Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.
The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron. We used freshly isolated aldosterone-sensitive distal nephron from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC, but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than 2 times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the aldosterone-sensitive distal nephron. In contrast, in the setting of Ang II-dependent hypertension, ENaC activity is upregulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels.


Unprotected anal intercourse behavior and intention among male sex workers in Shenzhen serving cross-boundary male clients coming from Hong Kong, China - prevalence and associated factors.
The HIV epidemic among men who have sex with men (MSM) in China is becoming very serious. Unprotected anal intercourse (UAI) among MSM during cross-boundary commercial sex spread HIV across geographic areas. This study interviewed 186 Chinese male sex workers (MSW) in Shenzhen, China, serving cross-boundary Hong Kong male clients; 49.5% had had UAI with their Hong Kong male clients (last six months) and 24.2% intended to do so (future six months). Multivariate analyses showed that perceived efficacy of condom use for HIV prevention, perceived prevalence of HIV among Hong Kong MSM (>4%), and perceived ability to convince Hong Kong male clients to use condoms during anal sex were associated with lower likelihoods of UAI with such clients (OR = 0.04-0.09); the reverse was true for those who left the decision of condom use to their Hong Kong male clients (OR = 6.44). Perceived condom efficacy, self-efficacy in protection against HIV infection, and perceived control over condom use were associated with an intention for UAI (OR = 0.06-80.44). Adjusting for background variables, the scales representing contextual (Clients Characteristics, Substance Use, or Environmental Influences) and affective factors (Fear of Diseases) were associated with UAI (adjusted OR = 0.44-32.61). Except the Fear of Diseases scale, other scales were associated with an intention for UAI (adjusted OR = 4.59-43.32). MSW are at high risk of HIV transmission. Various factors are associated with UAI with male cross-boundary clients; these factors and the context of sex work need to be considered when designing HIV prevention programs.


Evolution of the primate beta-globin gene region: nucleotide sequence of the delta-beta-globin intergenic region of gorilla and phylogenetic relationships between African apes and man.
A 6.0-kb DNA fragment from Gorilla gorilla including the 5' part of the beta-globin gene and about 4.5 kb of its upstream flanking region was cloned and sequenced. The sequence was compared to the human, chimpanzee, and macaque delta-beta intergenic region. This analysis reveals four tandemly repeated sequences (RS), at the same location in the four species, showing a variable number of repeats generating both intraspecific (polymorphism) and interspecific variability. These tandem arrays delimit five regions of unique sequence called IG for intergenic. The divergence for these IG sequences is 1.85 +/- 0.22% between human and gorilla, which is not significantly different from the value estimated in the same region between chimpanzee and human (1.62 +/- 0.21%). The CpG and TpA dinucleotides are avoided. CpGs evolve faster than other sequence sites but do not confuse phylogenetic inferences by producing parallel mutations in different lineages. About 75% of CpG doublets have become TpG or CpA since the common ancestor, in agreement with the methylation/deamination pattern. Comparison of this intergenic region gives information on branching order within Hominoidea. Parsimony and distance-based methods when applied to the delta-beta intergenic region provide evidence (although not statistically significant) that human and chimpanzee are more closely related to each other than to gorilla. CpG sites are indeed rich in information by carrying substitutions along the short internal branch. Combining these results with those on the psi eta-delta intergenic region, shows in a statistically significant way that chimpanzee is the closest relative of human.


Empowering self-help groups for caregivers of children with disabilities in Kilifi, Kenya: Impacts and their underlying mechanisms.
Bringing up a child with disabilities in a low-income setting is challenged by inadequate resources, limited psycho-social support and poverty. Not surprisingly, many caregivers experience fatigue, distress and isolation. To address and investigate these issues, action was taken to set up twenty self-help groups focusing on caregiver empowerment. A realist evaluation design was adopted to evaluate impacts associated with the self-help process and to identify mechanisms determining the outcomes. Monthly monitoring visits were conducted to the groups during a ten-month set-up period, at the end of which eleven active groups remained, nine having dissolved due to disputes, corruption and extreme environmental conditions. A facilitated intervention was delivered to the active groups (N = 154) over a six-month period. The members were guided to review and discuss topics such as economic empowerment, personal situation, peer support, community inclusion, access to health and education. Evaluation employed mixed methods using questionnaires (n = 75) and semi-structured interviews (n = 36) pre- and post-intervention. At baseline, the burden of caregiving was characterised by aloneness, challenges, stigma and discrimination. Post-intervention, caregiver agency was defined by togetherness, capacity-building, acceptance and well-being. Significant impacts associated with caregiver perceptions included increased social support, reduced severity of child's disability and decreased effects of extrinsic factors affecting the caregiver's role. Mechanisms of 'handling goods and money' and 'social ties and support' appeared to underpin the outcomes. Caregiver empowerment was associated with newly developed skills, social connectedness and resource mobilisation. Documentation of group processes contributes to the evidence on community-based inclusive development.


Assessment and Characterisation of Ireland's Green Tides (Ulva Species).
Enrichment of nutrients and metals in seawater associated with anthropogenic activities can threaten aquatic ecosystems. Consequently, nutrient and metal concentrations are parameters used to define water quality. The European Union's Water Framework Directive (WFD) goes further than a contaminant-based approach and utilises indices to assess the Ecological Status (ES) of transitional water bodies (e.g. estuaries and lagoons). One assessment is based upon the abundance of opportunistic Ulva species, as an indication of eutrophication. The objective of this study was to characterise Ireland's Ulva blooms through the use of WFD assessment, metal concentrations and taxonomic identity. Furthermore, the study assessed whether the ecological assessment is related to the metal composition in the Ulva. WFD algal bloom assessment revealed that the largest surveyed blooms had an estimated biomass of 2164 metric tonnes (w/w). DNA sequences identified biomass from all locations as Ulva rigida, with the exception of New Quay, which was Ulva rotundata. Some blooms contained significant amounts of As, Cu, Cr, Pb and Sn. The results showed that all metal concentrations had a negative relationship (except Se) with the Ecological Quality Ratio (EQR). However, only in the case of Mn were these differences significant (p = 0.038). Overall, the metal composition and concentrations found in Ulva were site dependent, and not clearly related to the ES. Nevertheless, sites with a moderate or poor ES had a higher variability in the metals levels than in estuaries with a high ES.


Biodegradable shape memory polymer foams with appropriate thermal properties for hemostatic applications.
Shape memory polymer (SMP) foams are a promising material for hemostatic dressings due to their biocompatibility, high surface area, excellent shape recovery, and ability to quickly initiate blood clotting. Biodegradable SMP foams could eliminate the need for a secondary removal procedure of hemostatic material from the patients' wound, further facilitating wound healing. In this study, we developed hydrolytically and oxidatively biodegradable SMP foams by reacting polyols (triethanolamine or glycerol) with 6-aminocaproic acid or glycine to generate foaming monomers with degradable ester bonds. These monomers were used in foam synthesis to provide highly crosslinked SMP foam structures. The ester-containing foams showed clinically relevant thermal properties that were comparable to controls and excellent shape recovery within eight min. Triethanolamine-based ester-containing foams showed interconnected porous structure along with increased mechanical strength. Faster hydrolytic and oxidative biodegradation rates were achieved in ester-containing foams in comparison to controls. These biodegradable SMP foams with clinically applicable thermal properties possess great potential as an effective hemostatic device for use in hospitals or on battlefields.


Tailoring the separation selectivity of metal complexes and organometallic compounds resolved by capillary electrophoresis using auxiliary separation processes.
The use of auxiliary separation mechanisms to manipulate the separation selectivity of metal complexes and organometallic species is reviewed. Auxiliary separation mechanisms included in the review are micellar electrokinetic capillary chromatography, ion-pairing and ion-exchange electrokinetic chromatography. This paper discusses how these secondary mechanisms can be effectively employed to tailor separation selectivity.


Total synthesis of spiromastilactone A.
The total synthesis of spiromastilactone A is reported for the first time. A swift strategy is presented that involves a pivotal enantioselective nucleophilic 1,2-alkylation of an aldehyde prepared in four quantitative synthetic steps from commercial 2,4-dihydroxybenzoic acid. This key reaction, which was described very recently by our group and carried out here on a gram scale, involves cheap and easily accessible tricoordinated chiral lithium amido zincates. The resulting enantioenriched secondary alcohol is involved afterward in an efficient intramolecular cyclization providing the phthalide core of the target, and two quantitative additional steps aiming to deprotect the phenol groups then introduce chlorine atoms end the synthetic scheme. Spiromastilactone A is obtained in 44% overall yield in eight synthetic steps, among which six are quantitative, and the 89 : 11 enantiomeric ratio (78% ee value) is in favor of the right enantiomer (R configuration).


British Dietetic Association evidence-based guidelines for the dietary management of Crohn's disease in adults.
Crohn's disease is a debilitating chronic inflammatory bowel disease. Appropriate use of diet and nutritional therapy is integral to the overall management strategy of Crohn's disease. The aim was to develop evidence-based guidelines on the dietary management of Crohn's disease in adults. Questions relating to the dietary management of Crohn's disease were developed. These included the roles of enteral nutrition to induce remission, food re-introduction diets to structure food re-introduction and maintain remission, and dietary management of stricturing disease, as well as whether probiotics or prebiotics induce or maintain remission. A comprehensive literature search was conducted and relevant studies from January 1985 to November 2009 were identified using the electronic database search engines CINAHL, Cochrane Library, EMBASE, MEDLINE, Scopus and Web of Science. Evidence statements, recommendations, practical considerations and research recommendations were developed. Fifteen research papers were critically appraised and the evidence formed the basis of these guidelines. Although corticosteroids appear to be more effective, enteral nutrition (elemental or non-elemental) can be offered as an alternative option to induce disease remission. After a course of enteral nutrition, food re-introduction diets may be useful to structure food re-introduction and help maintain disease remission. Dietary fibre is contraindicated in the presence of strictures as a result of the risk of mechanical obstruction. The use of probiotics and prebiotics is not currently supported. As an alternative to corticosteroids, evidence supports enteral nutrition to induce disease remission. Food re-introduction diets provide structure to food re-introduction and help maintain disease remission. These guidelines aim to reduce variation in clinical practice.


Acute toxicity of boron, molybdenum, and selenium to fry of chinook salmon and coho salmon.
The acute toxicities of boron, molybdenum, and various forms of selenium, individually and in environmentally relevant mixtures, to swim-up and advanced fry of chinook salmon (Oncorhynchus tshawytscha) and coho salmon (O. kisutch) were determined in site-specific fresh and brackish waters. Boron and molybdenum were relatively non-toxic (96-hr LC50s greater than 100 mg/L) to both life stages of both species. Selenite was significantly more toxic than selenate to both species. Swim-up fry tested in fresh water were significantly more sensitive than advanced fry in brackish water to selenate and selenite. No mortalities occurred in any concentrations tested of seleno-DL-methionine; however, in the highest concentration (21.6 mg Se/L), at least 50% of the fish showed pronounced surfacing behavior. Coho salmon were more sensitive than chinook salmon to both selenate and selenite at either life stage; only the swim-up fry of coho salmon were more sensitive than chinook salmon to boron. In additional tests with swim-up chinook salmon, differences in the characteristics of the dilution water did not significantly modify the relative toxicities of boron, selenate, and selenite. In binary mixture studies, the joint acute toxic action of selenate and selenite, combined in various ratios, was additive to both species. Based on a comparison of the individual acute values for chinook salmon to the expected environmental concentrations, the margin of safety for boron was only 56 in fresh and 46 in brackish water. The margins of safety for selenate and selenite exceeded 275 in both fresh and brackish waters. However, the margin of safety for both selenate and selenite in the mixture test was 145 in fresh water and 220 in brackish water.


Fluorescence measurements on the E.coli DNA polymerase clamp loader: implications for conformational changes during ATP and clamp binding.
Sliding clamps are ring-shaped proteins that tether DNA polymerases to their templates during processive DNA replication. The action of ATP-dependent clamp loader complexes is required to open the circular clamps and to load them onto DNA. The crystal structure of the pentameric clamp loader complex from Escherichia coli (the gamma complex), determined in the absence of nucleotides, revealed a highly asymmetric and extended form of the clamp loader. Consideration of this structure suggested that a compact and more symmetrical inactive form may predominate in solution in the absence of crystal packing forces. This model has the N-terminal domains of the delta and delta' subunits of the clamp loader close to each other in the inactive state, with the clamp loader opening in a crab-claw-like fashion upon ATP-binding. We have used fluorescence resonance energy transfer (FRET) to investigate the structural changes in the E.coli clamp loader complex that result from ATP-binding and interactions between the clamp loader and the beta clamp. FRET measurements using fluorophores placed in the N-terminal domains of the delta and delta' subunits indicate that the distances between these subunits in solution are consistent with the previously crystallized extended form of the clamp loader. Furthermore, the addition of nucleotide and clamp to the labeled clamp loader does not appreciably alter these FRET distances. Our results suggest that the changes that occur in the relative positioning of the delta and delta' subunits when ATP binds to and activates the complex are subtle, and that crab-claw-like movements are not a significant component of the clamp loader mechanism.


Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells.
Electrically excitable cells, such as neurons, exhibit tremendous diversity in their firing patterns, a consequence of the complex collection of ion channels present in any specific cell. Although numerous methods are capable of measuring cellular electrical signals, understanding which types of ion channels give rise to these signals remains a significant challenge. Here, we describe exogenous probes which use a novel mechanism to report activity of voltage-gated channels. We have synthesized chemoselective derivatives of the tarantula toxin guangxitoxin-1E (GxTX), an inhibitory cystine knot peptide that binds selectively to Kv2-type voltage gated potassium channels. We find that voltage activation of Kv2.1 channels triggers GxTX dissociation, and thus GxTX binding dynamically marks Kv2 activation. We identify GxTX residues that can be replaced by thiol- or alkyne-bearing amino acids, without disrupting toxin folding or activity, and chemoselectively ligate fluorophores or affinity probes to these sites. We find that GxTX-fluorophore conjugates colocalize with Kv2.1 clusters in live cells and are released from channels activated by voltage stimuli. Kv2.1 activation can be detected with concentrations of probe that have a trivial impact on cellular currents. Chemoselective GxTX mutants conjugated to dendrimeric beads likewise bind live cells expressing Kv2.1, and the beads are released by channel activation. These optical sensors of conformational change are prototype probes that can indicate when ion channels contribute to electrical signaling.


Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment: routine care data from 13 registries in the EuroSpA collaboration.
To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries. Real-life data from 13 European registries participating in the European Spondyloarthritis Research Collaboration Network were pooled. Kaplan-Meier with log-rank test, Cox regression, χ² and logistic regression analyses were performed to assess 6-month and 12-month secukinumab retention, inactive disease/low-disease-activity states (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <2/<4, Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3/<2.1) and response rates (BASDAI50, Assessment of Spondyloarthritis International Society (ASAS) 20/40, ASDAS clinically important improvement (ASDAS-CII) and ASDAS major improvement (ASDAS-MI)). We included 1860 patients initiating secukinumab as part of routine care. Overall 6-month/12-month secukinumab retention rates were 82%/72%, with significant (p<0.001) differences between the registries (6-month: 70-93%, 12-month: 53-86%) and across number of previous b/tsDMARDs (b/tsDMARD-naïve: 90%/73%, 1 prior b/tsDMARD: 83%/73%, ≥2 prior b/tsDMARDs: 78%/66%). Overall 6-month/12-month BASDAI<4 were observed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% of the patients. All rates differed significantly across number of previous b/tsDMARDs, were numerically higher for b/tsDMARD-naïve patients and varied significantly across registries. Overall, time since diagnosis was not associated with secukinumab effectiveness. In this study of 1860 patients from 13 European countries, we present the first comprehensive real-life data on effectiveness of secukinumab in patients with axSpA. Overall, secukinumab retention rates after 6 and 12 months of treatment were high. Secukinumab effectiveness was consistently better for bionaïve patients, independent of time since diagnosis and differed across the European countries.


Magnetic resonance imaging study of cross-sectional area of the cervical extensor musculature in an asymptomatic cohort.
Magnetic Resonance Imaging (MRI) can be regarded as the gold standard for muscle imaging; however there is little knowledge about in vivo morphometric features of neck extensor muscles in healthy subjects and how muscle size alters across vertebral segments. It is not known how body size and activity levels may influence neck muscle cross-sectional area (CSA) or if the muscles differ from left and right. The purpose of this study was to establish relative CSA (rCSA) data for the cervical extensor musculature with a reliable MRI measure in asymptomatic females within a defined age range and to determine if side-side and vertebral level differences exist. MRI of the cervical spine was performed on 42 asymptomatic female subjects within the age range of 18-45. The rCSA values for the cervical extensor muscles were measured from axial T1-weighted images. We found significant side-side rCSA differences for the rectus capitis posterior minor, major (P < 0.001), multifidus (P = 0.002), and the semispinalis cervicis/capitis (P = 0.001, P < 0.001). There were significant vertebral level differences in rCSA of the semispinalis cervicis/capitis, multifidus, splenius capitis, and upper trapezius (P < 0.001). Activity levels were shown to impact on the size of semispinalis cervicis (P = 0.027), semispinalis capitis (P = 0.003), and the splenius capitis (P = 0.004). In conclusion, measuring differences in neck extensor muscle rCSA with MRI in an asymptomatic population provides the basis for future study investigating relationships between muscular atrophy and symptoms in patients suffering from persistent neck pain. Clin.


Innovative public-private partnership: a diagonal approach to combating women's cancers in Africa.
In low- and middle-income countries, breast and cervical cancer have a poor prognosis, partly owing to barriers to treatment. To redress this situation, health systems must be strengthened. Pink Ribbon Red Ribbon (PRRR) is an innovative partnership designed to leverage public and private investments in global health and to build on the successful United States President's Emergency Plan for AIDS Relief (PEPFAR) platform to combat cancers of the breast and cervix in sub-Saharan Africa and Latin America. By supporting a comprehensive set of country-owned and country-driven interventions, PRRR seeks to reduce deaths from cervical cancer among women screened and treated through the programme and to reduce deaths from breast cancer by promoting early detection. In its initial phase, PRRR is supporting the governments of Botswana, Zambia and other countries in expanding cervical cancer prevention, screening and treatment coverage - especially to high-risk women with human immunodeficiency virus infection - and in strengthening breast cancer education and control services. PRRR has introduced a diagonal strategy based on the life course and continuum of care approaches to cancer control. Its work has resulted in the delivery of the human papillomavirus vaccine to young girls in several settings and in the strengthening of prevention, screening and treatment delivery systems from the community to the tertiary level. This paper outlines the approach PRRR has taken as a country-aligned public-private partnership and the preliminary lessons learnt, including the need for flexible implementation, effective country coordination mechanism and regular communication with all stakeholders.


THE ANTIGENIC COMPLEX OF STREPTOCOCCUS HAEMOLYTICUS : I. DEMONSTRATION OF A TYPE-SPECIFIC SUBSTANCE IN EXTRACTS OF STREPTOCOCCUS HAEMOLYTICUS.
1. Hydrochloric acid extracts of Streptococcus haemolyticus contain type-specific, as well as non-type-specific, substances. The precipitates formed by these crude extracts with homologous antibacterial serum are flocculent, while those obtained with heterologous serum are usually disc-like. 2. The type-specific substance may be detected by the use of anti-bacterial sera absorbed with heterologous strains of hemolytic streptococci. Such absorbed sera are type-specific: they are precipitated only by extracts of strains of the homologous type. 3. Any heterologous strain of hemolytic streptococcus absorbs the antibodies for all other heterologous strains, but homologous strains absorb type-specific antibodies as well. Numerous repeated absorptions with heterologous hemolytic streptococci tend to lower the titer of the type-specific antibody. A possible explanation of this fact is suggested. 4. Three strains did not yield a type-specific substance; and it seems probable that they had lost this function because of long continued cultivation in artificial media. 5. Classification based on the precipitin test with absorbed serum agrees with that previously determined by agglutination and protection tests. The method is, therefore, applicable to the problem of classification of the hemolytic streptococci.


The prevalence and clinical characteristics of mitral valve prolapse in a large population-based epidemiologic study: the MELEN study.
Mitral valve prolapse (MVP) is the most common cardiac valvular abnormality in industrialized countries. Its prevalence has been estimated to be between 2% to 4%. However, some studies found the prevalence of MVP less than 1% which is significantly lower than the prevalence reported in the Framingham Heart Study. The purpose of this study was to determine the prevalence, demographic, clinical and echocardiographic characteristics of MVP in a large population-based epidemiologic study. The final cohort included 2,228 participants. Data were obtained by a validated questionnaire, physical examination of the cardiovascular system, recording of a resting electrocardiogram, transthoracic echocardiographic examination. The echocardiographic prevalence of MVP was 0.36%. Baseline demographic and clinical characteristics of patients were as follows; 12.5% had hypertension, 37.5% had depression, 12.5% had migraine, 12.5% had diabetes mellitus, 12.5% had diastolic dysfunction, 25% had multi-nodular goiter, 12.5% had diffuse goiter and 25% had hyperthyroidism. During the follow-up of 36 months no major adverse events occurred in patients with MVP during the follow-up. This finding suggests that MVP is a benign disorder and the prevalence of MVP is lower than previously studies. There might be a relationship between MVP and goiter, and depression.


Polarization independent varifocal lens using KTN crystals.
We fabricated a polarization-independent varifocal lens using KTa(1-x)Nb(x)O3 (KTN) crystals. The polarization dependence of the KTN crystal is effectively compensated for by combining a pair of KTN lenses and a half-wave plate. This compensation is achieved by a total electro-optic effect, which consists of the Kerr effect and the elasto-optic effects via the electrostrictive and elastic strains in the KTN crystal.


Deconstructive and Reconstructive Techniques in Treatment of Vertebrobasilar Dissecting Aneurysms: A Systematic Review and Meta-Analysis.
Various endovascular techniques have been applied to the treatment of vertebrobasilar dissecting aneurysms, including parent artery preservation with coiling, stent placement or flow diverter placement, and trapping and proximal occlusion. We performed a systematic review and meta-analysis to study clinical and angiographic outcomes of patients undergoing endovascular treatment of vertebrobasilar dissecting aneurysms. We performed a comprehensive literature search for studies on the endovascular treatment of vertebrobasilar dissecting aneurysms. From each study we abstracted the following data: immediate occlusion, long-term occlusion, long-term good neurologic outcome, perioperative morbidity, perioperative mortality, rebleed (ruptured only), recurrence, and retreatment. We performed subgroup analyses of patients undergoing deconstructive-versus-reconstructive techniques. Meta-analysis was performed by using a random effects model. Seventeen studies with 478 patients were included in this analysis. Sixteen studies had at least 6 months of clinical/angiographic follow-up. Endovascular treatment was associated with high rates of long-term occlusion (87.0%; 95% CI, 74.0%-94.0%) and low recurrence (7.0%; 95% CI, 5.0%-10.0%) and retreatment rates (3.0%; 95% CI, 2.0%-6.0%). Long-term good neurologic outcome was 84.0% (95% CI, 65.0%-94.0%). Deconstructive techniques were associated with higher rates of long-term complete occlusion compared with reconstructive techniques (88.0%; 95% CI, 35.0%-99.0% versus 81.0%; 95% CI, 64.0%-91.0%; P < .0001). Deconstructive and reconstructive techniques were both associated with high rates of good neurologic outcome (86.0%; 95% CI, 68.0%-95.0% versus 92.0%; 95% CI, 86.0%-95.0%; P = .10). Endovascular treatment of vertebrobasilar dissecting aneurysms is associated with high rates of complete occlusion and good long-term neurologic outcomes. Deconstructive techniques are associated with higher occlusion rates. There was no statistical difference in neurologic outcomes between groups, possibly due to low power.


Comparing two epidemiologic surveillance methods to assess underestimation of human stampedes in India.
Two separate but complementary epidemiologic surveillance methods for human stampedes have emerged since the publication of the topic in 2009. The objective of this study is to estimate the degree of underreporting in India. The Ngai Search Method was compared to the Roy Search Method for human stampede events occurring in India between 2001 and 2010. A total of 40 stampedes were identified by both search methods. Using the Ngai method, 34 human stampedes were identified. Using a previously defined stampede scale: 2 events were class I, 21 events were class II, 8 events were class III, and 3 events were class IV. The median deaths were 5.5 per event and median injuries were 13.5 per event. Using the Roy method, 27 events were identified, including 9 events that were not identified by the Ngai method. After excluding events based on exclusion criteria, six additional events identified by the Roy's method had a median of 4 deaths and 30 injuries. In multivariate analysis using the Ngai method, religious (6.52, 95%CI 1.73-24.66, p=0.006) and political (277.09, 95%CI 5.12-15,001.96, p=0.006) events had higher relative number of deaths. Many causes accounting for the global increase in human stampede events can only be elucidated through systematic epidemiological investigation. Focusing on a country with a high recurrence of human stampedes, we compare two independent methods of data abstraction in an effort to improve the existing database and to identify pertinent risk factors. We concluded that our previous publication underestimated stampede events in India by approximately 18% and an international standardized database to systematically record occurrence of human stampedes is needed to facilitate understanding of the epidemiology of human stampedes.


Real-time computing platform for spiking neurons (RT-spike).
A computing platform is described for simulating arbitrary networks of spiking neurons in real time. A hybrid computing scheme is adopted that uses both software and hardware components to manage the tradeoff between flexibility and computational power; the neuron model is implemented in hardware and the network model and the learning are implemented in software. The incremental transition of the software components into hardware is supported. We focus on a spike response model (SRM) for a neuron where the synapses are modeled as input-driven conductances. The temporal dynamics of the synaptic integration process are modeled with a synaptic time constant that results in a gradual injection of charge. This type of model is computationally expensive and is not easily amenable to existing software-based event-driven approaches. As an alternative we have designed an efficient time-based computing architecture in hardware, where the different stages of the neuron model are processed in parallel. Further improvements occur by computing multiple neurons in parallel using multiple processing units. This design is tested using reconfigurable hardware and its scalability and performance evaluated. Our overall goal is to investigate biologically realistic models for the real-time control of robots operating within closed action-perception loops, and so we evaluate the performance of the system on simulating a model of the cerebellum where the emulation of the temporal dynamics of the synaptic integration process is important.


Gene silencing by DNA methylation in haematological malignancies.
The past decade has seen an explosion of interest in the epigenetics of cancer, with an increasing understanding that this form of genomic modification plays a critical role in pathogenesis. The malignant phenotype results from a step-wise increase of both genetic abnormalities and epigenetic modifications, leading to dysregulation of critical genes controlling cell growth, differentiation and apoptosis. The methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer. This phenomenon (methylation of CpG islands) plays a critical role in the transcriptional silencing of tumour suppressor genes in cancer and has prompted the development and testing of several demethylating agents aimed at reversing this process. Clinical trials using epigenetically targeted therapies have yielded particularly promising results in the myelodysplastic syndromes (MDS), in which tumour suppressor gene silencing by promoter methylation is a frequent event. Several genes and gene pathways disrupted by aberrant CpG island methylation have now been identified in haematological malignancies, the most frequently studied being the cell cycle inhibitors p16 (now termed CDKN2A; mostly methylated in lymphoid malignancy) and p15 (now termed CDKN2B; commonly methylated in lymphoid and myeloid malignancies). This review will discuss the role that aberrant gene silencing by promoter hypermethylation plays in the molecular pathogenesis of haematological malignancies and assess the clinical potential of demethylating agents for the management of patients.


Social cognition and its relationship to functional outcomes in patients with sustained acquired brain injury.
Deficits in social cognition are common after traumatic brain injury (TBI). However, little is known about how such deficits affect functional outcomes. The purpose of this study was to investigate the relationship between social cognition and functional outcomes in patients with TBI. We studied this relationship in 20 patients with TBI over the course of 1 year post-injury. Patients completed neurocognitive assessments and social cognition tasks. The social cognition tasks included an emotion-perception task and three theory of mind tasks: the Faux Pas test, Reading the Mind in the Eyes (Eyes) test, and the Moving-Shapes paradigm. The Craig Handicap Assessment and Reporting Technique was used to assess functional outcomes. Compared with our database of normal subjects, patients showed impairments in all social cognition tasks. Multiple regression analysis revealed that theory of mind ability as measured by the Eyes test was the best predictor of the cognitive aspects of functional outcomes. The findings of this pilot study suggest that the degree to which a patient can predict what others are thinking is an important measure that can estimate functional outcomes over 1 year following TBI.


Evaluation of a U.K. community-based clinical teaching/outreach program by former dental students two and five years after graduation.
Over the past few years, community-based clinical teaching/outreach teaching programs have been established in many dental schools in the United Kingdom. One such program was developed by Cardiff University at the local St. David's Hospital in 2002. Students visit this unit throughout their dental school program--as an assistant/observer initially, but gaining a significant amount of clinical operating experience within the unit during their final year of studies. While contemporaneous feedback from current dental students at this and other programs has been positive, very little information exists on the impact of this form of training on the subsequent clinical careers and working practices of qualified dentists. In autumn 2009, a postal questionnaire was distributed to dentists who graduated from the School of Dentistry at Cardiff in 2004 (n=41) and 2007 (n=51). Fifty-eight responses were returned, for a response rate of 63 percent: 2004 (66 percent), 2007 (61 percent). Forty-seven respondents (81 percent) reported that their learning experience at the St. David's outreach teaching program had been of significant assistance in their professional development in their subsequent clinical careers. Positive features of the program included the availability of a suitably trained dental nurse for all procedures (n=26, 45 percent), ready access to helpful/approachable teaching staff (n=24, 41 percent), and a good working atmosphere (n=23, 40 percent). Overwhelmingly, former dental students reported that the educational experiences they gained were positive and have had a beneficial effect on their subsequent clinical careers. Further development of community-based clinical teaching/outreach training as part of dental school training programs is encouraged.


Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population.
East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4), OR = 1.05, 95% confidence interval: 1.02-1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.


Can We AlphaFold Our Way Out of the Next Pandemic?
The announcement of the outstanding performance of AlphaFold 2 in the CASP 14 protein structure prediction competition came at the end of a long year defined by the COVID-19 pandemic. With an infectious organism dominating the world stage, the developers of Alphafold 2 were keen to play their part, accurately predicting novel structures of two proteins from SARS-CoV-2. In their blog post of December 2020, they highlighted this contribution, writing "we've also seen signs that protein structure prediction could be useful in future pandemic response efforts". So, what role does structural biology play in guiding vaccine immunogen design and what might be the contribution of AlphaFold 2?


The influence of food consumption and running activity on the activity-stress ulcer in the rat.
Rats housed in activity cages and fed 1 hour daily died before the end of the 21-day experimental period and revealed extensive ulcers in the glandular stomach, whereas food-yoked control rats, not housed in activity cages, did not die and were ulcer-free. Rats demonstrating high running-activity levels under ad lib feeding conditions subsequently revealed a higher incidence of lesions as compared to low-activity rats. Attempts to attenuate activity and lesion incidence by reversing the light-dark cycle failed, but the higher mortality level in rats under the reversed light-dark condition was related to higher activity levels in these rats. Young rats with high activity levels died sooner and had ulcers when compared to older rats with low activity levels. These results suggested that running activity, and not reduced food intake, was critically involved in the development of the activity-stress ulcer.


Patient demand for smoking cessation advice in dentist offices after introduction of graphic health warnings in Australia.
The effectiveness of smoking cessation intervention by dentists has not been conclusively established. This study aimed to investigate whether the inclusion of graphic health warning pictures (including mouth and throat cancer) as part of the Australian National Tobacco Campaign strategy would elicit measurably increased demand for smoking cessation advice in dental practices. A cross-sectional survey of private dental practices in New South Wales, Australia. Separate questionnaires were answered by dentists and patients from their practice. Questions comprised smoking practices and attitudes toward smoking cessation activities in dental practice. The majority of dentists (85.7 per cent; n = 29) and dental patients (92.4 per cent; n = 800) recalled seeing the graphic health warnings, with mouth and throat cancer the most commonly observed. Television was the main medium. Nineteen per cent of dental patients (n = 152) reported themselves as current smokers. Half of them were planning to quit within six months (49.7 per cent) and agreed that graphic health warnings made them more likely to quit (47.7 per cent). Dentists showed positive attitudes toward cessation activities but believed many patients lacked motivation to quit smoking; a perception that was seen to be the main barrier in offering smoking cessation advice. Forty per cent of smokers would try to quit if asked by their dentists, but only 28.4 per cent preferred a dentist for cessation advice. In general, dentists found no change in demand for smoking cessation advice since the launch of the National Tobacco Campaign in 2006. Health warning pictures seemed to increase the patients' awareness and intention to quit smoking, however it did not appear to generate more demand for smoking cessation advice from their dentists. Dentists had low expectations about their patients' motivation to stop smoking.


Evaluation of a common variant of the gene encoding clara cell 10 kd protein (CC10) as a candidate determinant for asthma severity and steroid responsiveness among Chinese children.
The gene (SCGB1A1) encoding Clara cell 10-kDa protein (CC10), a steroid-inducible immune modulator, is a candidate gene for asthma, but the evidence is equivocal. The potential influence of a common variant on asthma severity and serum CC10 levels during acute exacerbation and after corticosteroid treatment in Chinese case-control children and its functional relevance was investigated. Genotyping of a non-coding variant G+38A was performed in 489 children, of whom 277 had asthma with varying severity, and 212 healthy controls. Associations were tested for asthma, asthma severity, and responsiveness to steroid treatment. The transcriptional activity of this variant was examined in a Clara-like cell line (H358) using transient transfection assays. Significant association was observed for the combined GA and AA genotypes of the CC10 G+38A variant and an increased risk of asthma [odds ratio (OR), 2.62, p < .001]. This association was correlated with asthma severity (moderate: OR, 2.85, p < .001; near-fatal: OR, 4.81, p < .001). Also, patients with the GA and AA genotypes showed significantly lower serum CC10 (p < .01) and provocation concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1)) (p < .0001) when compared with those with the GG. After glucocorticoid treatment, the CC10 levels were significantly increased in asthmatic patients with GG (p < .0001), but not those with the GA and AA genotypes. Moreover, a lower dexamethasone-induced reporter (luciferase) activity was observed for H358 cells transiently transfected with the G38A risk allele (A) compared with wild-type allele (G). These findings suggest that the CC10 G+38A variant may contribute to the severity of asthma and lower level of steroid responsiveness.


Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-kappaB.
Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are frequently overexpressed in tumor tissues or transformed cells. In the present work, we assessed the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on expression of iNOS and COX-2 in mouse skin. Topical application to the dorsal skin of female ICR mice of 10 nmol TPA led to maximal induction of iNOS and COX-2 protein expression at approximately 2 and 4 h, respectively. When applied topically onto shaven backs of mice 30 min prior to TPA, the NOS inhibitor aminoguanidine (AG) inhibited the expression of COX-2 protein at the pharmacologically effective dose. Pretreatment with a more specific iNOS inhibitor, N(G)-nitro-l-arginine-methyl ester, also suppressed TPA-induced COX-2 expression. Immunohistochemical analysis of TPA-treated mouse skin using an anti-nitrotyrosine antibody reveals enhanced levels of nitrotyrosine protein localized in epidermal and dermal layers. Topical application of NO donors, such as sodium nitroprusside (SNP) and S-nitroso-N-acetyl-d,l-penicillamine, induced expression of COX-2 in mouse skin, which was attenuated by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide. SNP treatment stimulated NF-kappaB activation in mouse skin, which was associated with the degradation of IkappaBalpha. Topical application of inhibitors of NF-kappaB, such as pyrrolidine dithiocarbamate or N-alpha-p-tosyl-l-lysine chloromethylketone, inhibited the SNP-induced COX-2 expression. SNP induced a weak but concentration-related increase in COX-2 expression in cultured mouse keratinocytes, which was abolished by treatment with SN50, a specific inhibitor of nuclear translocation of NF-kappaB. Mouse keratinocytes treated with SNP exhibited an elevated NF-kappaB-driven COX-2 promoter activity. Topical application of AG (10 micro mol) prior to each TPA treatment after initiation reduced the multiplicity of papillomas by 44% at 22 weeks. In conclusion, up-regulation of COX-2 by NO may be mediated by activation of NF-kappaB in mouse skin, which provides a molecular mechanism by which COX-2 is induced during tumor promotion.


Atrial fibrillation in patients treated with intravenous zoledronic or pamidronic acid: a pharmacoepidemiological study.
Atrial fibrillation (AF) may be triggered by intravenous bisphosphonates (IVBPs) such as zoledronic acid or pamidronic acid. Our objective was to confirm the association between AF and IVBPs in a real-life large pharmacovigilance database. A systematic analysis of VigiBase, the World Health Organization's pharmacovigilance database. Analysis of adverse events reported as 'atrial fibrillation' (according to the Medical Dictionary for Drug Regulatory Activities) associated with the use of zoledronic acid or pamidronic acid, in VigiBase, the World Health Organization's global Individual Case Safety Report (ICSR) database. All ICSRs reporting AF associated with zoledronic acid or pamidronic acid were included in a disproportionality analysis determining the lower end of the 95% credibility interval for the information component (IC025), showing a statistical association when >0. 530 ICSRs reporting on the association between AF and IVBPs were extracted. Bayesian disproportionality analysis detected a significant association between AF and use of zoledronic acid (IC025 = 1.83) and pamidronic acid (IC025 = 2.16). Further analysis of these ICSRs determined that AF was severe in 85.0% of cases and with a mortality of 17.7%. The risk of severe AF was increased (OR: 2.98 (95% CI: 1.17-7.57), P = 0.02) following zoledronic acid vs pamidronic acid, after adjustment for age and gender. This is the first VigiBase pharmacoepidemiological study confirming the association between IVBPs and AF. Most AF were severe, with a high frequency of lethal outcome. The risk of severe AF was increased following zoledronic acid use compared to pamidronic acid, advocating for a cautious use of IVBPs.


Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis.
Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.


White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study.
Several neurobiological models of obsessive-compulsive disorder (OCD) posit a primary role for dysfunction of the anterior cingulate gyrus. Both functional and structural neuroimaging studies have implicated anterior cingulate gray matter abnormalities in the pathophysiology of OCD, but there has been little investigation of the anterior cingulate white matter in this disorder. To test the hypothesis that patients with OCD have abnormal white matter microstructure in the anterior cingulate gyrus compared with healthy volunteers as inferred from diffusion tensor imaging. Additional analyses examined group differences in white matter integrity across the entire brain. Fifteen patients with a DSM-IV diagnosis of OCD and 15 healthy volunteers matched for age, sex, and handedness underwent diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy (FA), a robust intravoxel measure of water self-diffusion, was compared between groups on a voxel-by-voxel basis in the anterior cingulate white matter after standardization in Talairach space. Clinical ratings of symptom severity (ie, Yale-Brown Obsessive-Compulsive Scale) and FA. Compared with healthy volunteers, patients demonstrated significantly lower FA bilaterally in 3 areas of the anterior cingulate gyrus white matter. Additional analyses conducted across the rest of the brain white matter revealed lower FA bilaterally in the parietal region (supramarginal gyri), right posterior cingulate gyrus, and left occipital lobe (lingual gyrus). No areas of significantly higher FA were observed in patients compared with healthy volunteers. Lower FA in the parietal region correlated significantly with higher Yale-Brown Obsessive-Compulsive Scale scores. These preliminary findings provide evidence of an abnormality that involves the anterior cingulate white matter in the pathogenesis of OCD and are consistent with neurobiological models that posit a defect in connectivity in the anterior cingulate basal ganglia-thalamocortical circuit. White matter abnormalities in other brain regions may also be implicated in the neurobiology of OCD.


Morbidity of contemporary radical retropubic prostatectomy for localized prostate cancer.
Complication rates in 1,000 consecutive patients who underwent radical retropubic prostatectomy for clinically localized prostate cancer between November 1989 and January 1992 were assessed and compared to complication rates in a historical group of patients operated on by primarily the same surgeons prior to 1987. In the contemporary series, there were no operative deaths, only 22% of patients required blood transfusion, and only six (0.6%) patients suffered rectal injuries. Early complications, including myocardial infarction, pulmonary embolism, bacteremia, and wound infection, occurred in less than 1% of patients. Vesical neck contracture, the most common late complication, developed in 87 patients (8.7%). At 1 year post-surgery, 80% of patients were completely continent, and fewer than 1% were totally incontinent.


Design of RNAi hairpins for mutation-specific silencing of ataxin-7 and correction of a SCA7 phenotype.
Spinocerebellar ataxia type 7 is a polyglutamine disorder caused by an expanded CAG repeat mutation that results in neurodegeneration. Since no treatment exists for this chronic disease, novel therapies such post-transcriptional RNA interference-based gene silencing are under investigation, in particular those that might enable constitutive and tissue-specific silencing, such as expressed hairpins. Given that this method of silencing can be abolished by the presence of nucleotide mismatches against the target RNA, we sought to identify expressed RNA hairpins selective for silencing the mutant ataxin-7 transcript using a linked SNP. By targeting both short and full-length tagged ataxin-7 sequences, we show that mutation-specific selectivity can be obtained with single nucleotide mismatches to the wild-type RNA target incorporated 3' to the centre of the active strand of short hairpin RNAs. The activity of the most effective short hairpin RNA incorporating the nucleotide mismatch at position 16 was further studied in a heterozygous ataxin-7 disease model, demonstrating significantly reduced levels of toxic mutant ataxin-7 protein with decreased mutant protein aggregation and retention of normal wild-type protein in a non-aggregated diffuse cellular distribution. Allele-specific mutant ataxin7 silencing was also obtained with the use of primary microRNA mimics, the most highly effective construct also harbouring the single nucleotide mismatch at position 16, corroborating our earlier findings. Our data provide understanding of RNA interference guide strand anatomy optimised for the allele-specific silencing of a polyglutamine mutation linked SNP and give a basis for the use of allele-specific RNA interference as a viable therapeutic approach for spinocerebellar ataxia 7.


Urinary polyphenols, glutathione S-transferases copy number variation, and breast cancer risk: results from the Shanghai women's health study.
In vitro studies have found that flavanol epigallocatechin (EGC) and flavonols, but not flavanol epicatechin (EC), activate glutathione S-transferases (GSTs), a family of phase II enzymes that detoxify reactive oxygen species, such as catechol estrogen metabolites. This study was designed to investigate prospectively whether urinary excretion of tea polyphenols interacts with GST polymorphisms to influence breast cancer risk. We conducted a study of 352 incident breast cancer cases and 701 individually matched controls nested within the Shanghai Women's Health Study cohort of women aged 40-70 yr at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR was used to quantify the copy number variation in the GSTM1 and GSTT1 genes. Urinary excretion of flavonols and flavanols, particularly EGC (P = 0.02), was significantly higher among women null for GSTM1 than those positive for GSTM1. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, with a P-value of 0.04 for the interaction between EGC and GSTM1 polymorphism. In contrast, among women possessing both GSTM1 and GSTT1, breast cancer risk increased with levels of flavonols, particularly kaempferol. The differential associations between polyphenols and breast cancer risk by GST polymorphisms, if confirmed, may provide a new avenue for the personalized prevention of breast cancer.


Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection.
The N-terminal truncated form of a protein synthesis enzyme, tryptophanyl-tRNA synthetase (mini-WRS), is secreted as an angiostatic ligand. However, the secretion and function of the full-length WRS (FL-WRS) remain unknown. Here, we report that the FL-WRS, but not mini-WRS, is rapidly secreted upon pathogen infection to prime innate immunity. Blood levels of FL-WRS were increased in sepsis patients, but not in those with sterile inflammation. FL-WRS was secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production. Administration of FL-WRS into Salmonella typhimurium-infected mice reduced the levels of bacteria and improved mouse survival, whereas its titration with the specific antibody aggravated the infection. The N-terminal 154-amino-acid eukaryote-specific peptide of WRS was sufficient to recapitulate FL-WRS activity and its interaction mode with TLR4-MD2 is now suggested. Based on these results, secretion of FL-WRS appears to work as a primary defence system against infection, acting before full activation of innate immunity.


Biological feedbacks in global desertification.
Studies of ecosystem processes on the Jornada Experimental Range in southern New Mexico suggest that longterm grazing of semiarid grasslands leads to an increase in the spatial and temporal heterogeneity of water, nitrogen, and other soil resources. Heterogeneity of soil resources promotes invasion by desert shrubs, which leads to a further localization of soil resources under shrub canopies. In the barren area between shrubs, soil fertility is lost by erosion and gaseous emissions. This positive feedback leads to the desertification of formerly productive land in southern New Mexico and in other regions, such as the Sahel. Future desertification is likely to be exacerbated by global climate warming and to cause significant changes in global biogeochemical cycles.


Ecology of Trypanosoma cruzi I genotypes across Rhodnius prolixus captured in Attalea butyracea palms.
Trypanosoma cruzi, the agent of Chagas disease exhibits significant genetic diversity. This parasite is divided into six discrete typing units (DTUs) where T. cruzi I (TcI) is the most widespread in the Americas. TcI genotypes have been associated to domestic and sylvatic cycles of transmission (TcIDom and sylvatic TcI). Due to the importance of the enzootic transmission, we determined the frequency of TcI genotypes present in Rhodnius prolixus captured in different regions of the palm A. butyracea to understand the ecology of the disease and the importance of A. butyracea palms as ecotopes of R. prolixus. Forty A. butyracea palms were sampled (base crown, mid-point and crown) capturing 105 individuals identified as R. prolixus by morphological and molecular barcoding. We conducted molecular detection and typing of T. cruzi across 59 individuals. The results showed that all the insects were infected with TcI; 28.57% were sylvatic TcI, 12.38% TcIDom and 15,24% mixed infections (TcIDom/sylvatic TcI). Statistical analysis showed a similar behavior between TcIDom and mixed infections in the mid-point and at the crown of the palm, being more frequent in the crown, while sylvatic TcI does not seem to have a specific association with any of the sampled areas. These findings are consistent with other studies showing high mobility of the insect vector between different ecotopes, increasing the need to develop improvements in the programs of disease control.


Supercapacitor Electrodes with Remarkable Specific Capacitance Converted from Hybrid Graphene Oxide/NaCl/Urea Films.
A novel approach to improve the specific capacitance of reduced graphene oxide (rGO) films is reported. We combine the aqueous dispersion of liquid-crystalline GO incorporating salt and urea with a blade-coating technique to make hybrid films. After drying, stacked GO sheets mediated by solidified NaCl and urea are hydrothermally reduced, resulting in a nanoporous film consisting of rumpled N-doped rGO sheets. As a supercapacitor electrode, the film exhibits a high gravimetric specific capacitance of 425 F g-1 and a record volumetric specific capacitance of 693 F cm-3 at 1 A g-1 in 1 M H2SO4 aqueous electrolyte when integrated into a symmetric cell. When using Li2SO4 aqueous electrolyte, which can extend the potential window to 1.6 V, the device exhibits high energy densities up to 35 Wh kg-1, and high power densities up to 104 W kg-1. This novel strategy to intercalate solidified chemicals into stacked GO sheets to functionalize them and prevent them from restacking provides a promising route toward supercapacitors with high specific capacitance and energy density.


Increased permeability of oxygen atoms through graphene with ripples.
Graphene is an ideal membrane for selective separation because of its unique properties and single-layer structure. Considerable efforts have been made to alter the permeability of graphene. In this study, we investigate the pathways for an oxygen atom to pass through graphene sheets. We also identify the effect of the ripple's curvature in graphene sheets on the energy barrier of permeation through density functional theory calculations. Results show that oxygen atoms can easily pass through the concave side of graphene ripples with a large curvature. The analysis of transition states reveals that the space where an oxygen atom passes through keeps an almost identical structure with similar bond lengths regardless of the curvature. We find that the Cu(111) substrate may draw out the C-C bond lengths of graphene at the Cu(111) surface because of the strong interaction between the graphene edge and copper atoms. Consequently, the energy barrier of the permeation of oxygen atoms through graphene is reduced. These results suggest that the rippling of graphene significantly affects its permeation.


Crossmodal semantic priming by naturalistic sounds and spoken words enhances visual sensitivity.
We propose a multisensory framework based on Glaser and Glaser's (1989) general reading-naming interference model to account for the semantic priming effect by naturalistic sounds and spoken words on visual picture sensitivity. Four experiments were designed to investigate two key issues: First, can auditory stimuli enhance visual sensitivity when the sound leads the picture as well as when they are presented simultaneously? And, second, do naturalistic sounds (e.g., a dog's "woofing") and spoken words (e.g., /dɔg/) elicit similar semantic priming effects? Here, we estimated participants' sensitivity and response criterion using signal detection theory in a picture detection task. The results demonstrate that naturalistic sounds enhanced visual sensitivity when the onset of the sounds led that of the picture by 346 ms (but not when the sounds led the pictures by 173 ms, nor when they were presented simultaneously, Experiments 1-3A). At the same SOA, however, spoken words did not induce semantic priming effects on visual detection sensitivity (Experiments 3B and 4A). When using a dual picture detection/identification task, both kinds of auditory stimulus induced a similar semantic priming effect (Experiment 4B). Therefore, we suggest that there needs to be sufficient processing time for the auditory stimulus to access its associated meaning to modulate visual perception. Besides, the interactions between pictures and the two types of sounds depend not only on their processing route to access semantic representations, but also on the response to be made to fulfill the requirements of the task.


The effect of impurities in ultra-thin hydrogenated silicene and germanene: a first principles study.
Spin polarized density functional theory within the GGA-PBE and HSE06 approach for the exchange correlation term has been used to investigate the stability and electronic properties of nitrogen and boron impurities in single layers of silicane and germanane. We have observed that these impurities have lower formation energies in silicane and germanane when compared to their counterparts in graphane. We have also noticed that the adsorption of H atoms in the vicinity of defects stabilizes the system. In addition, we have shown that the electronic properties of silicane and germanane can be tuned when N and B are incorporated in the Si and Ge network. N-doping and B-doping give rise to n-type and p-type semiconductor properties. However, the adsorption of H atoms quenches the doping effects.


Relationship between dairy product consumption and incidence of IDDM in childhood in Italy.
To test the hypothesis that the consumption of dairy products, including fluid cows' milk and cheese, is related to the incidence of insulin-dependent diabetes mellitus (IDDM), we correlated incidence rates in children 0-14 years of age with cows' milk and cheese consumption in nine regions of a single country, Italy. Data on the incidence of IDDM were derived from the only nine Italian regions where primary and secondary sources of ascertainment were available for 1991. Data on fluid cows' milk and cheese consumption in the corresponding year in each region were obtained from the National Institute of Statistics. The correlation between fluid milk consumption and incidence of IDDM in Italy was 0.84 (P < 0.004, Poisson regression analysis). Cheese consumption was not related to IDDM incidence. The results indicate that there is a relationship, even in a single country, between dairy product consumption and the incidence of IDDM that is confined to fluid milk consumption. Cows' milk may contain a triggering factor for the development of diabetes, but the high incidence of IDDM in Sardinia and in other countries worldwide cannot be explained simply by the quantity of fluid cows' milk consumed.


Confronting social disparities in child health: a critical appraisal of life-course science and research.
The utility of the life-course framework to address disparities in child health is based on its ability to integrate the science of child development with the requirements of effective and just public policy. I argue that the life-course framework is best assessed in a historical context and through 4 essential observations. First, early genetic and environmental interactions are complex and influence outcomes in different settings in very different ways. Second, these early-life interactions are themselves subject to considerable later influences and, therefore, may not be highly predictive of later outcomes. Third, the etiologic nature or timing of early-life interactions does not, per se, determine if their life-course effects are amenable to later interventions. Fourth, a highly deterministic view of early-life interactions is not supported by the science and can generate counterproductive approaches to research and policy development. Finally, an alternative approach is proposed on the basis of a "human-capacity" model of the life course that connects the search for underlying basic mechanisms with a policy-based examination of the comparative effectiveness of influences at different developmental stages. This approach suggests an expanded research and policy agenda that might be more capable of generating urgently needed strategies for reducing disparities in child health. Such an approach could ultimately define more comprehensively the power and limits of life-course effects in shaping the social distribution of health outcomes in the real world.


Optically-generated Overhauser dynamic nuclear polarization: A numerical analysis.
Recently, an alternative approach to dynamic nuclear polarization (DNP) in the liquid state was introduced using optical illumination instead of microwave pumping. By exciting a suitable dye to the triplet state which undergoes a diffusive encounter with a persistent radical forming a quartet-doublet pair in the encounter complex, dynamic electron polarization (DEP) is generated via the radical-triplet pair mechanism. Subsequent cross-relaxation generates nuclear polarization without the need for microwave saturation of the electronic transitions. Here, we present a theoretical justification for the initial experimental results by means of numerical simulations. These allow investigation of the effects of various experimental parameters, such as radical and dye concentrations, sample geometry, and laser power, on the DNP enhancement factors, providing targets for experimental optimization. It is predicted that reducing the sample volume will result in larger enhancements by permitting a higher concentration of triplets in a sample of increased optical density. We also explore the effects of the pulsed laser rather than continuous-wave illumination, rationalizing the failure to observe the optical DNP effect under illumination conditions common to DEP experiments. Examining the influence of the illumination duty cycle, the conditions necessary to permit the use of pulsed illumination without compromising signal enhancement are determined, which may reduce undesirable laser heating effects. This first simulation of the optical DNP method therefore underpins the further development of the technology.


Small-scale properties of a stochastic cubic-autocatalytic reaction-diffusion model.
We investigate the small-scale properties of a stochastic cubic-autocatalytic reaction-diffusion (CARD) model using renormalization techniques. We renormalize noise-induced ultraviolet divergences and obtain β functions for the decay rate and coupling at one loop. Assuming colored (power-law) noise, our results show that the behavior of both decay rate and coupling with scale depends crucially on the noise exponent. Interpreting the CARD model as a proxy for a (very simple) living system, our results suggest that power-law correlations in environmental fluctuations can both decrease or increase the growth of structures at smaller scales.


Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.


Age-related changes of IgA immunocytes and serum and salivary IgA after tonsillectomy.
For determining treatment options of tonsillar diseases, the authors compared immunohistochemical differences for IgA immunocytes and measured the changes in concentrations of the serum immunoglobulin A and salivary secretory immunoglobulin A before and after tonsillectomy according to age in 126 cases (60 control cases, 66 tonsillectomy cases). The serum IgA and salivary SIgA concentrations of the control group reached to adult's level at the age of 11 to 13. In the tonsillectomies, the serum IgA concentrations below the age of 10 were higher than that of controls and were decreased to the levels of the controls after tonsillectomy in all ages and the salivary SIgA concentrations were decreased to the levels of the controls at the 30th postoperative day, especially at the age of 5 to 7 and 8 to 10. Morphometric features of tonsils in the group below the age of 8 were more active than those in the group above the age of 8 in the controls. In the tonsillectomies, morphometric features of the tonsils were similar to those in the group above the age of 8, but the reticular part of the crypt epithelium remained significantly. Total number of IgA immunocytes was the highest at the age of 5 to 7 with a decline by age, especially at the age of 19 in the controls. In the tonsillectomy group, the number of IgA immunocytes of the extrafollicular area and the reticular part of crypt epithelium decreased below the levels of the control group. In conclusion, tonsils in preschool children are important as a local immunologic defense mechanism, but no significant changes in the immunologic system occurs after tonsillectomy.


Detrimental effects of physical inactivity on neurogenesis.
Patients diagnosed with neurological disorders exhibit a variety of physical and psychiatric symptoms, including muscle atrophy, general immobility, and depression. Patients who participate in physical rehabilitation at times show unexpected clinical improvement, which includes diminished depression and other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for central nervous system (CNS) disorders, transplantation of exogenous stem cells, and enhancing the endogenous neurogenesis. The latter therapy utilizes a natural method of re-innervating the injured brain, which may mend neurological impairments. In this study, we examine how inactivity-induced atrophy, using the hindlimb suspension model, alters neurogenesis in rats. The hypothesis is that inactivity inhibits neurogenesis by decreasing circulation growth or trophic factors, such as vascular endothelial growth or neurotrophic factors. The restriction modifies neurogenesis and stem cell differentiation in the CNS, the stem cell microenvironment is examined by the trophic and growth factors, including stress-related proteins. Despite growing evidence revealing the benefits of "increased" exercise on neurogenesis, the opposing theory involving "physical inactivity," which simulates pathological states, continues to be neglected. This novel theory will allow us to explore the effects on neurogenesis by an intransigent stem cell microenvironment likely generated by inactivity. 5-bromo-2-deoxyuridine labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid, and brain levels of trophic factors, growth factors, and stress-related proteins are suggested identifiers of neurogenesis, while evaluation of spontaneous movements will give insight into the psychomotor effects of inactivity. Investigations devised to show how in vivo stimulation, or lack thereof, affects the stem cell microenvironment are necessary to establish treatment methods to boost neurogenesis in bedridden patients.


Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.
Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.


Speciation of Gram-positive bacteria in fresh and ambient-stored sub-tropical marine fish.
This study identified Gram-positive bacteria in three sub-tropical marine fish species; Pseudocaranx dentex (silver trevally), Pagrus auratus (snapper) and Mugil cephalus (sea mullet). It further elucidated the role played by fish habitat, fish body part and ambient storage on the composition of the Gram-positive bacteria. A total of 266 isolates of Gram-positive bacteria were identified by conventional biochemical methods, VITEK, PCR using genus- and species-specific primers and/or 16S rRNA gene sequencing. The isolates were found to fall into 13 genera and 30 species. In fresh fish, Staphylococcus epidermidis and Micrococcus luteus were the most frequent isolates. After ambient storage, S. epidermidis, S. xylosus and Bacillus megaterium were no longer present whereas S. warneri, B. sphaericus, Brevibacillus borstelensis, Enterococcus faecium and Streptococcus uberis increased in frequency. Micrococcus luteus and S. warneri were the most prevalent isolates from P. dentex, while E. faecium and Strep. uberis were the most frequent isolates from P. auratus and M. cephalus. With respect to different parts of the fish body, E. faecium, Strep. uberis and B. sphaericus were the most frequent isolates from the muscles, E. faecium, Strep. uberis from the gills and M. luteus from the gut. This study showed a diversity of Gram-positive bacteria in sub-tropical marine fish; however, their abundance was affected by fish habitat, fish body part and ambient storage.


Simultaneous pulse amplification and compression in all-fiber-integrated pre-chirped large-mode-area Er-doped fiber amplifier.
A large-mode-area Erbium-doped fiber amplifier (LMA-EDFA) based all-fiber-integrated amplified compressor with ultrashort length of 5.37 m and ultralow pumping power (260 mW) is proposed. The LMAEDFA suppresses nonlinear soliton-self-frequency-shift effect happened during femtosecond pulse amplification, in which the fiber laser pulse is reshaped to a low-pedestal hyperbolic-second shape with nearly 100% energy confinement. The pre-chirped amplification from 0.96 to 104 mW and the simultaneous compression of a passively mode-locked fiber laser pulse from 300 to 56 fs is demonstrated. The input pulse energy of 24 pJ is amplified up to 2.6 nJ with shortened pulsewidth of 56 fs and peak power as high as 46 kW.


The interpretive research group as an alternative to the interpersonal process recording.
In the spirit of trying something new, we abandoned the traditional interpersonal process recording for an entirely new way to teach students about communication--an interpretive research group. We propose the interpretive research group as a strategy for teaching communication and analysis that encourages active student-faculty participation, provides for more egalitarian student-teacher relationships, and creates a liberating learning environment.


Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.


Are performance measures based on automated medical records valid for physician/practice profiling of asthma care?
The use of physician profiles in "pay for performance" initiatives depend on their reliability and accuracy. To evaluate whether health care delivery units (practices) can be reliably differentiated using the Health Employers Data Information System (HEDIS) performance measure. Simulation was used to describe the relationship between practice size (number of children with persistent asthma) and precision of practice measures to estimate performance. Children enrolled in 1 of the 39 practice groups from 1 of 3 managed care organizations participating in the Pediatric Asthma Care Patient Outcomes Research Team (PAC PORT). The main outcome was reproducibility of 4 performance measures, the HEDIS measure and 3 additional measures available from automated claims data: the proportion of children with asthma related-hospitalization, emergency department visits and oral steroid dispensings for asthma. The ability to reproducibly rank a practice is dependent on the performance measure, practice size, and the reproducibility threshold chosen. Of measures evaluated, none achieved a reproducibility >85% for practice size of 50 or less. At a practice size of 100 subjects, the HEDIS measure reproducibly ranked practices 89% of the time, compared with 85% for emergency department visits and 83% for hospitalizations. Only at a practice size of 100 children with persistent asthma, was reproducibility of ranking greater than 85% with all performance measures evaluated. The reliability of ranking medical practices depends on practice size. Only at the level of the health care organization can asthma measures, available within claims data, be used to rank performance reliably.


A conserved phosphatase cascade that regulates nuclear membrane biogenesis.
A newly emerging family of phosphatases that are members of the haloacid dehalogenase superfamily contains the catalytic motif DXDX(T/V). A member of this DXDX(T/V) phosphatase family known as Dullard was recently shown to be a potential regulator of neural tube development in Xenopus [Satow R, Chan TC, Asashima M (2002) Biochem Biophys Res Commun 295:85-91]. Herein, we demonstrate that human Dullard and the yeast protein Nem1p perform similar functions in mammalian cells and yeast cells, respectively. In addition to similarity in primary sequence, Dullard and Nem1p possess similar domains and show similar substrate preferences, and both localize to the nuclear envelope. Additionally, we show that human Dullard can rescue the aberrant nuclear envelope morphology of nem1Delta yeast cells, functionally replacing Nem1p. Finally, Nem1p, has been shown to deposphorylate the yeast phosphatidic acid phosphatase Smp2p [Santos-Rosa H, Leung J, Grimsey N, Peak-Chew S, Siniossoglou S (2005) EMBO J 24:1931-1941], and we show that Dullard dephosphorylates the mammalian phospatidic acid phosphatase, lipin. Therefore, we propose that Dullard participates in a unique phosphatase cascade regulating nuclear membrane biogenesis, and that this cascade is conserved from yeast to mammals.


Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization.
Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.


Low background FRET-substrates for lipases and esterases suitable for high-throughput screening under basic (pH 11) conditions.
FRET-based fluorogenic substrates for lipases and esterases were prepared in four steps from commercially available building blocks. The substrates are pyrenebutyric acid monoesters of aliphatic 1,2-diols bearing a dinitrophenylamino group as a quencher. The most enzyme-reactive substrate is ester 2a. The substrates do not show any measurable background reaction in the absence of enzyme even at pH 11, but react fast and specifically with lipases and esterases. These substrates offer an unprecedented and practical solution to the long-standing problem of a simple yet efficient high-throughput screening tool for lipase activities under basic conditions.


Overlap syndrome: a diagnostic dilemma.
We report an interesting case of a young patient who came with a concern for missing teeth and lack of hair on scalp and body. Examination revealed complete absence of teeth, absence of eyebrows, eyelashes and hair over scalp. He was short-statured, had hyperextensible joints and hyperelastic skin, protuberant lips and many other anomalies such that the overall pattern of defects was not recognisable. A wide array of investigations involving the dental and medical faculties were done; however, the final diagnosis could not be reached, since it appeared to involve features of more than one syndrome, thus the name 'overlap syndrome'.


Comparison of a calculated and measured XANES spectrum of α-Fe2O3.
Comparison and prediction of the experimental XANES spectrum is a good measurement of the quality of the electronic structure calculations employed, and their ability to predict electronic transitions in solids. Here we present a comparison between BLYP + U and hybrid-BLYP calculations regarding the geometric, magnetic and electronic structures of α-Fe(2)O(3) (hematite). Several values of U and different percentages of Fock-exchange have been screened to see how their contributions affect different properties of hematite, paying particular attention to the electronic structure. To estimate the quality of the various methods the calculated density-of-states were compared to the experimentally collected XANES spectrum of the iron K-edge, providing information about the orbitals describing the conduction band. We find that in agreement with previous studies DFT + U and hybrid-functional simulations can correctly predict the character of the valence band, but only Fock-exchange higher than 30% or U-values equal or larger than 6 eV properly reproduce the order between the t(g) and e orbitals in the conduction band, and can, therefore, be used to study and predict XANES spectra and electronic transitions in hematite.


Manual Resistance versus Conventional Resistance Training: Impact on Strength and Muscular Endurance in Recreationally Trained Men.
Manual resistance training (MRT) has been widely used in the field of physical therapy. It has also been used as a strength training method due to the accommodating resistance nature of this modality. The aim of the present study was to compare the effects of an 8-week MRT program on maximum strength and muscular endurance in comparison to conventional resistance training in recreationally trained men. Twenty healthy recreationally trained male subjects were recruited and divided into a MRT training group and a conventional training (CT) group. CT group performed bench press and lat pull-down exercises, and the MRT group performed similar movements with resistance provided by a personal trainer. Both groups completed similar training protocol and training load: 2 training sessions weekly for 3 sets of 8 repetitions at an intensity of 8 to 10 on the perceived exertion scale of 0-10. Initial maximum strength differences were not significant between the groups. Neither group showed significant changes in muscular strength or endurance. Despite the statistically non-significant pre- to post differences, a trend for improvement was observed and effect size (ES) calculations indicated greater magnitude of effects for strength and endurance changes in the MRT group in lat pulldown (g=0.84) compared to CT group. Effectiveness of MRT is similar to CT for improving muscular strength and endurance. MRT can be used as a supplemental or alternative strength training modality for recreationally trained subjects, or be considered by personal trainers especially in low equipped facility conditions.


Potential mRNA degradation targets of hsa-miR-200c, identified using informatics and qRT-PCR.
Using an anchored oligo(dT) based RT-PCR approach we quantified endogenous expression of ten microRNAs in six cell lines. This identified a miRNA, miR-200c, with variable expression, ranging from undetectable in MDA-MB-231 and HT1080 to highly expressed in MCF7. The variable expression provided a model system to investigate endogenous interactions between miRNAs and their computationally predicted targets. As the expression level of the predicted mRNA targets and miR-200c in these lines should have an inverse relationship if cleavage or degradation results from the interaction. To select targets for analysis we used Affymetrix expression data and computational prediction programs. Affymetrix data indicated approximately 3500 candidate mRNAs, absent in MCF7 and present in MDA-MB-231 or HT1080. These targets were cross-referenced against approximately 600 computationally predicted miR-200c targets, identifying twenty potential mRNAs. Expression analysis by qRT-PCR of these targets and an additional ten mRNAs (selected using the prediction program ranking alone) revealed four mRNAs, BIN1, TCF8, RND3 and LHFP with an inverse relationship to miR-200c. Of the remainder, the majority did not appear to be degraded (and may be translational targets) or were undetectable in the cell lines examined. Finally, inhibition of miR-200c using an anti-miRNA 2'-0-Methyl oligonucleotide (AMO) resulted in an increase in expression of one of the targets, the transcription factor TCF8. These results indicate that a single miRNA could directly affect the mRNA levels of an important transcription factor, albeit in a manner specific to cell lines. Further investigation is required to confirm this in vivo and determine any translational effects.


Interactions between nitric oxide and renal nerves in the excretion of a saline load in obese Zucker rats.
The present study investigated the potential role of nitric oxide (NO) and its interaction with renal sympathetic nerves in modulating the excretory responses to an acute saline volume expansion (VE), of 10% of body weight, in the innervated and denervated kidneys of both lean and obese Zucker rats. This was done using the NO synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME), 7-nitroindazole and aminoguanidine. In lean rats, cumulative urinary sodium excretion (cuU(Na)V) after 40 min of VE in the innervated kidney was enhanced by 48% in L-NAME-treated rats compared with that in untreated rats, but this was not the case for the denervated kidney. VE in untreated obese rats raised cuU(Na)V to a lesser extent than in the untreated lean rats, by 36% and 46% in the denervated and innervated kidneys respectively (both P<0.001). L-NAME treatment of obese rats increased cuU(Na)V after VE compared with that in untreated obese rats, by 48% in the denervated kidney and by 136% in the innervated kidney (both P<0.001). The magnitude of cuU(Na)V after VE in both kidneys of 7-nitroindazole-treated obese rats was not different from that in untreated obese rats. However, cuU(Na)V was raised (P<0.01) by 56% in the innervated, but not the denervated, kidney of aminoguanidine-treated obese rats. These data show that NO is partially involved in mediating the reflex renal responses to VE in Zucker rat strains. NO, possibly generated by endothelial NO synthase, exerts its effects in obese rats through a renal-nerve-independent mechanism, while the effect of NO generated by inducible NO synthase requires intact renal innervation.