Antiplatelet treatment in ischemic stroke treatment.
Antiplatelets represent a diverse group of agents that share the ability to reduce platelet activity through a variety of mechanisms. Antithrombotic agents are effective in the secondary prevention of ischemic strokes. Most strokes are caused by a sudden blockage of an artery in the brain (called an ischaemic stroke) that is usually due to a blood clot. Immediate treatment with antiplatelet drugs such as aspirin may prevent new clots from forming and hence improve recovery after stroke. Several studies have evaluated the role of one antiplatelet agent, aspirin, in reducing stroke severity. The International Stroke Trial (IST) of 20,000 patients with acute stroke from other countries. In this study there was a significant 14% proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]. Few studies examined the role of ticlopidin in acute stroke setting the results showed treatment with ticlopidine improved the neurologic outcome. In the Examining the Safety of Loading of Aspirin and Clopidogrel in Acute Ischemic Stroke and TIA (LOAD) study, 40 consecutive ischemic stroke patients were treated with 325 mg of aspirin and 375 mg of clopidogrel within 36 hours of symptom onset. Overall, 37.5% (n = 15) of the patients had an improvement of 2 or more points on the NIHSS 24 hours after antiplatelet administration. The antiplatelet efficacy of aspirin in preventing secondary stroke was established by three studies conducted in the late 1980s and early 1990s: the Swedish Aspirin Low-dose Trial (SALT) trials have demonstrated that aspirin-even in doses as low as 30 mg/day-reduces secondary stroke, MI, or vascular death in patients with. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity.


Developmental effects associated with exposure to xylene: a review.
Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all of the above mentioned effects, with the exception of cleft palate. The o- and p-isomers appeared more hazardous to offspring than did the m-isomer. Malformations (i.e., cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to exposure to xylene has yet to be presented.


Novel senescence associated gene, YPEL3, is repressed by estrogen in ER+ mammary tumor cells and required for tamoxifen-induced cellular senescence.
Estrogen signaling plays an important role in breast carcinogenesis. An increased understanding of estrogen gene targets and their effects will allow for more directed and effective therapies for individuals with breast cancer, particularly those with estrogen receptor positive tumors resistant to tamoxifen therapy. Here, we identify YPEL3 as a growth suppressive protein downregulated by estrogen in estrogen receptor positive breast cancer cell lines. Estrogen repression of YPEL3 expression was found to be independent of p53 but dependent on estrogen receptor alpha expression. Importantly, YPEL3 expression, which is induced by the removal of estrogen or treatment with tamoxifen triggers cellular senescence in MCF-7 cells while loss of YPEL3 increases the growth rate of MCF-7 cells. Taken together these findings suggest that YPEL3 may represent a potential target for directed hormonal therapy for estrogen receptor positive breast cancer patients.


Insights into the conformational variability and regulation of human Nek2 kinase.
The Nek family of serine/threonine kinases regulates centrosome and cilia function; in addition, several of its members are potential targets for drug discovery. Nek2 is dimeric, is cell cycle regulated and functions in the separation of centrosomes at G2/M. Here, we report the crystal structures of wild-type human Nek2 kinase domain bound to ADP at 1.55-A resolution and T175A mutant in apo form as well as that bound to a non-hydrolyzable ATP analog. These show that regions of the Nek2 structure around the nucleotide-binding site can adopt several different but well-defined conformations. None of the conformations was the same as that observed for the previously reported inhibitor-bound structure, and the two nucleotides stabilized two conformations. The structures suggest mechanisms for the auto-inhibition of Nek2 that we have tested by mutagenesis. Comparison of the structures with Aurora-A and Cdk2 gives insight into the structural mechanism of Nek2 activation. The production of specific inhibitors that target individual kinases of the human genome is an urgent challenge in drug discovery, and Nek2 is especially promising as a cancer target. We not only identify potential challenges to the task of producing Nek2 inhibitors but also propose that the conformational variability provides an opportunity for the design of Nek2 selective inhibitors because one of the conformations may provide a unique target.


Genetic variation in the invasive avian parasite, Philornis downsi (Diptera, Muscidae) on the Galápagos archipelago.
Understanding the dispersal and genetic structure of invasive insects across islands is important for designing management plans that are appropriate at spatial and temporal scales. For invasive parasites, population dynamics are largely determined by the distribution and density of their host species. The introduced parasitic fly, Philornis downsi, parasitises nestlings of endemic birds on all major islands of the Galápagos archipelago. The fly's high mortality and fitness impacts are of conservation concern for vulnerable and declining species of Darwin's finches. Using microsatellite data in Bayesian clustering and landscape genetic analyses, we examine gene flow and dispersal in P. downsi between three islands and across habitats (highlands, lowlands) and examine for the presence of population bottlenecks. We also examine variation at the mitochondrial gene CO1 across islands to establish if cryptic species were present. Both the mitochondrial and microsatellite data were consistent with there being a single species across islands. We found low genetic differentiation between islands and strong evidence for inter-island gene flow, or shared recent ancestry among individuals. Landscape genetic analysis identified two genetic clusters: one encompassing Santa Cruz and Isabela, and one on Floreana Island. There was no evidence of genetic differentiation between habitats and molecular variance was mainly attributable to within individuals. The combined P. downsi population was found to have undergone a population bottleneck. Philornis downsi populations have high connectivity within and between islands, with low levels of genetic differentiation between Floreana and the other two islands examined. The genetic bottleneck found across islands suggests there was a small founding population or few introduction events of P. downsi. The high dispersal capacity and wide habitat use of P. downsi highlights the significant threat that this parasite poses to the Galápagos avifauna. Our findings are relevant for assessing the viability of methods to control P. downsi on Galápagos, such as the sterile insect technique.


Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy.
We conducted a prospective survey of a family presenting a new syndrome characterized mainly by recurrent strokelike episodes and neuroimaging evidence of leukoencephalopathy. Forty-five members of a single family were studied clinically and with magnetic resonance imaging. Nine had strokelike episodes, including transient ischemic attacks, and minor or major strokes starting between the fourth and sixth decades, with neuroimaging evidence of small, deep infarcts and a widespread white matter disorder. Other symptoms included migraine (three), dementia (two), epilepsy (one), and hearing loss (one). In some patients, we found various immunologic anomalies and muscular lipidosis without ragged-red fibers. Eight other family members were clinically normal, but had identical neuroimaging signs of leukoencephalopathy. No abnormality was detected in the 28 other members of the family examined. Extensive investigations failed to reveal any known cause of cerebral ischemia. There appears to be a new syndrome in this family that is characterized by recurrent subcortical strokelike episodes, leukoencephalopathy, immunologic anomalies, muscular lipidosis, and an autosomal dominant pattern of transmission.


Comparing Quality of Dying and Death Perceived by Family Members and Nurses for Patients Dying in US and Dutch ICUs.
The Quality of Dying and Death (QODD) questionnaire is used as a self-reported measure to allow families and clinicians to assess patients' quality of dying and death. We evaluated end-of-life (EOL) experiences as measured by the QODD completed by families and nurses in the United States and the Netherlands to explore similarities and differences in these experiences and identify opportunities for improving EOL care. Questionnaire data were gathered from family members of patients dying in the ICU and nurses caring for these patients. In The Netherlands, data were gathered in three teaching hospitals, and data was gathered from 12 sites participating in a randomized trial in the United States. The QODD consists of 25 items and has been validated in the United States. Data from 446 patients were analyzed (346 in the United States and 100 in the Netherlands). Dutch patients were older than those in the United States (72 + 10.2 years vs 65 + 16.0 years; P < .0025). The family-assessed overall QODD score was the same in both countries: the Netherlands = median, 9; interquartile range (IQR), 8-10 and the United States = median, 8; IQR, 5-10. US family members rated the quality of two items higher than did the Netherlands families: "time spent with loved ones" and "time spent alone." Nurse-assessed QODD ratings varied: the single-item QODD summary score was significantly higher in the Netherlands (the Netherlands: median, 9; IQR, 8-10 vs the United States: median, 7; IQR, 5-8; P < .0025), whereas the QODD total score was higher in the United States (the Netherlands: median, 6.9; IQR, 5.5-7.6 vs the United States: median, 7.1; IQR, 5.8-8.4; P = .014), although it did not meet our criteria for statistical significance. Of the 22 nurse-assessed items, 10 were significantly different between the Netherlands and the United States, with eight having higher scores in the United States and 2 having higher scores in the Netherlands. The QODD was rated similarly by family members in the United States and the Netherlands but varied when assessed by nurses. These differences may be due to organizational or cultural differences between the two countries or to expectations of respondents.


Isolation and characterization of coactivator-binding peptoids from a combinatorial library.
Pharmacologic agents capable of activating the expression of specific genes would be valuable tools in biological research and could potentially be useful therapeutically. Efforts to develop a general solution to this problem have focused on the discovery of cell permeable mimics of native transcription factors comprised of linked DNA-binding and activation domain surrogates. Recently, we reported the isolation of a peptoid, called KBPo2, that binds a fragment of the mammalian coactivator CREB-binding protein (CBP). When delivered to a promoter-bound DNA-binding domain, this peptoid acted as a potent activation domain mimic in human cells. In this paper, we provide full details of the screening experiments and also report further characterization of this molecule as well as the other peptoids that came out of the screen. Of the three peptoids identified as putative CBP ligands, only KBPo2 demonstrated the necessary combination of binding affinity, specificity and cell permeability necessary to function as a potent activation domain mimic in cells. KBPo2 binds to CBP in a region different than that recognized by the native activation peptide from the transcription factor CREB.


A range-normalization model of context-dependent choice: a new model and evidence.
Most utility theories of choice assume that the introduction of an irrelevant option (called the decoy) to a choice set does not change the preference between existing options. On the contrary, a wealth of behavioral data demonstrates the dependence of preference on the decoy and on the context in which the options are presented. Nevertheless, neural mechanisms underlying context-dependent preference are poorly understood. In order to shed light on these mechanisms, we design and perform a novel experiment to measure within-subject decoy effects. We find within-subject decoy effects similar to what have been shown previously with between-subject designs. More importantly, we find that not only are the decoy effects correlated, pointing to similar underlying mechanisms, but also these effects increase with the distance of the decoy from the original options. To explain these observations, we construct a plausible neuronal model that can account for decoy effects based on the trial-by-trial adjustment of neural representations to the set of available options. This adjustment mechanism, which we call range normalization, occurs when the nervous system is required to represent different stimuli distinguishably, while being limited to using bounded neural activity. The proposed model captures our experimental observations and makes new predictions about the influence of the choice set size on the decoy effects, which are in contrast to previous models of context-dependent choice preference. Critically, unlike previous psychological models, the computational resource required by our range-normalization model does not increase exponentially as the set size increases. Our results show that context-dependent choice behavior, which is commonly perceived as an irrational response to the presence of irrelevant options, could be a natural consequence of the biophysical limits of neural representation in the brain.


Sequestration of flue gas CO₂ by direct gas-solid carbonation of air pollution control system residues.
Direct gas-solid carbonation reactions of residues from an air pollution control system (APCr) were conducted using different combinations of simulated flue gas to study the impact on CO₂ sequestration. X-ray diffraction analysis of APCr determined the existence of CaClOH, whose maximum theoretical CO₂ sequestration potential of 58.13 g CO₂/kg APCr was calculated by the reference intensity ratio method. The reaction mechanism obeyed a model of a fast kinetics-controlled process followed by a slow product layer diffusion-controlled process. Temperature is the key factor in direct gas-solid carbonation and had a notable influence on both the carbonation conversion and the CO₂ sequestration rate. The optimal CO₂ sequestrating temperature of 395 °C was easily obtained for APCr using a continuous heating experiment. CO₂ content in the flue gas had a definite influence on the CO₂ sequestration rate of the kinetics-controlled process, but almost no influence on the final carbonation conversion. Typical concentrations of SO₂ in the flue gas could not only accelerate the carbonation reaction rate of the product layer diffusion-controlled process, but also could improve the final carbonation conversion. Maximum carbonation conversions of between 68.6% and 77.1% were achieved in a typical flue gas. Features of rapid CO₂ sequestration rate, strong impurities resistance, and high capture conversion for direct gas-solid carbonation were proved in this study, which presents a theoretical foundation for the applied use of this encouraging technology on carbon capture and storage.


A comparison of SNPs and microsatellites as linkage mapping markers: lessons from the zebra finch (Taeniopygia guttata).
Genetic linkage maps are essential tools when searching for quantitative trait loci (QTL). To maximize genome coverage and provide an evenly spaced marker distribution a combination of different types of genetic marker are sometimes used. In this study we created linkage maps of four zebra finch (Taeniopygia guttata) chromosomes (1, 1A, 2 and 9) using two types of marker, Single Nucleotide Polymorphisms (SNPs) and microsatellites. To assess the effectiveness and accuracy of each kind of marker we compared maps built with each marker type separately and with both types of marker combined. Linkage map marker order was validated by making comparisons to the assembled zebra finch genome sequence. We showed that marker order was less reliable and linkage map lengths were inflated for microsatellite maps relative to SNP maps, apparently due to differing error rates between the two types of marker. Guidelines on how to minimise the effects of error are provided. In particular, we show that when combining both types of marker the conventional process of building linkage maps, whereby the most informative markers are added to the map first, has to be modified in order to improve map accuracy. When using multiple types and large numbers of markers to create dense linkage maps, the least error prone loci (SNPs) rather than the most informative should be used to create framework maps before the addition of other potentially more error prone markers (microsatellites). This raises questions about the accuracy of marker order and predicted recombination rates in previous microsatellite linkage maps which were created using the conventional building process, however, provided suitable error detection strategies are followed microsatellite-based maps can continue to be regarded as reasonably reliable.


Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments.
Skin aging has long been considered only as a cosmetic problem. With the increase in lifespan, we are now more often experiencing a further dimension of skin aging, which is no longer only cosmetic, but also functional, in the sense that the skin has lost its protective mechanical function. Dermatoporosis is the name proposed to capture, in a holistic approach, all the aspects of this chronic cutaneous insufficiency/fragility syndrome. In this paper, we review the clinical aspects of dermatoporosis, its histological features and the current understanding of its etiological factors. The clinical manifestations of dermatoporosis comprise (i) morphological markers of fragility--rather trivial--such as senile purpura, stellate pseudoscars and skin atrophy, and (ii) functional expression of skin fragility resulting from minor traumas such as frequent skin laceration, delayed wound healing, nonhealing atrophic ulcers and subcutaneous bleeding with the formation of dissecting hematomas leading to large zones of necrosis. Dissecting hematomas bear significant morbidity needing hospitalization and urgent surgical procedures. Molecular mechanisms implying hyaluronate-CD44 pathways in the control and maintenance of epithelial growth and the viscoelastic properties of the extracellular matrix offer new opportunities for preventive intervention. We propose to group the different manifestations and implications of this syndrome under the umbrella term of 'dermatoporosis', because we think it will help to capture the understanding of health professionals that, as osteoporosis, 'dermatoporosis' should be prevented and treated to avoid complications. Dermatologists should be aware of this emerging syndrome and function as key players in prevention and therapy. Randomized clinical trials should demonstrate which intervention may best prevent and/or reverse dermatoporosis.


Criteria for identifying radiologists with acceptable screening mammography interpretive performance on basis of multiple performance measures.
Using a combination of performance measures, we updated previously proposed criteria for identifying physicians whose performance interpreting screening mammography may indicate suboptimal interpretation skills. In this study, six expert breast imagers used a method based on the Angoff approach to update criteria for acceptable mammography performance on the basis of two sets of combined performance measures: set 1, sensitivity and specificity for facilities with complete capture of false-negative cancers; and set 2, cancer detection rate (CDR), recall rate, and positive predictive value of a recall (PPV1) for facilities that cannot capture false-negative cancers but have reliable cancer follow-up information for positive mammography results. Decisions were informed by normative data from the Breast Cancer Surveillance Consortium (BCSC). Updated combined ranges for acceptable sensitivity and specificity of screening mammography are sensitivity≥80% and specificity≥85% or sensitivity 75-79% and specificity 88-97%. Updated ranges for CDR, recall rate, and PPV1 are: CDR≥6 per 1000, recall rate 3-20%, and any PPV1; CDR 4-6 per 1000, recall rate 3-15%, and PPV1≥3%; or CDR 2.5-4.0 per 1000, recall rate 5-12%, and PPV1 3-8%. Using the original criteria, 51% of BCSC radiologists had acceptable sensitivity and specificity; 40% had acceptable CDR, recall rate, and PPV1. Using the combined criteria, 69% had acceptable sensitivity and specificity and 62% had acceptable CDR, recall rate, and PPV1. The combined criteria improve previous criteria by considering the interrelationships of multiple performance measures and broaden the acceptable performance ranges compared with previous criteria based on individual measures.


Variations in Mn(II) speciation among organisms: what makes D. radiodurans different.
The manganese(II) speciation in intact cells of D. radiodurans, E. coli, S. cerevisiae and Arabidopsis thaliana seeds was measured using high-field electron paramagnetic resonance techniques. The majority of the Mn(II) ions in these organisms were six-coordinate, bound predominately by water, phosphates and nitrogen-based molecules. The relative distribution of the different phosphates in bacteria and S. cerevisiae was the same and dominated by monophosphate monoesters. Mn(II) was also found bound to the phosphate backbone of nucleic acids in these organisms. Phosphate ligation in Arabidopsis seeds was dominated by phytate. The extent of nitrogen ligation in the four organisms was also determined. On average, the Mn(II) in D. radiodurans had the most nitrogen ligands followed by E. coli. This was attributed to higher concentrations of Mn(II) bound to proteins in these species. Although constitutively expressed in all four organisms, MnSOD was only detected in D. radiodurans. As previously reported, D. radiodurans also accumulates a second abundant Mn containing protein species. The high concentration of proteinaceous Mn(II) is a unique feature of D. radiodurans.


Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo.
Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production. We implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK α2 [D¹⁵⁷A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo. MBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production. Molecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.


Use of temperature alterations to characterize vascular reactivity.
Monitoring alterations in fingertip temperature during ischaemia and the subsequent hyperaemia provides a novel way of studying microvascular reactivity. The relations between parameters characterizing blood perfusion and the thermal response of fingertips were studied using experimental and theoretical approaches. During the experimental protocol, two brachial artery occlusion tests were conducted in 12 healthy volunteers, and fingertip temperature, heat flux and skin perfusion using laser Doppler flowmetry (LDF) were measured. The temperature curves provide a smooth and robust response that is able to capture occlusion and reperfusion. The temperature fall during occlusion as well as the maximum temperature recorded depended linearly on the initial temperature. The magnitude of the LDF signal was associated with local tissue temperature and followed an exponential response. Heat flux measurements demonstrated rapid changes and followed variations in blood perfusion closely. The time points at which the heat flux reached its maximum corresponded to the time at which the fingertip temperature curves showed an inflection point after cuff release. The time required for the fingertip temperature to arrive at the maximum temperature was greater than the time to peak for the heat flux signal, which was greater than the LDF signal to reach a maximum. The time lag between these signals was a function of the finger size and finger temperature at the moment reperfusion restarted. Our present results indicate that finger temperature, heat flux and perfusion display varying rates of recovery following ischaemic stimuli and that differential responses are associated with the initial finger temperature.


Phytotoxic Effects and Phytochemical Fingerprinting of Hydrodistilled Oil, Enriched Fractions, and Isolated Compounds Obtained from Cryptocarya massoy (Oken) Kosterm. Bark.
The hydrodistilled oil of Cryptocarya massoy bark was characterized by GC-FID and GC/MS analyses, allowing the identification of unusual C10 massoia lactone (3, 56.2%), C12 massoia lactone (4, 16.5%), benzyl benzoate (1, 12.7%), C8 massoia lactone (3.4%), δ-decalactone (5, 1.5%), and benzyl salicylate (2, 1.8%) as main constituents. The phytotoxic activities of the oil, three enriched fractions (lactone-rich, ester-rich, and sesquiterpene-rich), and four constituents (compounds 1, 2, 5, and δ-dodecalactone (6)) against Lycopersicon esculentum and Cucumis sativus seeds and seedlings were screened. At a concentration of 1000 μl/l, the essential oil and the massoia lactone-rich fraction caused a complete inhibition of the germination of both seeds, and, when applied on tomato plantlets, they induced an 85 and 100% dieback, respectively. These performances exceeded those of the well-known phytotoxic essential oils of Syzygium aromaticum and Cymbopogon citratus, already used in commercial products for the weed and pest management. The same substances were also evaluated against four phytopathogenic bacteria and ten phytopathogenic fungi, providing EC50 values against the most susceptible strains in the 100-500 μl/l range for the essential oil and in the 10-50 μl/l range for compound 6 and the lactone-rich fraction. The phytotoxic behavior was related mainly to massoia lactones and benzyl esters, while a greater amount of 6 may infer a good activity against some phytopathogenic fungi. Further investigations of these secondary metabolites are warranted, to evaluate their use as natural herbicides.


Wick's theorem for matrix product states.
Matrix product states and their continuous analogues are variational classes of states that capture quantum many-body systems or quantum fields with low entanglement; they are at the basis of the density-matrix renormalization group method and continuous variants thereof. In this work we show that, generically, N-point functions of arbitrary operators in discrete and continuous translation invariant matrix product states are completely characterized by the corresponding two- and three-point functions. Aside from having important consequences for the structure of correlations in quantum states with low entanglement, this result provides a new way of reconstructing unknown states from correlation measurements, e.g., for one-dimensional continuous systems of cold atoms. We argue that such a relation of correlation functions may help in devising perturbative approaches to interacting theories.


First Report of Fusicoccum aesculi Causing Leaf Spots of Paeonia suffruticosa in Henan Province, China.
Tree peony (Paeonia suffruticosa) is regarded as the national flower of China and is cultivated throughout the country. In early August 2010, a moderately severe leaf spot was observed on tree peony cultivated in a garden of Zhengzhou, Henan Province, where approximately 15% of trees were diseased. In 2011, a less damaging leaf spot was also observed in another area of the city with approximately 10% of trees diseased. Early symptoms appeared as small, round, pale-brown lesions on the leaves. Lesions expanded into 5- to 20-mm-diameter spots that were elliptical or irregular, brown to dark brown. A fungus was consistently isolated from the leaf spots on potato dextrose agar (PDA) in grey-black colonies, but produced few pycnidia. Black pycnidia were ostiolate, globose, papillate, formed in uniloculate or multiloculate stromata that were immersed in the leaf, and became erumpent at maturity. Conidiophores or conidiogenous cells were hyaline and cylindrical. Conidia were hyaline, granular, fusoid to ellipsoid, aseptate, with a sub-truncate base, and 20 to 28 × 4.5 to 7.5 μm (mean dimensions of 50 conidia: 24.5 × 5.2 μm). The pathogen was identified as Fusicoccum aesculi, anamorphic stage of Botryosphaeria dothidea, on the basis of morphology (2). The identity of the fungus was confirmed to be F. aesculi by DNA sequence analysis of the internal transcribed spacer (ITS) region (GenBank Accession No. JQ323001), which was 100% identical to those of other F. aesculi isolates (GenBank Accession Nos. GU997686.1 and GU723469.1) (1). Pathogenicity tests were done by inoculating each of 10 leaves on one 7-year-old tree with a mycelial plug (0.5 cm diameter) harvested from the periphery of a 7-day-old colony. An equal number of leaves on the same tree, serving as controls, were mock-inoculated with plugs of PDA medium. Inoculated leaves were covered with plastic for 24 h to maintain high relative humidity and incubated at about 25°C. The plugs were removed after 48 h. After 7 days, 80% of the inoculated leaves showed symptoms identical to those observed in the field under natural conditions, whereas controls remained symptom-free. Reisolation of the fungus from lesions on inoculated leaves confirmed that the causal agent was F. aesculi. Pathogenicity tests were repeated on the other two trees by the same methods with the same results. To our knowledge, this is the first report of F. aesculi infecting P. suffruticosa in China. References: (1) S. Mohali et al. Mycol. Res. 110:405, 2006. (2) B. C. Sutton. The Coelomycetes. CABI Publishing, New York, 1980.


Why GPS makes distances bigger than they are.
Global navigation satellite systems such as the Global Positioning System (GPS) is one of the most important sensors for movement analysis. GPS is widely used to record the trajectories of vehicles, animals and human beings. However, all GPS movement data are affected by both measurement and interpolation errors. In this article we show that measurement error causes a systematic bias in distances recorded with a GPS; the distance between two points recorded with a GPS is - on average - bigger than the true distance between these points. This systematic 'overestimation of distance' becomes relevant if the influence of interpolation error can be neglected, which in practice is the case for movement sampled at high frequencies. We provide a mathematical explanation of this phenomenon and illustrate that it functionally depends on the autocorrelation of GPS measurement error (C). We argue that C can be interpreted as a quality measure for movement data recorded with a GPS. If there is a strong autocorrelation between any two consecutive position estimates, they have very similar error. This error cancels out when average speed, distance or direction is calculated along the trajectory. Based on our theoretical findings we introduce a novel approach to determine C in real-world GPS movement data sampled at high frequencies. We apply our approach to pedestrian trajectories and car trajectories. We found that the measurement error in the data was strongly spatially and temporally autocorrelated and give a quality estimate of the data. Most importantly, our findings are not limited to GPS alone. The systematic bias and its implications are bound to occur in any movement data collected with absolute positioning if interpolation error can be neglected.


Pre- and post-harvest interventions to reduce pathogen contamination in the U.S. beef industry.
Significant effort has been targeted at reducing the risk of pathogens in U.S. beef products since the mid-1990s. These efforts were focused on Escherichia coli O157:H7 after it was declared an adulterant in ground beef or its components. Post-harvest interventions applied to hides and carcasses by beef processors resulted in significant progress. Effective pre-harvest approaches proved hard to identify and implement. Six additional pathogenic E. coli serogroups were made adulterants in some beef products in 2012 and discussion regarding Salmonella is ongoing. Success to date has resulted from the combination of regulatory, research, and industry efforts to reduce the presence of pathogens in beef.


Self-organized learning of purely temporal information in a photorefractive optical resonator.
A photorefractive resonator containing an optical delay line is shown to learn temporal information through a self-organization process. We present experiments in which a resonator mode selectively learns the mostfrequently presented signals at the input. We also demonstrate the self-organized association of two different analog signals with two different resonator modes.


Robot-aided assessment of lower extremity functions: a review.
The assessment of sensorimotor functions is extremely important to understand the health status of a patient and its change over time. Assessments are necessary to plan and adjust the therapy in order to maximize the chances of individual recovery. Nowadays, however, assessments are seldom used in clinical practice due to administrative constraints or to inadequate validity, reliability and responsiveness. In clinical trials, more sensitive and reliable measurement scales could unmask changes in physiological variables that would not be visible with existing clinical scores.In the last decades robotic devices have become available for neurorehabilitation training in clinical centers. Besides training, robotic devices can overcome some of the limitations in traditional clinical assessments by providing more objective, sensitive, reliable and time-efficient measurements. However, it is necessary to understand the clinical needs to be able to develop novel robot-aided assessment methods that can be integrated in clinical practice.This paper aims at providing researchers and developers in the field of robotic neurorehabilitation with a comprehensive review of assessment methods for the lower extremities. Among the ICF domains, we included those related to lower extremities sensorimotor functions and walking; for each chapter we present and discuss existing assessments used in routine clinical practice and contrast those to state-of-the-art instrumented and robot-aided technologies. Based on the shortcomings of current assessments, on the identified clinical needs and on the opportunities offered by robotic devices, we propose future directions for research in rehabilitation robotics. The review and recommendations provided in this paper aim to guide the design of the next generation of robot-aided functional assessments, their validation and their translation to clinical practice.


Prognostic value of the C-reactive protein to albumin ratio in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction
This study investigated whether baseline serum level of C-reactive protein (CRP)/albumin ratio is associated with infarct localization, number of vascular lesions, and in-hospital mortality in patients undergoing primary percutaneous coronary intervention (PCI) for acute ST elevation myocardial infarction (STEMI). The study population consisted of 116 patients diagnosed with STEMI. The CRP/albumin ratio at first admission, cardiac troponin-I (cTnI), PCI results, and clinical outcomes were recorded. The mean CRP/albumin ratio, cTnI level, and mean number of vascular lesions were significantly higher in non-survivors than in survivors (p = 0.006, p = 0.004, and p = 0.007, respectively). Multivariate logistic regression analysis demonstrated that the CRP/ albumin ratio and number of coronary artery lesions were independent predictors of mortality in STEMI patients. According to these analyses, the presence of ≥ 2 vessel lesions was the most important predictor of mortality, with an odds ratio of 2.009 (95% confidence interval: 1.191–3.387, p = 0.009). This study demonstrates the potential utility of the CRP/albumin ratio for predicting the clinical outcome of patients with STEMI. In addition, the presence of ≥ 2 vascular lesions contributed to a 2-fold increase in mortality rate in STEMI patients.


A critical evaluation of high performance liquid chromatography-electrospray ionisation-mass spectrometry and capillary electrophoresis-electrospray-mass spectrometry for the detection and determination of small molecules of significance in clinical and forensic science.
A critical review of applications for the period 2000-2003, taken from the Web of Knowledge database, of the techniques high performance liquid chromatography-electrospray ionisation-mass spectrometry (HPLC-ESI-MS) and capillary electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) to the detection and determination of small molecules of significance in clinical and forensic science is presented. The molecules of mass less than 500 Da are chosen according to selected structural classes in which they give ESI signals primarily as [M+H](+) ions although other ions such as [M-H](-), [M+Na](+) and [M+NH(4)](+) are also reported. The structural classes are drugs with amine-containing side chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines, carbohydrates, benzimidazoles, other heterocycles, sulphonylureas, anthracyclines, sulphonamides, penicillins, cephalosporins, tetracyclines, nitrocatechols, steroids, flavonoids, oxazaphosphorines, cannabinols, and miscellaneous molecules. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion-trap, triple quadrupole and time-of-flight mass spectrometers. The review then gives a critical evaluation of these recent HPLC-ESI-MS and CE-ESI-MS analytical methods for the detection and determination of small molecules of clinical and forensic significance. Analytical information on, for example, sample concentration techniques, HPLC and CE separation conditions, recoveries from biological media and limits of detection (LODs) are provided.


LAT is required for tyrosine phosphorylation of phospholipase cgamma2 and platelet activation by the collagen receptor GPVI.
In the present study, we have addressed the role of the linker for activation of T cells (LAT) in the regulation of phospholipase Cgamma2 (PLCgamma2) by the platelet collagen receptor glycoprotein VI (GPVI). LAT is tyrosine phosphorylated in human platelets heavily in response to collagen, collagen-related peptide (CRP), and FcgammaRIIA cross-linking but only weakly in response to the G-protein-receptor-coupled agonist thrombin. LAT tyrosine phosphorylation is abolished in CRP-stimulated Syk-deficient mouse platelets, whereas it is not altered in SLP-76-deficient mice or Btk-deficient X-linked agammaglobulinemia (XLA) human platelets. Using mice engineered to lack the adapter LAT, we showed that tyrosine phosphorylation of Syk and Btk in response to CRP was maintained in LAT-deficient platelets whereas phosphorylation of SLP-76 was slightly impaired. In contrast, tyrosine phosphorylation of PLCgamma2 was substantially reduced in LAT-deficient platelets but was not completely inhibited. The reduction in phosphorylation of PLCgamma2 was associated with marked inhibition of formation of phosphatidic acid, a metabolite of 1,2-diacylglycerol, phosphorylation of pleckstrin, a substrate of protein kinase C, and expression of P-selectin in response to CRP, whereas these parameters were not altered in response to thrombin. Activation of the fibrinogen receptor integrin alpha(IIb)beta(3) in response to CRP was also reduced in LAT-deficient platelets but was not completely inhibited. These results demonstrate that LAT tyrosine phosphorylation occurs downstream of Syk and is independent of the adapter SLP-76, and they establish a major role for LAT in the phosphorylation and activation of PLCgamma2, leading to downstream responses such as alpha-granule secretion and activation of integrin alpha(IIb)beta(3). The results further demonstrate that the major pathway of tyrosine phosphorylation of SLP-76 is independent of LAT and that there is a minor, LAT-independent pathway of tyrosine phosphorylation of PLCgamma2. We propose a model in which LAT and SLP-76 are required for PLCgamma2 phosphorylation but are regulated through independent pathways downstream of Syk.


Perspective: Understanding the Intersection of Climate/Environmental Change, Health, Agriculture, and Improved Nutrition - A Case Study: Type 2 Diabetes.
Efforts to promote health through improved diet and nutrition demand an appreciation of the nutritional ecology that accounts for the intersection of agriculture, food systems, health, disease and a changing environment. The complexity and implications of this ecology is exemplified by current trends and efforts to address nutrition-related non-communicable diseases (NCDs), most prominently type 2 diabetes. The global prevalence of type 2 diabetes continues to rise unabated. Of particular concern is how to address the unhealthy dietary patterns that are contributing to this pandemic in a changing environment. A multi- disciplinary approach is required that will engage those communities that comprise the continuum of effort from research to translation and implementation of evidence-informed interventions, programs and policies. Using the prevention of type 2 diabetes by increasing fruit and vegetable consumption as an exemplar, we argue that the ability to effect positive change in this and other persistent nutrition-related problems can be achieved by moving away from siloed approaches that limit the integration of key components of the diet-health continuum. Ultimately the impact of preventing type 2 diabetes via increased fruit and vegetable consumption will depend on how the entire diet changes, not just fruits and vegetables. In addition, the rapidly changing physical environment that will confront our food production system going forward will also shape the interventions that are possible. Nonetheless, the proposed "team science" approach that accounts for all the elements of the nutrition ecology will better position us to achieve public health goals through safe and sustainable food systems.


Identifying potentially cost effective chronic care programs for people with COPD.
To review published evidence regarding the cost effectiveness of multi-component COPD programs and to illustrate how potentially cost effective programs can be identified. Systematic search of Medline and Cochrane databases for evaluations of multi-component disease management or chronic care programs for adults with COPD, describing process, intermediate, and end results of care. Data were independently extracted by two reviewers and descriptively summarized. Twenty articles describing 17 unique COPD programs were included. There is little evidence for significant improvements in process and intermediate outcomes, except for increased provision of patient self-management education and improved disease-specific knowledge. Overall, the COPD programs generate end results equivalent to usual care, but programs containing >or=3 components show lower relative risks for hospitalization. There is limited scope for programs to break-even or save money. Identifying cost effective multi-component COPD programs remains a challenge due to scarce methodologically sound studies that demonstrate significant improvements on process, intermediate and end results of care. Estimations of potential cost effectiveness of specific programs illustrated in this paper can, in the absence of 'perfect data', support timely decision-making regarding these programs. Nevertheless, well-designed health economic studies are needed to decrease the current decision uncertainty.


Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury.
Chronic neuropathic pain affects millions of individuals worldwide, is typically long-lasting, and remains poorly treated with existing therapies. Neuropathic pain arising from peripheral nerve lesions is known to be dependent on the emergence of spontaneous and evoked hyperexcitability in damaged nerves. Here, we report that the potassium channel subunit Kv9.1 is expressed in myelinated sensory neurons, but is absent from small unmyelinated neurons. Kv9.1 expression was strongly and rapidly downregulated following axotomy, with a time course that matches the development of spontaneous activity and pain hypersensitivity in animal models. Interestingly, siRNA-mediated knock-down of Kv9.1 in naive rats led to neuropathic pain behaviors. Diminished Kv9.1 function also augmented myelinated sensory neuron excitability, manifested as spontaneous firing, hyper-responsiveness to stimulation, and persistent after-discharge. Intracellular recordings from ex vivo dorsal root ganglion preparations revealed that Kv9.1 knock-down was linked to lowered firing thresholds and increased firing rates under physiologically relevant conditions of extracellular potassium accumulation during prolonged activity. Similar neurophysiological changes were detected in animals subjected to traumatic nerve injury and provide an explanation for neuropathic pain symptoms, including poorly understood conditions such as hyperpathia and paresthesias. In summary, our results demonstrate that Kv9.1 dysfunction leads to spontaneous and evoked neuronal hyperexcitability in myelinated fibers, coupled with development of neuropathic pain behaviors.


The role of the endoplasmic reticulum in antigen processing. N-glycosylation of influenza hemagglutinin abrogates CD4+ cytotoxic T cell recognition of endogenously processed antigen.
Evidence is presented for an endogenous route of Ag processing for CD4+ T cell recognition of influenza hemagglutinin that requires obligatory traffic of de novo synthesized hemagglutinin across the lumen of the endoplasmic reticulum for processing in a cytosolic compartment. I-Ad-restricted T cell clones that recognize synthetic peptides corresponding to two distinct antigenic regions of the HA1 subunit, HA1 56-76 and HA1 177-199, are cytotoxic and, dependent on epitope specificity can recognize endogenously processed Ag and lyse class II+ target cells infected with a recombinant vaccinia-X31 HA virus. HA1 56-76 specific T cell clones fail to recognize (target cells infected with) influenza X31 viruses, containing a single residue change, HA1 63 Asp----Asn that introduces an oligosaccharide attachment site: Asp63Cys64Thr65. Recognition is restored, however, by tunicamycin treatment of mutant virus infected target cells. Inasmuch as N-glycosylation of nascent hemagglutinin polypeptides occurs in the lumen of the endoplasmic reticulum, this indicates a route of endogenous processing for hemagglutinin, requiring transport across the endoplasmic reticulum, which has been confirmed by the failure of CD4+ T cells to recognize a recombinant VACC-hemagglutinin virus in which the same single residue change, HA1 63 Asp----Asn has been introduced by site directed mutagenesis.


The Diagnosis of Fungal Neglected Tropical Diseases (Fungal NTDs) and the Role of Investigation and Laboratory Tests: An Expert Consensus Report.
The diagnosis of fungal Neglected Tropical Diseases (NTD) is primarily based on initial visual recognition of a suspected case followed by confirmatory laboratory testing, which is often limited to specialized facilities. Although molecular and serodiagnostic tools have advanced, a substantial gap remains between the desirable and the practical in endemic settings. To explore this issue further, we conducted a survey of subject matter experts on the optimal diagnostic methods sufficient to initiate treatment in well-equipped versus basic healthcare settings, as well as optimal sampling methods, for three fungal NTDs: mycetoma, chromoblastomycosis, and sporotrichosis. A survey of 23 centres found consensus on the key role of semi-invasive sampling methods such as biopsy diagnosis as compared with swabs or impression smears, and on the importance of histopathology, direct microscopy, and culture for mycetoma and chromoblastomycosis confirmation in well-equipped laboratories. In basic healthcare settings, direct microscopy combined with clinical signs were reported to be the most useful diagnostic indicators to prompt referral for treatment. The survey identified that the diagnosis of sporotrichosis is the most problematic with poor sensitivity across the most widely available laboratory tests except fungal culture, highlighting the need to improve mycological diagnostic capacity and to develop innovative diagnostic solutions. Fungal microscopy and culture are now recognized as WHO essential diagnostic tests and better training in their application will help improve the situation. For mycetoma and sporotrichosis, in particular, advances in identifying specific marker antigens or genomic sequences may pave the way for new laboratory-based or point-of-care tests, although this is a formidable task given the large number of different organisms that can cause fungal NTDs.


Molecular and morphological characterisation of Echinococcus from food producing animals in India.
In view of the medical, veterinary and economic importance of hydatid disease in India, our study aimed to determine the prevalence and genotypes of Echinococcus present in domestic livestock in India. Out of 21,861 animals examined, cattle were found with the highest prevalence of hydatid cysts (5.10%) followed by buffaloes (3.81%), pigs (0.87%) and sheep (0.075%). Phylogenetic analysis of the cytochrome oxidase-1 gene revealed that the buffalo strain or G3 genotype was the predominant genotype (29/46) in all species of livestock followed by the cattle strain or G5 genotype (9/46), the G1 genotype or the common sheep strain (6/46) and the G2 genotype or Tasmanian Sheep strain (2/46). The ability of the G3 (buffalo) and G5 (cattle) genotypes of Echinococcus granulosus to infect and produce fertile hydatid cysts in pigs was also demonstrated for the first time. Both morphological and molecular results support earlier studies suggesting that Echinococcus of buffalo origin is phenotypically and genetically similar to the sheep (G1) and Tasmanian Sheep (G2) strains of Echinococcus, which adds further evidence to support its recognition as one species, viz., E. granulosus sensu stricto. Our molecular, morphological and biological characteristics also support earlier studies suggesting that Echinococcus of cattle origin, designated the G5 genotype, should be recognised as a separate species, viz. Echinococcus ortleppi. Finally, the study reveals that the prevalence of hydatidosis in urban centres in India has been showing a consistently declining trend over the past few decades, possibly owing to economic development and improved government legislation of abattoirs.


Coenzyme Q10 distribution in blood is altered in patients with fibromyalgia.
Coenzyme Q10 (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Signs and symptoms associated with muscular alteration and mitochondrial dysfunction, including oxidative stress, have been observed in patients with fibromyalgia (FM). The aim was to study CoQ(10) levels in plasma and mononuclear cells, and oxidative stress in FM patients. We studied CoQ(10) level by HPLC in plasma and peripheral mononuclear cells obtained from patients with FM and healthy control subjects. Oxidative stress markers were analyzed in both plasma and mononuclear cells from FM patients. Higher level of oxidative stress markers in plasma was observed respect to control subjects. CoQ(10) level in plasma samples from FM patients was doubled compared to healthy controls and in blood mononuclear cells isolated from 37 FM patients was found to be about 40% lower. Higher levels of ROS production was observed in mononuclear cells from FM patients compared to control, and a significant decrease was induced by the presence of CoQ(10). The distribution of CoQ(10) in blood components was altered in FM patients. Also, our results confirm the oxidative stress background of this disease probably due to a defect on the distribution and metabolism of CoQ(10) in cells and tissues. The protection caused in mononuclear cells by CoQ(10) would indicate the benefit of its supplementation in FM patients.


Time multiplexing technique of holographic view and Maxwellian view using a liquid lens in the optical see-through head mounted display.
We report a liquid lens based optical see-through head mounted display that can simultaneously display both a maxwellian view and a hologram. Holograms are reconstructed by an angular spectrum layer based synthesis method. A hologram and Maxwellian view are simultaneously displayed by focusing the liquid lens from 0 D to 20 D with 60 Hz. The hologram is reconstructed at a position 1.5 m from the eye, and it is confirmed that the Maxwellian view is clear, even if the focus of the eye changes from 50 cm to 1.7 m. In the proposed system, the liquid lens acts as a low-pass filter. Since the PSNR is about 23 dB in the currently used 10 mm diameter liquid lens, the image quality is not adequate. However, we successfully verify the feasibility of our proposed system. In addition, if a large diameter liquid lens of 30 mm or more is applied, excellent image quality of 30 dB or more can be realized.


Comparative analysis of shell color variety and genetic structure among five high-quality freshwater pearl mussel populations.
Four Hyriopsis cumingii populations, a breeding population (BP), a cultured population (FP), two wild populations from Poyang Lake (PY) and Dongting Lake (DT), and an H. schlegelii population were collected (JX), and the first filial generations (F1) were bred synchronously. The shell nacre polymorphisms, population genetic diversity, and genetic structures of the F1 of each population were analyzed and compared using CIELAB colorimetric measurements and microsatellite markers. The color parameters of the shell nacre (L*, a*, dE*) in the BP were significantly different from those in the FP, PY, and JX populations (P < 0.05), whereas the shell nacre color did not differ significantly between the left and right sides of the shells within the same population (P > 0.05). The BP had relatively darker nacre at the posterior end of the shell, and the color parameters (L*, a*, b*, and dE*) differed significantly from those at the front end (P < 0.05). The five populations showed relatively high levels of genetic diversity (HO = 0.733-0.829). The genetic distance between the H. cumingii populations and H. schlegelii was the greatest, whereas that within the H. cumingii populations and between the FP and the PY population was the smallest. All the individuals tested in this study were optimally grouped into four theoretical populations. In conclusion, the BP was significantly different from the base populations of PY and DT in terms of genetic background and phenotypic parameters of shell nacre color, with potential for further genetic improvement.


Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia.
Defining the mechanisms underlying the control of mitochondrial fusion and fission is critical to understanding cellular adaptation to diverse physiological conditions. Here we demonstrate that hypoxia induces fission of mitochondrial membranes, dependent on availability of the mitochondrial scaffolding protein AKAP121. AKAP121 controls mitochondria dynamics through PKA-dependent inhibitory phosphorylation of Drp1 and PKA-independent inhibition of Drp1-Fis1 interaction. Reduced availability of AKAP121 by the ubiquitin ligase Siah2 relieves Drp1 inhibition by PKA and increases its interaction with Fis1, resulting in mitochondrial fission. High AKAP121 levels, seen in cells lacking Siah2, attenuate fission and reduce apoptosis of cardiomyocytes under simulated ischemia. Infarct size and degree of cell death were reduced in Siah2(-/-) mice subjected to myocardial infarction. Inhibition of Siah2 or Drp1 in hatching C. elegans reduces their life span. Through modulating Fis1/Drp1 complex availability, our studies identify Siah2 as a key regulator of hypoxia-induced mitochondrial fission and its physiological significance in ischemic injury and nematode life span.


High Dietary Magnesium Intake is Significantly and Independently Associated with Higher Insulin Sensitivity in a Mexican-Mestizo Population: A Brief Cross-Sectional Report.
Magnesium acts as a cofactor in many intracellular reactions including phosphorylation of the insulin receptor; therefore, its imbalance can potentially cause insulin resistance. Low serum magnesium concentration has been associated with the development of metabolic syndrome and type 2 diabetes mellitus. To study the association between the daily dietary magnesium intake and insulin resistance estimated by the homeostatic model assessment of insulin resistance and homeostatic model assessment 2, as well as insulin sensitivity estimated by the Matsuda index. In a university affiliated medical center, 32 participants (22 women, 10 men) that had an indication for testing for type 2 diabetes mellitus with an oral glucose tolerance test were enrolled in this cross-sectional, comparative study. Clinical and biochemical evaluations were carried out including an oral glucose tolerance test. Hepatic insulin resistance index, homeostatic model assessment 2, homeostatic model assessment of insulin resistance, and Matsuda insulin sensitivity were calculated for each participant. They were asked to recall their food ingestion (24 hours) of three days of the past week, including a weekend day; magnesium intake was calculated according to the food nutritional information. The low dietary magnesium intake group (< 4.5 mg/kg/day) had a higher two-hour insulin concentration after an oral glucose tolerance test compared to those with high dietary magnesium (119.5 [73.0-190.6] vs. 63.5 [25.4-114.2]; p = 0.008), and insulin sensitivity assessed by the Matsuda index was higher in the high dietary magnesium intake group (4.3 ± 3.1 vs. 2.4 ± 1.5; p = 0.042). In multiple linear regression analysis a higher dietary magnesium intake was independently associated (β = 4.93; p = 0.05) with a better insulin sensitivity estimated by the Matsuda index. Our results suggest that higher magnesium intake is independently associated with better insulin sensitivity in patients at risk for type 2 diabetes mellitus.


Molecular cloning of htra2-beta-1 and htra2-beta-2, two human homologs of tra-2 generated by alternative splicing.
A yeast two-hybrid screen was performed to find new factors involved in pre-mRNA splicing. Using SC35 as a bait, we isolated a human cDNA bearing high homology to the Drosophila transformer-2 (TRA-2) protein. This cDNA was named htra2-beta1. htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern. It interacts with several SR proteins tested in yeast. A second form named htra2-beta2 is generated by alternative splicing. This isoform gives rise to a truncated protein without an SR domain. Both isoforms are evenly distributed throughout adult rat tissue. The ratio of these two isoforms changes after stimulation of primary human T-cell and primary rat spleen cell cultures, indicating that alternative splicing is involved in regulation of htra2-beta activity.


The Fiscal Consequences Attributed to Changes in Morbidity and Mortality Linked to Investments in Health Care: A Government Perspective Analytic Framework.
Governments have an enormous economic and political stake in the health of their populations. Population health is not only fundamental to economic growth but also affects short-term and long-term government expenditure on health care, disability, and other social programs and influences direct and indirect tax receipts. Fiscal transfers between citizen and state are mostly ignored in conventional welfare economics analyses based on the hypothesis that there are no winners or losers through transference of wealth. However, from the government perspective, this position is flawed, as disability costs and lost taxes attributed to poor health and reduced productive output represent real costs that pose budgetary and growth implications. To address the value of health and health care investments for government, we have developed a fiscal health analytic framework that captures how changes in morbidity and mortality influence tax revenue and transfer costs (e.g., disability, allowances, ongoing health costs). The framework can be used to evaluate the marginal impact of discrete investments or a mix of interventions in health care to inform governmental budgetary consequences. In this context, the framework can be considered as a fiscal budget impact and/or cost-benefit analysis model that accounts for how morbidity and mortality linked to specific programs represent both ongoing costs and tax revenue for government. Mathematical models identical to those used in cost-effectiveness analyses can be employed in fiscal analysis to reflect how disease progression influences public accounts (e.g., tax revenue and transfers).


A Pilot Study to Investigate the Balance between Proteases and α1-Antitrypsin in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients.
: The neutrophilic component in bronchiolitis obliterans syndrome (BOS, the main form of chronic lung rejection), plays a crucial role in the pathogenesis and maintenance of the disorder. Human Neutrophil Elastase (HNE), a serine protease responsible of elastin degradation whose action is counteracted by α1-antitrypsin (AAT), a serum inhibitor specific for this protease. This work aimed to investigate the relationship between HNE and AAT in bronchoalveolar lavage fluid (BALf) from stable lung transplant recipients and BOS patients to understand whether the imbalance between proteases and inhibitors is relevant to the development of BOS. To reach this goal a multidisciplinary procedure was applied which included: (i) the use of electrophoresis/western blotting coupled with liquid chromatography-mass spectrometric analysis; (ii) the functional evaluation of the residual antiprotease activity, and (iii) a neutrophil count.


Association of a Frailty Screening Initiative With Postoperative Survival at 30, 180, and 365 Days.
As the US population ages, the number of operations performed on elderly patients will likely increase. Frailty predicts postoperative mortality and morbidity more than age alone, thus presenting opportunities to identify the highest-risk surgical patients and improve their outcomes. To examine the effect of the Frailty Screening Initiative (FSI) on mortality and complications by comparing the surgical outcomes of a cohort of surgical patients treated before and after implementation of the FSI. This single-site, facility-wide, prospective cohort quality improvement project studied all 9153 patients from a level 1b Veterans Affairs medical center who presented for major, elective, noncardiac surgery from October 1, 2007, to July 1, 2014. Assessment of preoperative frailty in all patients scheduled for elective surgery began in July 2011. Frailty was assessed with the Risk Analysis Index (RAI), and the records of all frail patients (RAI score, ≥21) were flagged for administrative review by the chief of surgery (or designee) before the scheduled operation. On the basis of this review, clinicians from surgery, anesthesia, critical care, and palliative care were notified of the patient's frailty and associated surgical risks; if indicated, perioperative plans were modified based on team input. Postoperative mortality at 30, 180, and 365 days. From October 1, 2007, to July 1, 2014, a total of 9153 patients underwent surgery (mean [SD] age, 60.3 [13.5] years; female, 653 [7.1%]; and white, 7096 [79.8%]). Overall 30-day mortality decreased from 1.6% (84 of 5275 patients) to 0.7% (26 of 3878 patients, P < .001) after FSI implementation. Improvement was greatest among frail patients (12.2% [24 of 197 patients] to 3.8% [16 of 424 patients], P < .001), although mortality rates also decreased among the robust patients (1.2% [60 of 5078 patients] to 0.3% [10 of 3454 patients], P < .001). The magnitude of improvement among frail patients increased at 180 (23.9% [47 of 197 patients] to 7.7% [30 of 389 patients], P < .001) and 365 days (34.5% [68 of 197 patients] to 11.7% [36 of 309 patients], P < .001). Multivariable models revealed improved survival after FSI implementation, controlling for age, frailty, and predicted mortality (adjusted odds ratio for 180-day survival, 2.87; 95% CI, 1.98-4.16). Implementation of the FSI was associated with reduced mortality, suggesting the feasibility of widespread screening of patients preoperatively to identify frailty and the efficacy of system-level initiatives aimed at improving their surgical outcomes. Additional investigation is required to establish a causal connection.


Components of a Fanconi-like pathway control Pso2-independent DNA interstrand crosslink repair in yeast.
Fanconi anemia (FA) is a devastating genetic disease, associated with genomic instability and defects in DNA interstrand cross-link (ICL) repair. The FA repair pathway is not thought to be conserved in budding yeast, and although the yeast Mph1 helicase is a putative homolog of human FANCM, yeast cells disrupted for MPH1 are not sensitive to ICLs. Here, we reveal a key role for Mph1 in ICL repair when the Pso2 exonuclease is inactivated. We find that the yeast FANCM ortholog Mph1 physically and functionally interacts with Mgm101, a protein previously implicated in mitochondrial DNA repair, and the MutSα mismatch repair factor (Msh2-Msh6). Co-disruption of MPH1, MGM101, MSH6, or MSH2 with PSO2 produces a lesion-specific increase in ICL sensitivity, the elevation of ICL-induced chromosomal rearrangements, and persistence of ICL-associated DNA double-strand breaks. We find that Mph1-Mgm101-MutSα directs the ICL-induced recruitment of Exo1 to chromatin, and we propose that Exo1 is an alternative 5'-3' exonuclease utilised for ICL repair in the absence of Pso2. Moreover, ICL-induced Rad51 chromatin loading is delayed when both Pso2 and components of the Mph1-Mgm101-MutSα and Exo1 pathway are inactivated, demonstrating that the homologous recombination stages of ICL repair are inhibited. Finally, the FANCJ- and FANCP-related factors Chl1 and Slx4, respectively, are also components of the genetic pathway controlled by Mph1-Mgm101-MutSα. Together this suggests that a prototypical FA-related ICL repair pathway operates in budding yeast, which acts redundantly with the pathway controlled by Pso2, and is required for the targeting of Exo1 to chromatin to execute ICL repair.


Non-radioactive assay methods for the assessment of telomerase activity and telomere length.
The Telomeric repeat amplification protocol (TRAP) is a highly sensitive PCR-based assay and prove to be an important tool for understanding the role of telomerase in cancer and various tissues that harbors telomerase positive stem cells. This assay measures telomerase activity where the amount of target is dependent upon the activity of the enzyme. This protocol consists of two steps: first, telomeric repeats are added to the substrate by telomerase present in the cell and second, the extended products are amplified by Taq-DNA polymerase. The amplified TRAP products are separated on 10 % native PAGE and detected by SYBR Green I dye.


A lab-on-a-chip utilizing microwaves for bacterial spore disruption and detection.
Bacterial spores are problematic in agriculture, the food industry, and healthcare, with the fallout costs from spore-related contamination being very high. Spores are difficult to detect since they are resistant to many of the bacterial disruption techniques used to bring out the biomarkers necessary for detection. Because of this, effective and practical spore disruption methods are desirable. In this study, we demonstrate the efficiency of a compact microfluidic lab-on-chip built around a coplanar waveguide (CPW) operating at 2.45 GHz. We show that the CPW generates an electric field hotspot of ∼10 kV/m, comparable to that of a commercial microwave oven, while using only 1.2 W of input power and thus resulting in negligible sample heating. Spores passing through the microfluidic channel are disrupted by the electric field and release calcium dipicolinic acid (CaDPA), a biomarker molecule present alongside DNA in the spore core. We show that it is possible to detect this disruption in a bulk spore suspension using fluorescence spectroscopy. We then use laser tweezers Raman spectroscopy (LTRS) to show the loss of CaDPA on an individual spore level and that the loss increases with irradiation power. Only 22% of the spores contain CaDPA after exposure to 1.2 W input power, compared to 71% of the untreated control spores. Additionally, spores exposed to microwaves appear visibly disrupted when imaged using scanning electron microscopy (SEM). Overall, this study shows the advantages of using a CPW for disrupting spores for biomarker release and detection.


Four novel suppressors of gic1 gic2 and their roles in cytokinesis and polarized cell growth in Saccharomyces cerevisiae.
Gic1 and Gic2 are two Cdc42/Rac interactive binding (CRIB) domain-containing effectors of Cdc42-GTPase that promote polarized cell growth in S. cerevisiae. To identify novel genes that functionally interact with Gic1 and Gic2, we screened for high-copy suppressors of a gic1 gic2 temperature-sensitive strain. We identified two pairs of structurally related genes, SKG6-TOS2 and VHS2-MLF3. These genes have been implicated in polarized cell growth, but their functions have not previously been characterized. We found that overproduction of Skg6 and Tos2 in wild-type cells causes aberrant localization of Cdc3 septin and actin structures as well as defective recruitment of Hof1 and impaired formation of the septum at the mother-bud neck. These data suggest a negative regulatory function for Skg6 and Tos2 in cytokinesis. Consistent with this model, deletion of SKG6 suppresses the growth defects associated with loss of HOF1, a positive regulator of cytokinesis. Our analysis of the second pair of gic1 gic2 suppressors, VHS2 and MLF3, suggests that they regulate polarization of the actin cytoskeleton and cell growth and function in a pathway distinct from and parallel to GIC1 and GIC2.


Precision medicine and its implementation in patients with NTRK fusion genes: perspective from developing countries.
Precision oncology is the field that places emphasis on the diagnosis and treatment of tumors that harbor specific genomic alterations susceptible to inhibition or modulation. Although most alterations are only present in a minority of patients, a substantial effect on survival can be observed in this subgroup. Mass genome sequencing has led to the identification of a specific driver in the translocations of the tropomyosin receptor kinase family (NTRK) in a subset of rare tumors both in children and in adults, and to the development and investigation of Larotrectinib. This medication was granted approval by the US Food and Drug Administration for NTRK-positive tumors, regardless of histology or age group, as such, larotrectinib was the first in its kind to be approved under the premise that molecular pattern is more important than histology in terms of therapeutic approach. It yielded significant results in disease control with good tolerability across a wide range of diseases including rare pediatric tumors, salivary gland tumors, gliomas, soft-tissue sarcomas, and thyroid carcinomas. In addition, and by taking different approaches in clinical trial design and conducting allocation based on biomarkers, the effects of target therapies can be isolated and quantified. Moreover, and considering developing nations and resource-limited settings, precision oncology could offer a tool to reduce cancer-related disability and hospital costs. In addition, developing nations also present patients with rare tumors that lack a chance of treatment, outside of clinical trials. This, in turn, offers the possibility for international collaboration, and contributes to employment, education, and health service provisions. The reviews of this paper are available via the supplemental material section.


Regulation and function of H3K36 di-methylation by the trithorax-group protein complex AMC.
The Drosophila Ash1 protein is a trithorax-group (trxG) regulator that antagonizes Polycomb repression at HOX genes. Ash1 di-methylates lysine 36 in histone H3 (H3K36me2) but how this activity is controlled and at which genes it functions is not well understood. We show that Ash1 protein purified from Drosophila exists in a complex with MRG15 and Caf1 that we named AMC. In Drosophila and human AMC, MRG15 binds a conserved FxLP motif near the Ash1 SET domain and stimulates H3K36 di-methylation on nucleosomes. Drosophila MRG15-null and ash1 catalytic mutants show remarkably specific trxG phenotypes: stochastic loss of HOX gene expression and homeotic transformations in adults. In mutants lacking AMC, H3K36me2 bulk levels appear undiminished but H3K36me2 is reduced in the chromatin of HOX and other AMC-regulated genes. AMC therefore appears to act on top of the H3K36me2/me3 landscape generated by the major H3K36 methyltransferases NSD and Set2. Our analyses suggest that H3K36 di-methylation at HOX genes is the crucial physiological function of AMC and the mechanism by which the complex antagonizes Polycomb repression at these genes.


Development of Diversity Arrays Technology markers as a tool for rapid genomic assessment in Nile tilapia, Oreochromis niloticus.
The development of genomic markers is described for Nile tilapia, Oreochromis niloticus, using the Diversity Arrays Technology (DArT) genotype-by-sequencing platform. A total of 13 215 single nucleotide polymorphism (SNP) markers and 12 490 silicoDArT (dominant) markers were identified from broodstock of two selective breeding programs [Genetically Improved Farmed Tilapia (GIFT) strain from Malaysia and the Abbassa strain from Egypt]. Over 10 000 SNPs were polymorphic in either strain, and 2985 and 3087 showed strain-specific polymorphisms for the GIFT and Abbassa strains respectively. We demonstrate the potential utility of these markers for rapid genomic screening and use in breeding programs.


A facile synthesis and photoluminescence properties of water-dispersible Re3+ doped CeF3 nanocrystals and solid nanocomposites with polymers.
Water-dispersible Re(3+) doped CeF(3) colloidal nanocrystals with well controllable morphology and high crystallinity have been successfully synthesized through a solvothermal process. The TEM images illustrate that the Re(3+) doped CeF(3) nanocrystals are rectangular (or cubic) with a mean diameter of ~10 nm. The excellent dispersibility in some of the polar solvents including water is achieved by using polyethyleneimine as the capping agent. The amine groups of the polymer chains on one hand bind to the nanocrystal surface; on the other hand the free ones could link to functional materials including bio-molecules. The CeF(3) nanocrystals doped with Tb(3+) and Dy(3+) ions show the characteristic emission of Tb(3+ 5)D(4)-(7)F(J) (J = 6-3, with (5)D(4)-(7)F(5) green emission at 542 nm as the strongest one) and Dy(3+ 4)F(9/2)-(6)H(15/2) (blue-green color at 478 nm) and (4)F(9/2)-(6)H(13/2) (yellow color at 571 nm) transitions, respectively. The energy transfer from Ce(3+) to Tb(3+) and Dy(3+) was also investigated in detail. In vitro studies of Re(3+) doped CeF(3) colloidal nanocrystals on HepG2 cells confirm their excellent biological compatibility. The obtained solid CeF(3) : Tb(3+)/PDMS nanocomposites are very stable and flexible and exhibit strong green photoluminescence upon UV excitation.


Treatment of superficial venous incompetence with the SAVAS technique--(Section Ambulatoire des Varices avec Sclérothérapie). A 4 year randomised, controlled trial comparing venous hemodynamic and costing after SAVAS, sclerotherapy and the dentist's technique.
Three techniques for treatment of chronic venous incompetence on an out patients basis were compared in a randomised study. One hundred thirty eight limbs (107 patients) with superficial venous incompetence were randomly treated with the dentist's technique (DT) [Group A, 44 limbs], compression sclerotherapy (CS) [Group B, 45 limbs] or the SAVAS (section en Ambulatoire des Varices avec Sclérothérapie) technique [Group C, 49 limbs]. Patients were evaluated and followed up (every year for 4 years) with ambulatory venous pressure (AVP) measurements and Quantum angiodynography (colour duplex scanning). DT consisted in the section under local anesthesia of incompetent veins. CS was done injecting polidocanol 3% with compression applied for 4 weeks. The SAVAS was done with a combination of DT and CS with section of the incompetent veins under local anesthesia and retrograde injection in the distal vein of polidocanol 3%. With this type of injection only incompetent veins were perfused. After 4 years there was a significantly lower refilling time (RT) with AVP in the SAVAS group (21 sec). RT was 13 sec in group B and 16 in A. The number of significantly incompetent residual veins was in average 0.5 in the SAVAS group, significantly lower than in the other two groups. Also the average cost per treated limb was significantly lower in the SAVAS group (917 francs in comparison with 1100 in group A and 1211 in group B). In conclusion considering the four year follow up, the SAVAS technique is a more effective treatment of superficial venous incompetence, its hemodynamic value is superior to sclerotherapy alone and its costs are lower.


Analysis of agreement between measurements of continuous variables: general principles and lessons from studies of imaging of carotid stenosis.
Clinical research often involves measurement of continuous variables. However, clinical measurements are seldom precise. It is frequently necessary, therefore, either for the reproducibility of measurements to be assessed (observer agreement studies), or for measurements made by different techniques to be compared (method comparison studies). There are numerous ways in which data can be analysed and reported in such studies, and several pitfalls. In order to determine which methods are commonly used in the medical literature, a systematic review of studies involving measurement of carotid stenosis was performed. A random sample of 40 studies were selected for detailed assessment. The methods of analysis of reproducibility of measurement of stenosis and/or comparison of two alternative techniques of measurement were recorded. Ten different methods were identified. The advantages and disadvantages of each of the methods are discussed in a non-technical and non-mathematical manner, and illustrated using data from a study of measurement of carotid stenosis by two observers on 1001 carotid angiograms.


Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women.
Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low-density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and postmenopausal women. We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride-enriched (production ratio of VLDL2- triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (rs=-0.49, P=0.006), de novo lipogenesis (rs=0.55, P=0.003), and desaturation (rs=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL-triglyceride secretion rate. In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.


Associations between antidepressant adherence and shared decision-making, patient-provider trust, and communication among adults with diabetes: diabetes study of Northern California (DISTANCE).
Depression and adherence to antidepressant treatment are important clinical concerns in diabetes care. While patient-provider communication patterns have been associated with adherence for cardiometabolic medications, it is unknown whether interpersonal aspects of care impact antidepressant medication adherence. To determine whether shared decision-making, patient-provider trust, or communication are associated with early stage and ongoing antidepressant adherence. Observational new prescription cohort study. Kaiser Permanente Northern California. One thousand five hundred twenty-three adults with type 2 diabetes who completed a survey in 2006 and received a new antidepressant prescription during 2006-2010. Exposures included items based on the Trust in Physicians and Interpersonal Processes of Care instruments and the Consumer Assessment of Healthcare Providers and Systems (CAHPS) communication scale. Measures of adherence were estimated using validated methods with physician prescribing and pharmacy dispensing data: primary non-adherence (medication never dispensed), early non-persistence (dispensed once, never refilled), and new prescription medication gap (NPMG; proportion of time without medication during 12 months after initial prescription). After adjusting for potential confounders, patients' perceived lack of shared decision-making was significantly associated with primary non-adherence (RR = 2.42, p < 0.05), early non-persistence (RR = 1.34, p < 0.01) and NPMG (estimated 5% greater gap in medication supply, p < 0.01). Less trust in provider was significantly associated with early non-persistence (RRs 1.22-1.25, ps < 0.05) and NPMG (estimated NPMG differences 5-8%, ps < 0.01). All patients were insured and had consistent access to and quality of care. Patients' perceptions of their relationships with providers, including lack of shared decision-making or trust, demonstrated strong associations with antidepressant non-adherence. Further research should explore whether interventions for healthcare providers and systems that foster shared decision-making and trust might also improve medication adherence.


Gastrointestinal symptoms before and during menses in healthy women.
Little is known as to the extent gastrointestinal (GI) complaints are reported by women around menses. We aimed to describe GI symptoms that occurred premenstrually and during menses in healthy women, and to specifically assess the relationship of emotional symptoms to GI symptoms around menses. We recruited healthy, premenopausal adult women with no indication of GI, gynecologic, or psychiatric disease who were attending an outpatient gynecology clinic for well-woman care. They completed a survey that queried menstrual histories and the presence of GI and emotional symptoms. We compared the prevalence of primary GI symptoms (abdominal pain, diarrhea, constipation, nausea, vomiting), as well as pelvic pain and bloating, in the 5 days preceding menses and during menses, and assessed whether emotional symptoms or other factors were associated with the occurrence of GI symptoms. Of 156 respondents, 73% experienced at least one of the primary GI symptoms either pre- or during menses, with abdominal pain (58% pre; 55% during) and diarrhea (24% pre; 28% during) being the most common. Those experiencing any emotional symptoms versus those without were more likely to report multiple (2 or more) primary GI symptoms, both premenstrually (depressed p = 0.006; anxiety p = 0.014) and during menses (depressed p < 0.001; anxiety p = 0.008). Fatigue was also very common (53% pre; 49% during), and was significantly associated with multiple GI symptoms in both menstrual cycle phases (pre p < 0.001; during p = 0.01). Emotional symptoms occurring in conjunction with GI symptoms are common perimenstrually, and as such may reflect shared underlying processes that intersect brain, gut, and hormonal pathways.


'It's just a social thing': drug use, friendship and borderwork among marginalized young people.
This article joins a growing chorus of researchers who doubt the utility of the concept of peer pressure for explaining young people's initiation to and use of drugs. Drawing on interview data with 45 patrons of a youth drop-in centre in Ottawa, Canada, we argue that drug use is more intricately woven into friendship - affective relationships of trust and intimacy, belonging and sharing - rather than simply part of the unidirectional pressures some young people put on others to fit in to a subculture. Marginalized young people's narratives show that drugs and alcohol furnish them with a relatively inexpensive pastime to share with friends, introducing opportunities for intimacy that are otherwise difficult to attain at the individualistic and isolating margins of neoliberal cities. We demonstrate how young drug users draw boundaries between acceptable and unacceptable relationships to drugs and alcohol, articulating an important sense of belonging to a superior group of drug users. Through this 'borderwork', they solidify the bonds they share with the people with whom they smoke cannabis and drink alcohol.


Modeling secondary accidents identified by traffic shock waves.
The high potential for occurrence and the negative consequences of secondary accidents make them an issue of great concern affecting freeway safety. Using accident records from a three-year period together with California interstate freeway loop data, a dynamic method for more accurate classification based on the traffic shock wave detecting method was used to identify secondary accidents. Spatio-temporal gaps between the primary and secondary accident were proven be fit via a mixture of Weibull and normal distribution. A logistic regression model was developed to investigate major factors contributing to secondary accident occurrence. Traffic shock wave speed and volume at the occurrence of a primary accident were explicitly considered in the model, as a secondary accident is defined as an accident that occurs within the spatio-temporal impact scope of the primary accident. Results show that the shock waves originating in the wake of a primary accident have a more significant impact on the likelihood of a secondary accident occurrence than the effects of traffic volume. Primary accidents with long durations can significantly increase the possibility of secondary accidents. Unsafe speed and weather are other factors contributing to secondary crash occurrence. It is strongly suggested that when police or rescue personnel arrive at the scene of an accident, they should not suddenly block, decrease, or unblock the traffic flow, but instead endeavor to control traffic in a smooth and controlled manner. Also it is important to reduce accident processing time to reduce the risk of secondary accident.


The bio-energetic theory of carcinogenesis.
The altered energy metabolism of tumor cells provides a viable target for a non toxic chemotherapeutic approach. An increased glucose consumption rate has been observed in malignant cells. Warburg (Nobel Laureate in medicine) postulated that the respiratory process of malignant cells was impaired and that the transformation of a normal cell to malignant was due to defects in the aerobic respiratory pathways. Szent-Györgyi (Nobel Laureate in medicine) also viewed cancer as originating from insufficient availability of oxygen. Oxygen by itself has an inhibitory action on malignant cell proliferation by interfering with anaerobic respiration (fermentation and lactic acid production). Interestingly, during cell differentiation (where cell energy level is high) there is an increased cellular production of oxidants that appear to provide one type of physiological stimulation for changes in gene expression that may lead to a terminal differentiated state. The failure to maintain high ATP production (high cell energy levels) may be a consequence of inactivation of key enzymes, especially those related to the Krebs cycle and the electron transport system. A distorted mitochondrial function (transmembrane potential) may result. This aspect could be suggestive of an important mitochondrial involvement in the carcinogenic process in addition to presenting it as a possible therapeutic target for cancer. Intermediate metabolic correction of the mitochondria is postulated as a possible non-toxic therapeutic approach for cancer.


The effect of intracortical bone pin application on kinetics and tibiocalcaneal kinematics of walking gait.
Bone anchored markers using intracortical bone pins are one of the few available methods for analyzing skeletal motion during human gait in-vivo without errors induced by soft tissue artifacts. However, bone anchored markers require local anesthesia and may alter the motor control and motor output during gait. The purpose of this study was to examine the effect of local anesthesia and the use of bone anchored markers on typical gait analysis variables. Five subjects were analyzed in two different gait analysis sessions. In the first session, a protocol with skin markers was used. In the second session, bone anchored markers were added after local anesthesia was applied. For both sessions, three dimensional infrared kinematics of the calcaneus and tibia segments, ground reaction forces, and plantar pressure data were collected. 95% confidence intervals and boxplots were used to compare protocols and assess the data distribution and data variability for each subject. Although considerable variation was found between subjects, within-subject comparison of the two protocols revealed non-systematic effects on the target variables. Two of the five subjects walked at reduced gait speed during the bone pin session, which explained the between-session differences found in kinetic and kinematic variables. The remaining three subjects did not systematically alter their gait pattern between the two sessions. Results support the hypothesis that local anesthesia and the presence of bone pins still allow a valid gait pattern to be analyzed.


A theoretical and shock tube kinetic study on hydrogen abstraction from phenyl formate.
The hydrogen abstraction reactions of phenyl formate (PF) by different radicals (H/O(3P)/OH/HO2) were theoretically investigated. We calculated the reaction energetics for PF + H/O/OH using the composite method ROCBS-QB3//M06-2X/cc-pVTZ and that for PF + HO2 at the M06-2X/cc-pVTZ level of theory. The high-pressure limit rate constants were calculated using the transition state theory in conjunction with the 1-D hindered rotor approximation and tunneling correction. Three-parameter Arrhenius expressions of rate constants were provided over the temperature range of 500-2000 K. To validate the theoretical calculations, the overall rate constants of PF + OH → Products were measured in shock tube experiments at 968-1128 K and 1.16-1.25 atm using OH laser absorption. The predicted overall rate constants agree well with the shock tube data (within 15%) over the entire experimental conditions. Rate constant analysis indicates that the H-abstraction at the formic acid site dominates the PF consumption, whereas the contribution of H-abstractions at the aromatic ring increases with temperature. Additionally, comparisons of site-specific H-abstractions from PF with methyl formate, ethyl formate, benzene, and toluene were performed to understand the effects of the aromatic ring and side-chain substituent on H-abstraction rate constants.


Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: double-blind, placebo controlled intervention trial.
Many of the flavonoids found in grapes and grape products such as juice or wine have been known to exert antioxidant, anti-inflammatory, platelet inhibitory and arterial relaxing effects either in vitro, in animal studies and in human trials. This study was designed to test the effect of Concord grape juice consumption on altering blood pressure in hypertensive patients. Forty subjects were given 5.5 ml/kg body weight/day of either Concord grape juice (CGJ) or a calorie-matched placebo drink every day for 8 weeks. Blood pressure (BP) was measured on weeks 0, 4 and 8. Compared to baseline, in the CGJ group systolic BP was reduced on average by 7.2 mm Hg (p = 0.005) and diastolic BP was reduced on average by 6.2 mm Hg (p = 0.001) at the end of 8 weeks. Comparable changes in the group getting the placebo product were -3.5 mm Hg (NS) and -3.2 mm Hg (p = 0.05) Consuming Concord grape juice, which is high in polyphenolic compounds, may favorably affect BP in hypertensive individuals.


Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction.
Berberine has a wide range of biochemical and pharmacologic effects, including antitumor activity, but the mechanisms involved in berberine-induced apoptosis remain unclear. The purpose of the present study was to investigate the changes in oxidative stress and endoplasmic reticulum (ER)-related molecules, which are closely associated with cell death-signaling transduction pathways, in human glioblastoma T98G cells treated with berberine. Berberine significantly decreased the cell viability of T98G cells in a dose-dependent manner. Berberine increased the production of reactive oxygen species (ROS) and level of intracellular Ca(2+). Berberine induced ER stress as evidenced by the detection of ER stress-associated molecules such as phosphorylated protein kinase-like ER kinase, eukaryotic translation initiation factor-2α, glucose-regulated protein 78/immunoglobulin heavy chain-binding protein, and CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible gene 153, which was associated with the activation of caspase-3. Furthermore, the administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis. Berberine also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of Bax/Bcl-2 proteins, disruption of the mitochondrial membrane potential, activation of caspase-9 and -3, and cleavage of the poly(ADP-ribose) polymerase (PARP). The inhibition of ER stress using salubrinal led to an increased the level of Bcl-2, whereas the level of Bax, cleavage of procaspase-9 and -3, and PARP were decreased when compared with cells treated with berberine alone, indicating that berberine-induced apoptosis is associated with mitochondrial dysfunction. These results demonstrate that berberine induces apoptosis via ER stress through the elevation of ROS and mitochondrial-dependent pathway in human glioblastoma T98G cells.