, indicating the potential use of HAp as vehicle for low concentrations of lavender EO with antibacterial properties. Flow cytometry analysis (FCM) allowed us to determine some of the potential mechanisms of the antimicrobial activities of EOs, suggesting that lavender EO was active against E. coli by interfering with membrane potential, the membrane depolarization effect being increased by incorporation of the EOs into the microporous structure of HAp. These findings could contribute to the development of new antimicrobial agents that are urgently needed for combating the antibiotic resistance phenomena.


Temporal trends of persistent organic pollutants in Arctic marine and freshwater biota.
More than 1000 time-series of persistent organic pollutants (POPs) in Arctic biota from marine and freshwater ecosystems some extending back to the beginning of 1980s were analyzed using a robust statistical method. The Arctic area encompassed extended from Alaska, USA in the west to northern Scandinavian in the east, with data gaps for Arctic Russia and Arctic Finland. The aim was to investigate whether temporal trends for different animal groups and matrices were consistent across a larger geographical area. In general, legacy POPs showed decreasing concentrations over the last two to three decades, which were most pronounced for α-HCH and least pronounced for HCB and β-HCH. Few time-series of legacy POPs showed increasing trends and only at sites suspected to be influenced by local source. The brominated flame retardant congener BDE-47 showed a typical trend of increasing concentration up to approximately the mid-2000s followed by a decreasing concentration. A similar trend was found for perfluorooctane sulfonic acid (PFOS). These trends are likely related to the relatively recent introduction of national and international controls of hexa- and hepta-BDE congeners and the voluntary phase-out of PFOS production in the USA in 2000. Hexabromocyclododecane (HBCDD) was the only compound in this study showing a consistent increasing trend. Only 12% of the long-term time-series were able to detect a 5% annual change with a statistical power of 80% at α < 0.05. The remaining 88% of time-series need additional years of data collection before fulfilling these statistical requirements. In the case of the organochlorine long-term time-series, 45% of these would require >20 years monitoring before this requirement would be fulfilled.


Connectivity and resilience of coral reef metapopulations in marine protected areas: matching empirical efforts to predictive needs.
Design and decision-making for marine protected areas (MPAs) on coral reefs require prediction of MPA effects with population models. Modeling of MPAs has shown how the persistence of metapopulations in systems of MPAs depends on the size and spacing of MPAs, and levels of fishing outside the MPAs. However, the pattern of demographic connectivity produced by larval dispersal is a key uncertainty in those modeling studies. The information required to assess population persistence is a dispersal matrix containing the fraction of larvae traveling to each location from each location, not just the current number of larvae exchanged among locations. Recent metapopulation modeling research with hypothetical dispersal matrices has shown how the spatial scale of dispersal, degree of advection versus diffusion, total larval output, and temporal and spatial variability in dispersal influence population persistence. Recent empirical studies using population genetics, parentage analysis, and geochemical and artificial marks in calcified structures have improved the understanding of dispersal. However, many such studies report current self-recruitment (locally produced settlement/settlement from elsewhere), which is not as directly useful as local retention (locally produced settlement/total locally released), which is a component of the dispersal matrix. Modeling of biophysical circulation with larval particle tracking can provide the required elements of dispersal matrices and assess their sensitivity to flows and larval behavior, but it requires more assumptions than direct empirical methods. To make rapid progress in understanding the scales and patterns of connectivity, greater communication between empiricists and population modelers will be needed. Empiricists need to focus more on identifying the characteristics of the dispersal matrix, while population modelers need to track and assimilate evolving empirical results.


Gräfenberg ring retained for 15 years: a case report.
A 41-year-old Chinese lady had a Gräfenberg ring in utero for 15 years. During that period of time, she had one normal vaginal delivery a year after insertion, followed by an ectopic pregnancy 12 years later. We discuss the possible mechanism of action of the Gräfenberg ring and sequelae of its prolonged presence in the uterus.


Diagnosis and treatment of community-acquired pneumonia.
Patients with community-acquired pneumonia often present with cough, fever, chills, fatigue, dyspnea, rigors, and pleuritic chest pain. When a patient presents with suspected community-acquired pneumonia, the physician should first assess the need for hospitalization using a mortality prediction tool, such as the Pneumonia Severity Index, combined with clinical judgment. Consensus guidelines from several organizations recommend empiric therapy with macrolides, fluoroquinolones, or doxycycline. Patients who are hospitalized should be switched from parenteral antibiotics to oral antibiotics after their symptoms improve, they are afebrile, and they are able to tolerate oral medications. Clinical pathways are important tools to improve care and maximize cost-effectiveness in hospitalized patients.


Inactivation of matrix-bound matrix metalloproteinases by cross-linking agents in acid-etched dentin.
Published transmission electron microscopy analysis of in vitro resin-dentin bonds shows that, after 44 months, almost 70% of collagen fibrils from the hybrid layer disappear. Matrix metalloproteinases (MMPs) play an important role in that process and are thought to be the main factor responsible for the solubilization of dentin collagen. Therefore, this study aimed to evaluate the inactivation of matrix-bound MMPs by two different cross-linking agents, carbodiimide (EDC) or proanthocyanidin (PA), or the MMP-inhibitor, chlorhexidine (CHX), on acid-etched dentin using a simplified MMP assay method. Dentin beams (2×1×6 mm) were obtained from mid-coronal dentin of sound third molars and randomly divided into six groups (G) according to the dentin treatment: G1: Deionized water (control); G2: 0.1 M EDC; G3: 0.5 M EDC; G4: 0.5 M EDC + 35% hydroxyethyl methacrylate (HEMA); G5: 5% PA; and G6: 2% CHX. The beams were etched for 15 seconds with 37% phosphoric acid, rinsed, and then immersed for 60 seconds in one of the treatment solutions. The data were expressed both in absorbance values at 412 nm and in MMP-9 activity equivalents. The total MMP activity of dentin was analyzed for one hour by colorimetric assay (Sensolyte). Data were submitted to Wilcoxon nonparametric test and Mann-Whitney tests (p>0.05). All experimental cross-linking solutions significantly reduced MMP activity from 79.8% to 95.2% when compared to the control group. No difference was observed among 0.1 M EDC (84.8%), 5% PA (87.6%), and 2% CHX (79.8%). Addition of 35% HEMA to 0.5 M EDC produced inactivation (95.2%) that was similar to that of 0.5 M EDC alone (92.7%). Dentin treatment with cross-linking agents is effective to significantly reduce MMP activity. Mixing 0.5 M EDC and 35% HEMA did not influence EDC inhibitor potential.


Inactivation of lignin peroxidase by hydrogen peroxide during the oxidation of phenols.
The oxidation of phenols by lignin peroxidase (LiP) was characterized by a rapid decrease in enzyme activity. The initial oxidation rate of phenol decreased at moderately high (i.e., 400 microM) concentrations of H2O2. Similar results were obtained with several phenols. However, LiP was not inactivated during the oxidation of veratryl alcohol (VA). The apparent second-order rate constants for the reaction of compound II with phenol and VA at pH 3.5 were very similar, about 2.1 x 10(4) and 4.7 x 10(4) M-1 s-1, respectively. However, unlike VA, phenols could not convert compound III back to ferric enzyme. The visible absorption spectra of compound II and III were observed during oxidation of VA and phenols, respectively. These results suggest that the inactivation of LiP during the oxidation of phenols was mainly due to the accumulation of compound III, which was attributed to the inability of phenols or phenoxyl radicals to revert compound III to ferric enzyme. All of these results also suggested that the inactivation mechanism of LiP during oxidation of phenols was different from that during oxidation of anisyl alcohol, since anisyl alcohol was neither a substrate of compound II nor could it revert compound III [K. Valli et al. (1990) Biochemistry 29, 8535-8539 and R.S. Koduri and M. Tien (1994) Biochemistry 33, 4225-4230].


Measuring and Achieving Equity in Multiperiod Emergency Material Allocation.
Emergency material allocation is an important part of postdisaster emergency logistics that is significant for improving rescue effectiveness and reducing disaster losses. However, the traditional single-period allocation model often causes local surpluses or shortages and high cost, and prevents the system from achieving an equitable or optimal multiperiod allocation. To achieve equitable allocation of emergency materials in the case of serious shortages relative to the demand by victims, this article introduces a multiperiod model for allocation of emergency materials to multiple affected locations (using an exponential utility function to reflect the disutility loss due to material shortfalls), and illustrates the relationship between equity of allocations and the cost of emergency response. Finally, numerical examples are presented to demonstrate both the feasibility and the usefulness of the proposed model for achieving multiperiod equitable allocation of emergency material among multiple disaster locations. The results indicate that the introduction of a nonlinear utility function to reflect the disutility of large shortfalls can make the material allocation fairer, and minimize large losses due to shortfalls. We found that achieving equity has a significant but not unreasonable impact on emergency costs. We also illustrate that using differing utility functions for different types of materials adds an important dimension of flexibility.


Overview of the new oral anticoagulants: opportunities and challenges.
The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.


Towards common ground in the biodiversity-disease debate.
The disease ecology community has struggled to come to consensus on whether biodiversity reduces or increases infectious disease risk, a question that directly affects policy decisions for biodiversity conservation and public health. Here, we summarize the primary points of contention regarding biodiversity-disease relationships and suggest that vector-borne, generalist wildlife and zoonotic pathogens are the types of parasites most likely to be affected by changes to biodiversity. One synthesis on this topic revealed a positive correlation between biodiversity and human disease burden across countries, but as biodiversity changed over time within these countries, this correlation became weaker and more variable. Another synthesis-a meta-analysis of generally smaller-scale experimental and field studies-revealed a negative correlation between biodiversity and infectious diseases (a dilution effect) in various host taxa. These results raise the question of whether biodiversity-disease relationships are more negative at smaller spatial scales. If so, biodiversity conservation at the appropriate scales might prevent wildlife and zoonotic diseases from increasing in prevalence or becoming problematic (general proactive approaches). Further, protecting natural areas from human incursion should reduce zoonotic disease spillover. By contrast, for some infectious diseases, managing particular species or habitats and targeted biomedical approaches (targeted reactive approaches) might outperform biodiversity conservation as a tool for disease control. Importantly, biodiversity conservation and management need to be considered alongside other disease management options. These suggested guiding principles should provide common ground that can enhance scientific and policy clarity for those interested in simultaneously improving wildlife and human health.


Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion.
The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit- and mKitL-expressing NIH3T3 cells results in signaling through mKitL: c-Kit-bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL-c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL-c-Kit signaling for their proliferation.


Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42.
Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.


Postoperative venous thromboembolism rates vary significantly after different types of major abdominal operations.
Venous thrombolism (VTE) is a significant cause of morbidity for surgical patients. Comparative risk across major procedures is unknown. Retrospective analysis of the Nationwide Inpatient Sample (2001-2005) was conducted. Eight surgeries were identified: bariatric surgery, colorectal surgery, esophagectomy, gastrectomy, hepatectomy, nephrectomy, pancreatectomy, splenectomy. Age < 18, patients with multiple major surgeries, and those admitted for treatment of VTE were excluded. Primary outcome was occurrence of VTE. Independent variables included age, gender, race, Charlson score, hospital teaching status, elective procedures, cancer/metastasis, trauma, and year. Patients, 375,748, were identified, 5,773 (1.54%) with VTE. Overall death rate was 3.97%, but 13.34% after VTE. Unadjusted rate (0.35%) and adjusted risk for VTE were lowest among bariatric patients. On multivariate analysis, highest risk for VTE was splenectomy (odds ratio 2.69, 95% CI 2.03-3.56). Odds ratio of in-hospital mortality following VTE was 1.84 (1.65-2.05), associated with excess stay of 10.88days and $9,612 excess charges, translating into $55 million/year nationwide. Highest risk for VTE was associated with splenectomy, lowest risk with bariatric surgery. Since bariatric patients are known to have greater risk for this complication, these findings may reflect better awareness/prophylaxis. Further studies are necessary to quantify effect of best-practice guidelines on prevention of this costly complication.


A novel constructive-optimizer neural network for the traveling salesman problem.
In this paper, a novel constructive-optimizer neural network (CONN) is proposed for the traveling salesman problem (TSP). CONN uses a feedback structure similar to Hopfield-type neural networks and a competitive training algorithm similar to the Kohonen-type self-organizing maps (K-SOMs). Consequently, CONN is composed of a constructive part, which grows the tour and an optimizer part to optimize it. In the training algorithm, an initial tour is created first and introduced to CONN. Then, it is trained in the constructive phase for adding a number of cities to the tour. Next, the training algorithm switches to the optimizer phase for optimizing the current tour by displacing the tour cities. After convergence in this phase, the training algorithm switches to the constructive phase anew and is continued until all cities are added to the tour. Furthermore, we investigate a relationship between the number of TSP cities and the number of cities to be added in each constructive phase. CONN was tested on nine sets of benchmark TSPs from TSPLIB to demonstrate its performance and efficiency. It performed better than several typical Neural networks (NNs), including KNIES_TSP_Local, KNIES_TSP_Global, Budinich's SOM, Co-Adaptive Net, and multivalued Hopfield network as wall as computationally comparable variants of the simulated annealing algorithm, in terms of both CPU time and accuracy. Furthermore, CONN converged considerably faster than expanding SOM and evolved integrated SOM and generated shorter tours compared to KNIES_DECOMPOSE. Although CONN is not yet comparable in terms of accuracy with some sophisticated computationally intensive algorithms, it converges significantly faster than they do. Generally speaking, CONN provides the best compromise between CPU time and accuracy among currently reported NNs for TSP.


Maternal and perinatal outcomes among eclamptic patients admitted to Bugando Medical Centre, Mwanza, Tanzania.
Eclampsia continues to be a major problem, particularly in developing countries such as Tanzania, contributing significantly to high maternal and perinatal morbidity and mortality. We conducted a study to establish the incidence of eclampsia and the associated maternal and perinatal outcomes among eclamptic patients admitted to our center. A descriptive cross-sectional study of all women presenting with eclampsia was performed from June 2009 to February 2010. Seventy-six patients presented with eclampsia out of a total 5562 deliveries during the study period (incidence of 1.37%). Antenatal attendance was 96% among patients with eclampsia; however, only 45.21% and 24.66% were screened for blood pressure and proteinuria respectively. Maternal and perinatal case fatality rates were 7.89% and 20.73% respectively. The main factors contributing to maternal deaths were acute renal failure (10.5%), pulmonary oedema (10.5%), maternal stroke (8.8%), HELLP syndrome (50.9%), and Disseminated Intravascular Coagulopathy (3.5%). Perinatal deaths were caused by prematurity (42.9%) and birth asphyxia (57.1%). Forty-eight babies had low-birth weight (58.54%). The high incidence of eclampsia and its complications during this study period may indicate the need for earlier and more meticulous intervention at both the clinic and hospital levels.


Oxidation of Cr(III) to Cr(VI) during chlorination of drinking water.
Drinking water treatment typically uses strong oxidants such as chlorine which are capable of converting Cr(III) to Cr(VI). The rates and extent of Cr(III) oxidation by chlorine are not well established. Cr(III) oxidation experiments were therefore conducted in distilled deionized water and New York City tap water dosed initially with Cr(III) and supplemented with sodium hypochlorite to increase free chlorine residual. Reaction progress was monitored using capillary electrophoresis which quenched reactions and allowed for quantification of Cr(VI). Three different forms of Cr(III) were used as reactants: a Cr(III) nitrate salt, Cr(III)-EDTA, and Cr(III) hydroxide. Rates of Cr(VI) production for all three forms of Cr(III) were rapid, on the order of hours. However, oxidation rates slowed and a plateau in Cr(VI) concentrations was reached. This resulted in less than 100% conversion of Cr(III) to Cr(VI) even at relatively high chlorine doses (10 to 100 mg L(-1) as Cl(2)). The loss of free chlorine due to a non-Cr chlorine demand, the precipitation of Cr(III) to Cr(OH)(3)(s), and the partial oxidation of Cr(III) to intermediate oxidation states (i.e. Cr(IV) and Cr(V)) were examined and eliminated as possible explanations for this behavior. Consumption of chlorine via reaction with intermediate oxidation states of Cr is therefore offered as a possible explanation for the plateau in Cr(VI) concentrations.


Clinical endpoints in the controlled human challenge model for Shigella: A call for standardization and the development of a disease severity score.
Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints.


Contribution of neighborhood income and access to quality physical activity resources to physical activity in ethnic minority women over time.
To create and test an index to indicate both availability and quality of physical activity (PA) resources (PARs), to examine associations between access to quality PARs and changes in PA, and to determine whether this association differed in lower- and higher-income neighborhoods. Longitudinal, 6-month intervention. Houston and Austin, Texas. African-American and Hispanic or Latina women. Women (N = 410) completed a questionnaire and accelerometry to measure PA. Neighborhoods (N = 163) were classified as lower- or higher-income by median household income at the census-tract level. PARs were audited using the PARA (physical activity resource assessment). Access to quality PARs was determined by a composite index (QPAR) of features, amenities, and incivilities. Repeated measures analyses of variance were used to examine changes in PA by (1) neighborhood income (lower/higher) and QPAR (lower/higher) groups, and (2) neighborhood income (lower/higher) and number of PARs (lower/higher) groups, adjusting for ethnicity, household income, and body mass index. Women in neighborhoods with lower QPAR scores had small increases in self-reported vigorous PA (M Δ = 327.8 metabolic equivalent of task [MET]-min/wk) and decreases in accelerometer PA (M = -3.4 min/d), compared to those with higher QPAR scores who had larger increases in self-reported vigorous PA (M Δ = 709.8 MET-min/wk) and increased accelerometer PA (M = 3.9 min/d). There was a significant interaction between changes in leisure-time PA, QPAR score, and number of PARs (p = .049). Women with both more PARs and higher QPAR scores reported greater increases in leisure-time PA than women with fewer PARs and lower QPAR scores. Access to higher-quality PARs can help increase or maintain PA over time regardless of neighborhood income. PAR quality is a separate and distinct, important determinant of PA in ethnic minority women.


Endoscopic pretrichial brow lift: surgical indications, technique and outcomes.
To present an alternative technique for rejuvenating the upper face of patients with high hairlines. A chart review was performed to ascertain the longevity and aesthetic quality of endoscopically assisted pretrichial brow lifts. The charts of a single surgeon were reviewed (2000 to 2003). The technique was noted to be consistent, and in the majority of cases, additive to other concurrent procedures. Morbidity was defined as asymmetry, poor longevity, and patient dissatisfaction. All patients were included who had the procedure performed. No exclusions were recognized for race, age, gender, medical history, or any other patient demographic. Results for the clinical outcome were graded as excellent, good, fair, or poor. Subjective and objective assessments were made by using history, examination, and photos. A rating of excellent incorporates symmetry, longevity, smoothness of the brow skin, and patient satisfaction both with the recovery process and with the results. In properly selected cosmetic patients, the endoscopic pretrichial brow lift is an effective method for rejuvenating the upper face. A more youthful appearance is achieved with the procedure, and it is easily combined with eyelid rejuvenation. We believe that this technique is the procedure of choice for addressing brow ptosis in patients with high hairlines.


Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro.
We studied the effect of menatetrenone, a vitamin K2 homolog, on bone resorption stimulated by interleukin-1 alpha (IL-1 alpha), prostaglandin E2 (PGE2), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Bone-resorbing activity was assessed by measurement of calcium and hydroxyproline in the media and calvariae. IL-1 alpha (0.1-100 U/ml), 1,25-(OH)2D3 (10(-10)-10(-7) M), PGE2 (10(-9)-10(-6) M), and PTH (3 x 10(-8)-3 x 10(-7) M) dose dependently increased the levels of calcium and hydroxyproline in the medium. Indomethacin (10(-6) M) completely inhibited bone resorption induced by IL-1 alpha and partially inhibited bone resorption induced by 1,25-(OH)2D3. However, indomethacin did not affect the action of PGE2 or PTH. Menatetrenone (3 x 10(-6)-3 x 10(-5) M) inhibited the bone resorption induced by IL-1 alpha (2 U/ml), PGE2 (10(-7) M), PTH (3 x 10(-7) M), and 1,25-(OH)2D3 (3 x 10(-10) M) in a dose-dependent manner. Menatetrenone also inhibited the PGE2 production stimulated by IL-1 alpha. These results indicate that menatetrenone may inhibit bone resorption through at least two different mechanisms; one possibly is an inhibitory effect on prostaglandin production.