Droplet microfluidics for the construction of compartmentalised model membranes.
The design of membrane-based constructs with multiple compartments is of increasing importance given their potential applications as microreactors, as artificial cells in synthetic-biology, as simplified cell models, and as drug delivery vehicles. The emergence of droplet microfluidics as a tool for their construction has allowed rapid scale-up in generation throughput, scale-down of size, and control over gross membrane architecture. This is true on several levels: size, level of compartmentalisation and connectivity of compartments can all be programmed to various degrees. This tutorial review explains and explores the reasons behind this. We discuss microfluidic strategies for the generation of a family of compartmentalised systems that have lipid membranes as the basic structural motifs, where droplets are either the fundamental building blocks, or are precursors to the membrane-bound compartments. We examine the key properties associated with these systems (including stability, yield, encapsulation efficiency), discuss relevant device fabrication technologies, and outline the technical challenges. In doing so, we critically review the state-of-play in this rapidly advancing field.


Relationship between condensed tannin structures and their ability to precipitate feed proteins in the rumen.
Tannins can bind to and precipitate protein by forming insoluble complexes resistant to fermentation and with a positive effect on protein utilisation by ruminants. Three protein types, Rubisco, rapeseed protein and bovine serum albumin (a single high-molecular weight protein), were used to test the effects of increasing concentrations of structurally different condensed tannins on protein solubility/precipitation. Protein type (PT) influenced solubility after addition of condensed tannins (P < 0.001) in the order: Rubisco < rapeseed < BSA (P < 0.05). The type of condensed tannin (CT) affected protein solubility (P = 0.001) with a CT × PT interaction (P = 0.001). Mean degree of polymerisation, proportions of cis- versus trans-flavanol subunits or prodelphinidins versus procyanidins among CTs could not explain precipitation capacities. Increasing tannin concentration decreased protein solubility (P < 0.001) with a PT × CT concentration interaction. The proportion of low-molecular weight rapeseed proteins remaining in solution increased with CT concentration but not with Rubisco. Results of this study suggest that PT and CT type are both of importance for protein precipitation but that the CT structures investigated did not allow identification of parameters that contribute most to precipitation. It is possible that the three-dimensional structures of tannins and proteins may be more important factors in tannin-protein interactions.


Financial conflicts of interest and the ethical obligations of medical school faculty and the profession.
Despite their potential benefits, relationships linking medical school faculty and the pharmaceutical and device industries may also challenge the professional value of primacy of patient welfare, a point highlighted in a recent Institute of Medicine report. Academic medical centers and professors have the added professional obligation to ensure the unbiased, evidence-based education of future doctors. This essay argues that faculty financial conflicts of interest may threaten this obligation by propagating the bias introduced by these relationships to students. This could occur directly through the process of curriculum determination and delivery, and also indirectly through the "hidden curriculum," which deserves particular attention, as its lessons may conflict with those professed in the formal curriculum. The essay concludes with guiding principles to consider when developing a conflict of interest policy at academic medical centers.


Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice.
The interferon (IFN) inducible MxA protein is endowed with antiviral activity against a broad range of RNA viruses. In a previous in vitro study, we demonstrated that MxA inhibits hepatitis B virus (HBV) replication, arguing that the antiviral activity of MxA is not restricted to RNA viruses but also includes a DNA virus. The aim of the present study was to further demonstrate in vivo the antiviral action of MxA against HBV. We generated HBV and HBV/MxA transgenic mice lacking a functional IFN-alpha/beta receptor and thus constituting a good model to evaluate MxA-induced virus resistance. HBV proteins expression, viral load and HBV replication were compared in HBV and HBV/MxA mice. An MxA-dependent moderate inhibitory effect on HBV expression was only observed in female HBV/MxA mice, in which MxA downregulates (i) viral HBeAg and capsid protein expression, (ii) viremia and (iii) HBV replication by decreasing the synthesis of HBV DNA replicative intermediates. Furthermore, these effects were not associated with changes to steady-state levels of HBV RNAs. Our results show that in vivo, MxA is able per se to reduce HBV expression by a post-transcriptional mechanism, and thus participates in the antiviral activity of IFN-alpha against HBV.


Anesthetic Management of Cardioband Implantation: Data From a Preliminary Experience and New Insights.
Percutaneous procedures for the treatment of mitral valve disease represent valuable therapeutic options for high-risk patients. The anesthetic management of these patients is complex, as they often suffer from cardiac failure and present multiple comorbidities. A recently developed device for transcatheter mitral valve annuloplasty (Cardioband - Valtech Cardio, Or Yehuda, Israel) is now available in clinical practice. The aim of this study was to present the authors' experience with Cardioband device implantation and to describe their anesthetic strategy. Retrospective study. Cardiac catheterization laboratory of a teaching hospital. Thirteen patients undergoing Cardioband implantation. All the procedures were performed under general anesthesia with continuous transesophageal echocardiographic monitoring. Three-dimensional echocardiography, inotropic therapy, cardiac pacing, and mechanical circulatory support always were available and performed as needed. Mean age was 73±7.1 years, and mean preoperative ejection fraction was 38±7.4%. No complications related to anesthetic management were recorded. The authors observed 1 episode of device malfunction and 1 case of accidental damage to the circumflex artery. Postoperative complications were observed in 3 patients, involving detachment of the anchors, anemia requiring transfusions, vascular injury, and new-onset atrial fibrillation. Six patients (46%) required ICU admission. All patients (100%) were discharged from the hospital. Cardioband device implantation under general anesthesia is a feasible approach when performed by skilled physicians with all the expertise and the resources of high-volume centers used to dealing with severely ill patients.


A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment.
The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.


Differential Response of Phenol Metabolism Associated with Antioxidative Network in Elicited Grapevine Suspension Cultured Cells under Saline Conditions.
Highly productive trans-resveratrol (t-R) grapevine suspension cultured cells (SCC) and two effective elicitors, methyl jasmonate (MJ) and randomly methylated β-cyclodextrins (CDs), were used to analyze the extent to which salt treatments alter the production of bioactive phenolic compounds. The expression/activity profile of the enzymes involved in phenol metabolism and antioxidant networks were also studied. A marked extracellular accumulation of phenolic compounds, especially t-R, was found in SCC elicited with CDs and/or MJ under saline conditions. However, the treatments with MJ alone and all those combined with salt favored the intracellular accumulation of catechin and ferulic acid. The salt-induced accumulation of phenolics was correlated with the higher total antioxidant capacity values found in cells, suggesting that cellular redox homeostasis under saline conditions was largely maintained by increasing phenolic compound production. These higher levels of phenolics found in elicited cells under saline conditions fit well with the highest activity of phenylalanine ammonia-lyase. Moreover, antioxidant enzyme activities were boosted in treatments with MJ and/or in those combined with salt and decreased in those treated with CDs. These results suggest a differential response of the antioxidative network to the presence of elicitors under saline conditions.


What is the lowest threshold to make a diagnosis of concussion?
The purpose of this review is to examine the evidence for determining the lowest threshold for diagnosing a sport-related concussion. MEDLINE, CINAHL, EMBASE, Mosby's Index, PsycEXTRA, PsycINFO and Scopus. Key words included sports concussion, concussion assessment, diagnosis, concussion symptoms, onfield assessment and sports-related traumatic brain injury. The majority of concussions in sport occur without loss of consciousness or frank neurological signs. Some of the hallmark signs of acute concussion include mental confusion, memory and balance disturbance. Over the course of the first 24 h, the most common symptoms include headache, nausea, dizziness and balance problems, blurred vision or other visual disturbance, confusion, memory loss and 'fatigue'. Symptoms such as tiredness, irritability, nervousness or anxiety, sleep disturbance and sensitivity to light or noise may be noticed in the days after injury. The pathophysiology of sports concussion remains poorly understood. There appears to be a period of vulnerability following concussion in which an overlapping injury might cause magnified pathophysiology. Sport-related concussions can be difficult to diagnose. Concussion produces an evolving constellation of somatic, cognitive and neurobehavioral symptoms that are typically most severe during the earliest acute postinjury period (ie, within the first 24-48 h) and diminish over a matter of several days to weeks in the majority of athletes. Athletes suspected of concussion should be removed from play and evaluated thoroughly.


Thrombus Length Estimation on Delayed Gadolinium-Enhanced T1.
Previous studies revealed a close relationship between thrombus length and recanalization rate after intravenous thrombolysis (IVT). As a novel approach, we prospectively adjusted the order of sequence acquisition to obtain delayed gadolinium-enhanced T1 (dGE-T1) and thereby assess thrombus length on dGE-T1 to evaluate its predictive value for recanalization after IVT. We reviewed prospectively collected clinical and imaging data from acute ischemic stroke patients with middle cerebral artery occlusion who underwent multimodal magnetic resonance imaging before and 24 hours after IVT. Perfusion-weighted imaging was performed followed by conventional T1. We measured thrombus length on dGE-T1 and examined its association with middle cerebral artery recanalization. Of the included 74 patients, the median age was 66 years and 28 (37.8%) were women. Thrombus length was 8.18±4.56 mm on dGE-T1, which was an acceptable predictor for no recanalization (odds ratio, 1.196; 95% confidence interval, 1.015-1.409; P=0.033), with a receiver-operator characteristic of 0.732 (95% confidence interval, 0.619-0.845; P=0.001). The optimal cut-off point was identified at 6.77 mm, which yielded a sensitivity of 77.8%, a specificity of 57.9%, and an odds ratio of 4.81 (95% confidence interval, 1.742-13.292; P=0.002). Moreover, no one achieved recanalization after IVT when length of thrombus exceeded 14 mm on dGE-T1. The dGE-T1, obtained by simply adjusting scanning order in multimodal magnetic resonance imaging protocol, is a useful tool for thrombus length estimation and middle cerebral artery recanalization prediction after IVT.


Visual Observations and Spectral Investigations of the Earth's Atmosphere Twilight Aureole from the Soyuz-5 Spacecraft.
Results are given of the spectrophotometric measurements of the earth's atmosphere twilight aureole as first performed from the Soyuz-5 spacecraft. The analysis is made of the experimental findings depending on the wavelength, the perigee height of the sight ray above the earth's surface, the sunset angle, etc.. The comparison is carried out of the vertical profiles for the twilight aureole monochromatic brightness with the results of the corresponding theoretical calculations for the aerosol Elterman model (1968). The color diagram and pictures of the twilight aureole are built using theoretical values of the brightness aureole for different terrestrial atmospheric models and employing the experimental data and the results of visual observations from the Soyuz-5 spacecraft.


A multi-targeted approach to suppress tumor-promoting inflammation.
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.


Managers and leaders: are they different?
The traditional view of management, back in 1977 when Abraham Zaleznik wrote this article, centered on organizational structure and processes. Managerial development at the time focused exclusively on building competence, control, and the appropriate balance of power. That view, Zaleznik argued, omitted the essential leadership elements of inspiration, vision, and human passion which drive corporate success. The difference between managers and leaders, he wrote, lies in the conceptions they hold, deep in their psyches, of chaos and order. Managers embrace process, seek stability and control, and instinctively try to resolve problems quickly--sometimes before they fully understand a problems significance. Leaders, in contrast, tolerate chaos and lack of structure and are willing to delay closure to understand the issues more fully. In this way, Zaleznik argued, business leaders have much more in common with artists, scientists, and other creative thinkers than they do with managers. Organizations need both managers and leaders to succeed, but developing both requires a reduced focus on logic and strategic exercises in favor of an environment where creativity and imagination are permitted to flourish.


Abdominal pregnancy: a perfusion confusion?
The uteroplacental blood supply is usually portrayed as a 'series' circuit. Differences seen in the uterine artery (UA) waveform in pregnancies destined to develop pre-eclampsia are often attributed to back pressure effects from the downstream flow through the spiral arteries of the placental bed. A third trimester abdominal pregnancy was successfully delivered by laparotomy at 30 weeks gestation. The UA waveforms of were recorded at 27 weeks. Both were 'normal' for the gestation, despite limited blood supply from the right uterine and the left not supplying the placenta at all. In the absence of pre-eclampsia, UAs can convert to a 'low resistance' waveform even when not directly connected to the placental bed. This case report adds to the evidence against the 'cause and effect' mechanism often used to explain the correlation between trophoblastic invasion and the UA waveform. Both may independently develop in response to a common underlying mechanism.


Anti-allergic properties of Mangifera indica L. extract (Vimang) and contribution of its glucosylxanthone mangiferin.
Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract.


Electrospun PGS:PCL microfibers align human valvular interstitial cells and provide tunable scaffold anisotropy.
Tissue engineered heart valves (TEHV) can be useful in the repair of congenital or acquired valvular diseases due to their potential for growth and remodeling. The development of biomimetic scaffolds is a major challenge in heart valve tissue engineering. One of the most important structural characteristics of mature heart valve leaflets is their intrinsic anisotropy, which is derived from the microstructure of aligned collagen fibers in the extracellular matrix (ECM). In the present study, a directional electrospinning technique is used to fabricate fibrous poly(glycerol sebacate):poly(caprolactone) (PGS:PCL) scaffolds containing aligned fibers, which resemble native heart valve leaflet ECM networks. In addition, the anisotropic mechanical characteristics of fabricated scaffolds are tuned by changing the ratio of PGS:PCL to mimic the native heart valve's mechanical properties. Primary human valvular interstitial cells (VICs) attach and align along the anisotropic axes of all PGS:PCL scaffolds with various mechanical properties. The cells are also biochemically active in producing heart-valve-associated collagen, vimentin, and smooth muscle actin as determined by gene expression. The fibrous PGS:PCL scaffolds seeded with human VICs mimick the structure and mechanical properties of native valve leaflet tissues and would potentially be suitable for the replacement of heart valves in diverse patient populations.


Innovation in veterinary medical education: the concept of 'One World, One Health' in the curriculum of the Faculty of Veterinary Medicine at the University of Calgary.
'One World, One Health' is a foundation concept in veterinary medicine, much like comparative medicine. However, teachers of veterinary medicine often fail to identify it or speak of its importance within the veterinary curriculum. The resurgence of interest in the 'One World, One Health' concept aligns well with the underlying principles on which the University of Calgary Faculty of Veterinary Medicine (UCVM) has been newly founded. This concept is therefore a key component of the UCVM programme, and one that is well highlighted for those studying in the Doctor of Veterinary Medicine (DVM) course and graduate students.


Electrically tunable transmission-type beam deflector using liquid crystal with high angular resolution.
Highly efficient transmission-type beam deflectors that have high angular resolution have been widely used for various applications. Continuously tunable beam deflectors have also been needed for many purposes. An indium-tin-oxide (ITO), widely used for transparent electrodes, was placed on the upper and lower glass substrate. The ITO layer on the lower substrate was patterned by the contact mask aligner for relatively wide input and output pad compared to main grating ITO patterns in the active area. These input and output pads on the lower substrate are connected to each driving integrated circuit (IC), which has 360 channels for continuous control. A small pixel pitch of grating patterns of 6 μm (the electrode width is 3 μm with a 3 μm spacing) was developed, and the maximum diffraction angle is calculated and measured at 2.541° with a wavelength of 532 nm. A minimal cell gap of 2.5 μm was applied for the full 2π phase modulation by using a high-birefringence liquid crystal. A driving module for continuous beam steering is also developed and applied to the beam deflector system. A diffraction efficiency of about 50.9% is observed at an angle of diffraction about 2.541°.


A focused microarray to study human mitochondrial and nuclear gene expression.
A focused microarray (huMITOchip) was developed to study alterations of human mitochondrial and nuclear gene expression in health and disease. The huMITOchip contains 4,774 probe sets identical to the Affymetrix U 133 plus 2.0 chip covering genes affecting mitochondrial, lipid, cytokine, apoptosis, and muscle function transcripts. Unlike other gene chips, the huMITOchip has 51 probe sets that interrogate 37 genes of the mitochondrial genome. The human mitochondrial gene chip was validated against the Affymetrix U133 plus 2.0 array using an in vitro system of CCL136 muscle cell line stimulated with or without interferon gamma (IFN-gamma). The 37 genes from the mtDNA demonstrated absolute gene expression levels ranging from 0.1 to 3,182. The comparison of the two gene chips yielded an excellent Pearson's correlation coefficient (r = 0.98). At least 17 probe sets were differentially expressed in response to IFN-gamma on both chips, with a high degree of concordance. This is the first report on the development of a focused oligonucleotide microarray containing genes of the mitochondrial genome.


Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Incident Diabetes and Microvascular Disease.
Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations. We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up. A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, P interaction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N-ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment. Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs.


Electron microscopic studies on ovarian oocytes and unfertilized tubal ova in the rat.
Developing rat ova have been studied with the electron microscope. Special attention was paid to relations of ova to the granulosa cells, the developmental stages of ovarian follicles, and the cytology of the unfertilized tubal ova. The relationship of the oocyte to the surrounding granulosa cells was found to change from one of a simple apposition of the plasma membranes to a complex interdigitation of microvilli from the ovular surface and processes from the granulosa cells extending into the matrix of the zona pellucida. This complex interrelation is maintained until the formation of the first polar body is initiated. At this time no microvilli are found and the oolemma presents a gently undulating outline. Also at this time, a perivitelline space forms and the granulosa cell processes retract. In the unfertilized tubal ova no microvilli are present and the processes of the follicular cells are completely withdrawn. The cytoplasmic elements of the oocyte in various stages of development are described in some detail. Of particular interest is the change noted in position and degree of aggregation of the Golgi complex as maturation proceeds. The distribution and structural characteristics of the mitochondria, ergastoplasm, dense particles, and multivesicular bodies are described.


Current aspects of bacterial infections of the skin.
The practicing dermatologist is faced with an ever-changing epidemiologic spectrum of cutaneous bacterial diseases. Studies have stated that bacterial skin infections may account for up to 17% of clinical visits. It is hoped that the information presented in this article will enable the practicing dermatologist to provide improved patient care in the diagnosis and management of bacterial infections of the skin.


Factors affecting survival in pediatric cardiac tamponade caused by central venous catheters.
Pediatric central venous catheter (CVC) placement is useful but associated with complications such as cardiac tamponade. We aimed to identify risk factors for death in cardiac tamponade. Published articles on pediatric CVC-associated cardiac tamponade were obtained by searching PubMed and Google and retrospectively reviewed to analyze risk factors for death. Factors examined for their effect on mortality risk included patient age, weight, CVC size, days from CVC insertion to tamponade occurrence, substances administered, insertion site, treatment, CVC material, and initial CVC tip position. Of 110 patients reported in 62 articles, 69 survived and 41 died. Among survivors, 55 of 69 patients were treated; among deaths, only 7 of 38 (OR 537.9, 95% CI 29.3-9,877, p < 0.0001). Multiple regression analysis in 44 cases showed that treatment (p < 0.0001) and initial CVC tip position (p = 0.020) were independent predictive factors related to improved cardiac tamponade survival. Past studies have mainly discussed how to avoid pediatric cardiac tamponade; by contrast, the present study focused on how to avoid deaths. The findings of this review suggest that cardiac tamponade survival is better when tamponade is detected early and treated promptly and might be affected by initial CVC tip position.


Sepsis and endotoxaemia in mice stimulate the expression of interleukin-I and interleukin-6 in the central nervous system.
1. In previous studies, experimental endotoxaemia was found to stimulate cytokine production in the central nervous system. The effect of sepsis on brain cytokines is not fully known. We compared the effect of endotoxaemia and sepsis on brain interleukin-1 and interleukin-6 expression. 2. Male A/J mice were injected subcutaneously with lipopolysaccharide (10 mg/kg) or an equal volume of saline as control. Sepsis was induced by caecal ligation and puncture (CLP); control mice underwent sham-operation. Brain tissue was assayed for interleukin-1 and interleukin-6 by ELISA. Northern blotting or the polymerase chain reaction was used to determine cytokine mRNA levels. 3. Administration of endotoxin induced a greater than fourfold increase in brain interleukin-1, a greater than threefold increase in interleukin-6 and an increase in mRNA for both cytokines. Caecal ligation and puncture resulted in increased brain interleukin-1 and interleukin-6 levels, but the changes were less pronounced and occurred later than after injection of endotoxin. There was no detectable difference in brain interleukin-1 mRNA between septic and sham-operated mice, whereas interleukin-6 mRNA was increased in brains of septic animals. 4. Sepsis and endotoxaemia resulted in similar, although not identical, changes in brain interleukin-1 and interleukin-6 concentrations and mRNA levels, suggesting that increased cytokine production in the central nervous system is part of the systemic response to sepsis and may be mediated by endotoxin.


Antiplatelet and anticoagulation for patients with prosthetic heart valves.
Patients with prosthetic heart valves are at increased risk for valve thrombosis and arterial thromboembolism. Oral anticoagulation alone, or the addition of antiplatelet drugs, has been used to minimise this risk. An important issue is the effectiveness and safety of the latter strategy. This is an update of our previous review; the goal was to create a valid synthesis of all available, methodologically sound data to further assess the safety and efficacy of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulant monotherapy in patients with prosthetic heart valves. We updated the previous searches from 2003 and 2010 on 16 January 2013 and searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2012, Issue 12), MEDLINE (OVID, 1946 to January Week 1 2013), and EMBASE (OVID, 1980 to 2013 Week 02). We have also looked at reference lists of individual reports, review articles, meta-analyses, and consensus statements. We included reports published in any language or in abstract form. All reports of randomised controlled trials comparing standard-dose oral anticoagulation to standard-dose oral anticoagulation and antiplatelet therapy in patients with one or more prosthetic heart valves. Two review authors independently performed the search strategy, assessed trials for inclusion and study quality, and extracted data. We collected adverse effects information from the trials. One new study has been identified and included in this update. In total, 13 studies involving 4122 participants were included in this review update. Years of publication ranged from 1971 to 2011. Compared with anticoagulation alone, the addition of an antiplatelet agent reduced the risk of thromboembolic events (odds ratio (OR) 0.43, 95% confidence interval (CI) 0.32 to 0.59; P < 0.00001) and total mortality (OR 0.57, 95% CI 0.42 to 0.78; P = 0.0004). Aspirin and dipyridamole reduced these events similarly. The risk of major bleeding was increased when antiplatelet agents were added to oral anticoagulants (OR 1.58, 95% CI 1.14 to 2.18; P = 0.006).For major bleeding, there was no evidence of heterogeneity between aspirin and dipyridamole and in the comparison of trials performed before and after 1990, around the time when anticoagulation standardisation with the international normalised ratio was being implemented. A lower daily dose of aspirin (< 100 mg) may be associated with a lower major bleeding risk than higher doses. Adding antiplatelet therapy, either dipyridamole or low-dose aspirin, to oral anticoagulation decreases the risk of systemic embolism or death among patients with prosthetic heart valves. The risk of major bleeding is increased with antiplatelet therapy. These results apply to patients with mechanical prosthetic valves or those with biological valves and indicators of high risk such as atrial fibrillation or prior thromboembolic events. The effectiveness and safety of low-dose aspirin (100 mg daily) appears to be similar to higher-dose aspirin and dipyridamole. In general, the quality of the included trials tended to be low, possibly reflecting the era when the majority of the trials were conducted (1970s and 1980s when trial methodology was less advanced).


Nitric oxide improves transpulmonary vascular mechanics but does not change intrinsic right ventricular contractility in an acute respiratory distress syndrome model with permissive hypercapnia.
To test the hypothesis that in a swine model of acute respiratory distress syndrome (ARDS) with permissive hypercapnia, inhaled nitric oxide would improve transpulmonary vascular mechanics and right ventricular workload while not changing intrinsic right ventricular contractility. Prospective, randomized, controlled laboratory trial. University research laboratory. Eleven swine (30 to 46 kg). The swine were anesthetized, intubated, and paralyzed. After median sternotomy, pressure transducers were placed in the right ventricle, pulmonary artery, and left atrium. An ultrasonic flow probe was placed around the pulmonary artery. Ultrasonic dimension transducers were sutured onto the heart at the base, apex, left ventricle (anterior, posterior, free wall), and right ventricle (free wall). An additional transducer was placed in the interventricular septum. A surfactant depletion model of ARDS was created by saline lung lavage. Nitric oxide was administered at 2, 4, and 6 parts per million (ppm), in a random order, under the condition of permissive hypercapnia (Paco2 55 to 75 torr [7.3 to 10.0 kPa]). We evaluated the pulmonary vascular and right ventricular effects of permissive hypercapnia, with and without inhaled nitric oxide, by measuring variables of transpulmonary vascular mechanics and right ventricular function. These variables included mean pulmonary arterial pressure, right ventricular total power, right ventricular stroke work, transpulmonary vascular efficiency, and right ventricular intrinsic contractility. Data were obtained after lung injury under the following conditions: a) normocapnia (Paco2 35 to 45 torr [4.7 to 6.0 kPa]) and nitric oxide at 0 ppm; b) hypercapnia and nitric oxide at 0 ppm; c) hypercapnia and nitric oxide at 2, 4, and 6 ppm; and d) repeat measurements with hypercapnia and nitric oxide at 0 ppm. In ARDS with permissive hypercapnia, inhaled nitric oxide therapy (2 to 6 ppm) improved transpulmonary vascular mechanics and right ventricular workload by lowering pulmonary arterial pressure (29.6 +/- 1.3 vs. 24.6 +/- 1.0 mm Hg, p = .0001), increasing transpulmonary vascular efficiency (13.9 +/- 0.5 vs. 16.1 +/- 0.7 L/W-min, p = .0001), decreasing right ventricular total power (142 +/- 9 vs. 115 +/- 9 mW, p = .001), and decreasing right ventricular stroke work (653 +/- 37 vs. 525 +/- 32 ergs x 10(3), p = .001). Inhaled nitric oxide did not change right ventricular contractility, as measured by preload-recruitable stroke work. Inhaled nitric oxide ameliorated any negative effects of hypoxic and hypercapnic pulmonary vasoconstriction. The beneficial effects of inhaled nitric oxide are related to alterations in right ventricular afterload and not intrinsic right ventricular contractility. The improved cardiopulmonary effects of inhaled nitric oxide with permissive hypercapnia potentially expand the use of nitric oxide in ARDS and other conditions in which this strategy is employed.


NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat.
Free radicals have gained wide acceptance as mediators of cerebral ischemic injury. It has previously been reported that a spin trap nitrone, alpha-phenyl-N-tert-butyl nitrone (PBN), can reduce infarct volumes in rats subjected to either permanent or transient focal cerebral ischemia. A recent study has demonstrated that NXY-059, a novel free radical trapping nitrone compound, has a neuroprotective effect against transient focal cerebral ischemia. This study was designed to determine the effect of NXY-059 in a rodent model of permanent focal cerebral ischemia. Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion (MCAO) by placement of a microaneurysm clip on the middle cerebral artery (MCA). Animals were divided into three groups: (1) physiological saline given as a 1 ml/kg i.v. bolus administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 0.5 ml/h of physiological saline for 24 h (n=10); (2) 30 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 30 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=9); (3) 60 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 60 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=12). Infarction was quantified after a survival period of 24 h. Differences in infarct volume were examined with one-way ANOVA following Dunnet's multiple comparison test. The percentage of cortical infarction in the saline control group was 22.6 +/- 6.8% (mean+/-S.D.) of contra-lateral hemisphere, and in the 30 mg/kg/h NXY-059-treated group was 17.4% +/- 6.8% (NS). Plasma concentration (microM/l) of NXY-059 in the 30 mg/kg/h group was 80.2 +/- 52.2 (n=9), while in the 60 mg/kg/h group plasma concentration (microM/l) of NXY-059 was 391.0 +/- 207.0 (n=10). Infarction in the 60 mg/kg/h NXY-059-treated group was significantly reduced (P=0.009) to 14.5 +/- 5%. Our preliminary data demonstrate that administration of NXY-059 (60 mg/kg/h for 24 h) ameliorates cortical infarction in rats subjected to permanent focal cerebral ischemia with 24 h survival.


Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl-10-deazaaminopterin (10-EDAM) against human lung cancer cell lines.
10-ethyl-10-deazaaminopterin (10-EDAM) is a rationally designed derivative of the antifolate, methotrexate (MTX). In a number of tumor models these design features have resulted in an improved spectrum of antiproliferative activity as compared with the parent compound. Using an MTT growth assay, we compared in vitro antiproliferative activity of 10-EDAM with MTX in eight lung cancer cell lines. Growth was inhibited in all lines tested by clinically achievable concentrations of 10-EDAM (0.1-1,000 nM). 10-EDAM was more cytotoxic than MTX at the same concentrations in all eight lung cancer cell lines. In an effort to enhance the antiproliferative effect, we evaluated the addition of dipyridamole (DPM), an inhibitor of nucleoside transport, to 10-EDAM (0.1-10 microns). DPM decreased the concentration of 10-EDAM required to cause 50% growth inhibition (IC50) in all eight cell lines tested. This suppression was statistically significant by 2-sided sign test (P = .0078). By contrast, the IC50 of MTX was decreased in only two of the eight cell lines when DPM was added (0.1-10 microM). In defined thymidine depleted media, cell kill by the combination of 10-EDAM and DPM was no greater than 10-EDAM alone, consistent with the possibility that DPM exerts some of its effect by inhibition of extrinsic nucleoside salvage. In consideration of the published activity of 10-EDAM in lung cancer and the modest clinical toxicity of DPM based biochemical modulation, we conclude the current in vitro data provide justification for clinical evaluation of this combination in patients with lung cancer.


Organophosphate flame retardants and bisphenol A in children's urine in Hong Kong: has the burden been underestimated?
The urine levels of organophosphate flame retardants (PFRs) and bisphenol A (BPA) in kindergarten children (n = 31, 4-6 years old, sampling performed in 2016) in Hong Kong were measured. The detection frequency of the target PFRs, tri(2-chloroethyl)phosphate (TCEP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(chloroisopropyl)phosphate (TCIPP), triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) ranged from 52% to 84%. The 95th percentile urinary concentrations of TPHP, TDCIPP, TCIPP, EHDPP and TCEP were 1.70, 0.24, 0.03, 0.05, 0.68 and 0.03 ng/mL, respectively. The median urine level of BPA was 1.69 ng/mL, with a detection frequency of 77%. Due to the lack of metabolism information, two scenarios were used to calculate the estimated daily intake (EDI) of these compounds. Back-calculated EDIs of PFRs using the urinary excretion rates from in vivo animal data (scenario 2) were up to 2.97 μg/kg/d (TDCIPP), which was only a little less than that observed in a sample of American infants, and the reference dose (RfD), meaning that the potential health risk of TDCIPP cannot be ignored. Dust ingestion was suggested to be the major pathway of exposure to PFRs, but when the levels in dust and air particles in kindergartens in Hong Kong were used to predict EDIs, these values were nearly half as much as those predicted from urinary TDCIPP in this study. This suggested that children's PFRs burden may be underestimated when considering only PFR levels in dust or air. There is thus a need for further studies with large-scale surveys and investigation of exposure routes.


Lithium Storage Properties of a Bioinspired 2-Line Ferrihydrite: A Silicon-Doped, Nanometric, and Amorphous Iron Oxyhydroxide.
Inspired by a nanometric iron-based oxide material of bacterial origin, silicon (Si)-doped iron oxyhydroxide nanoparticles or 2-line ferrihydrites (2Fhs) were prepared and their lithium (Li) storage properties were investigated. The structures of the Si-doped 2Fhs strongly depended on the Si molar ratio [x = Si/(Fe + Si)] whose long-range atomic ordering gradually vanished as the Si molar ratio increased, with a structural change from nanocrystalline to amorphous at x = 0.30. The most striking properties were observed for the sample with x = 0.30. Over the voltage range of 1.5-4.0 V at a current rate of 500 mA/g, this material exhibited a relatively high reversible capacity of ∼100 mAh/g, which was four times greater than that of the Si-free 2Fh and indicated a good rate capability and cyclability. The large capacity and good rate and cycle performances are presumably because of the amorphous structure and the strong and stabilizing covalent Si-O bonds, respectively. The minor amount of Si(4+) in the structure of the iron oxyhydroxides is considered to improve the electrochemical properties. Use of more appropriate doping elements and fabrication of more appropriate nanostructures could drastically improve the Li storage properties of the developed bioinspired material.


Primate granulosa cell response via prostaglandin E2 receptors increases late in the periovulatory interval.
Successful ovulation requires elevated follicular prostaglandin E2 (PGE2) levels. To determine which PGE2 receptors are available to mediate periovulatory events in follicles, granulosa cells and whole ovaries were collected from monkeys before (0 h) and after administration of an ovulatory dose of hCG to span the 40-h periovulatory interval. All PGE2 receptor mRNAs were present in monkey granulosa cells. As assessed by immunofluorescence, PTGER1 (EP1) protein was low/nondetectable in granulosa cells 0, 12, and 24 h after hCG but was abundant 36 h after hCG administration. PTGER2 (EP2) and PTGER3 (EP3) proteins were detected by immunofluorescence in granulosa cells throughout the periovulatory interval, and Western blotting showed an increase in PTGER2 and PTGER3 levels between 0 h and 36 h after hCG. In contrast, PTGER4 (EP4) protein was not detected in monkey granulosa cells. Granulosa cell response to PGE2 receptor agonists was examined 24 h and 36 h after hCG administration, when elevated PGE2 levels present in periovulatory follicles initiate ovulatory events. PGE2 acts via PTGER1 to increase intracellular calcium. PGE2 increased intracellular calcium in granulosa cells obtained 36 h, but not 24 h, after hCG; this effect of PGE2 was blocked by a PTGER1 antagonist. A PTGER2-specific agonist and a PTGER3-specific agonist each elevated cAMP in granulosa cells obtained 36 h, but not 24 h, after hCG. Therefore, the granulosa cells of primate periovulatory follicles express multiple receptors for PGE2. Granulosa cells respond to agonist stimulation of each of these receptors 36 h, but not 24 h, after hCG, supporting the hypothesis that granulosa cells are most sensitive to PGE2 as follicular PGE2 levels peak, leading to maximal PGE2-mediated periovulatory effects just before ovulation.


Biomechanical behaviour of human bile duct wall and impact of cadaveric preservation processes.
Biliary diseases are the third most common cause of surgical digestive disease. There is a close relationship between the mechanical performance of the bile duct and its physiological function. Data of biomechanical properties of human main bile duct are scarce in literature. Furthermore, mechanical properties of soft tissues are affected by these preservation procedures. The aim of the present work was, on the one hand, to observe the microstructure of the human bile duct by means of histological analysis, on the other hand, to characterize the mechanical behavior and describe the impact of different preservation processes. A mechanical study in a controlled environment consisting of cyclic tests was made. The results of the mechanical tests are discussed and explained using the micro-structural observations. The results show an influence of the loading direction, which is representative of an anisotropic behavior. A strong hysteresis due to the viscoelastic properties of soft tissues was also observed. Embalming and freezing preservation methods had an impact on the biomechanical properties of human main bile duct, with fiber network deterioration. That may further provide a useful quantitative baseline for anatomical and surgical training using embalming and freezing.


Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function.
Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function.


Cold-inducible RNA-binding protein is an important mediator of alcohol-induced brain inflammation.
Binge drinking has been associated with cerebral dysfunction. Ethanol induced microglial activation initiates an inflammatory process that causes upregulation of proinflammatory cytokines which in turn creates neuronal inflammation and damage. However, the molecular mechanism is not fully understood. We postulate that cold-inducible RNA-binding protein (CIRP), a novel proinflammatory molecule, can contribute to alcohol-induced neuroinflammation. To test this theory male wild-type (WT) mice were exposed to alcohol at concentrations consistent to binge drinking and blood and brain tissues were collected. At 5 h after alcohol, a significant increase of 53% in the brain of CIRP mRNA was observed and its expression remained elevated at 10 h and 15 h. Brain CIRP protein levels were increased by 184% at 10 h and remained high at 15 h. We then exposed male WT and CIRP knockout (CIRP(-/-)) mice to alcohol, and blood and brain tissues were collected at 15 h post-alcohol infusion. Serum levels of tissue injury markers (AST, ALT and LDH) were significantly elevated in alcohol-exposed WT mice while they were less increased in the CIRP(-/-) mice. Brain TNF-α mRNA and protein expressions along with IL-1β protein levels were significantly increased in WT mice, which was not seen in the CIRP(-/-) mice. In cultured BV2 cells (mouse microglia), ethanol at 100 mM showed an increase of CIRP mRNA by 274% and 408% at 24 h and 48 h respectively. Corresponding increases in TNF-α and IL-1β were also observed. CIRP protein levels were markedly increased in the medium, suggesting that CIRP was secreted by the BV2 cells. From this we conclude that alcohol exposure activates microglia to produce and secrete CIRP and possibly induce pro-inflammatory response and thereby causing neuroinflammation. CIRP could be a novel mediator of alcohol-induced brain inflammation.


Evidence, Quality, and Waste: Solving the Value Equation in Neonatology.
Rising health care costs challenge governments, payers, and providers in delivering health care services. Tremendous pressures result to deliver better quality care while simultaneously reducing costs. This has led to a wholesale re-examination of current practice methods, including explicit consideration of efficiency and waste. Traditionally, reductions in the costs of care have been considered as independent, and sometimes even antithetical, to the practice of high-quality, intensive medicine. However, it is evident that provision of evidence-based, locally relevant care can result in improved outcomes, lower resource utilization, and opportunities to reallocate resources. This is particularly relevant to the practice of neonatology. In the United States, 12% of the annual birth cohort is affected by preterm birth, and 3% is affected by congenital anomalies. Both of these conditions are associated with costly health care during, and often long after, the NICU admission. We will discuss how 3 drivers of clinical practice in neonatal care (evidence-based medicine, evidence-based economics, and quality improvement) can together optimize clinical and fiscal outcomes.


Initial antifungal strategy does not correlate with mortality in patients with candidemia.
The incidence of Candida bloodstream infections (BSIs) has increased over time, especially in medical wards. The objective of this study was to evaluate the impact of different antifungal treatment strategies on 30-day mortality in patients with Candida BSI not admitted to intensive care units (ICUs) at disease onset. This prospective, monocentric, cohort study was conducted at an 1100-bed university hospital in Rome, Italy, where an infectious disease consultation team was implemented. All cases of Candida BSIs observed in adult patients from November 2012 to April 2014 were included. Patients were grouped according to the initial antifungal strategy: fluconazole, echinocandin, or liposomal amphotericin B. Cox regression analysis was used to identify risk factors significantly associated with 15-day and 30-day mortality. During the study period, 130 patients with candidemia were observed (58 % with C. albicans, 7 % with C. glabrata, and 23 % with C. parapsilosis). The first antifungal drug was fluconazole for 40 % of patients, echinocandin for 57.0 %, and liposomal amphotericin B for 4 %. During follow-up, 33 % of patients died. The cumulative mortality 30 days after the candidemia episode was 30.8 % and was similar among groups. In the Cox regression analysis, clinical presentation was the only independent factor associated with 15-day mortality, and Acute Physiology and Chronic Health Evaluation (APACHE) II score and clinical presentation were the independent factors associated with 30-day mortality. No differences in 15-day and 30-day mortality were observed between patients with and without C. albicans candidemia. In patients with candidemia admitted to medical or surgical wards, clinical severity but not the initial antifungal strategy were significantly correlated with mortality.


Culture enriched molecular profiling of the cystic fibrosis airway microbiome.
The microbiome of the respiratory tract, including the nasopharyngeal and oropharyngeal microbiota, is a dynamic community of microorganisms that is highly diverse. The cystic fibrosis (CF) airway microbiome refers to the polymicrobial communities present in the lower airways of CF patients. It is comprised of chronic opportunistic pathogens (such as Pseudomonas aeruginosa) and a variety of organisms derived mostly from the normal microbiota of the upper respiratory tract. The complexity of these communities has been inferred primarily from culture independent molecular profiling. As with most microbial communities it is generally assumed that most of the organisms present are not readily cultured. Our culture collection generated using more extensive cultivation approaches, reveals a more complex microbial community than that obtained by conventional CF culture methods. To directly evaluate the cultivability of the airway microbiome, we examined six samples in depth using culture-enriched molecular profiling which combines culture-based methods with the molecular profiling methods of terminal restriction fragment length polymorphisms and 16S rRNA gene sequencing. We demonstrate that combining culture-dependent and culture-independent approaches enhances the sensitivity of either approach alone. Our techniques were able to cultivate 43 of the 48 families detected by deep sequencing; the five families recovered solely by culture-independent approaches were all present at very low abundance (<0.002% total reads). 46% of the molecular signatures detected by culture from the six patients were only identified in an anaerobic environment, suggesting that a large proportion of the cultured airway community is composed of obligate anaerobes. Most significantly, using 20 growth conditions per specimen, half of which included anaerobic cultivation and extended incubation times we demonstrate that the majority of bacteria present can be cultured.


Transforming representations of movement from body- to world-centric space.
When an animal moves through the world, its brain receives a stream of information about the body's translational velocity from motor commands and sensory feedback signals. These incoming signals are referenced to the body, but ultimately, they must be transformed into world-centric coordinates for navigation1,2. Here we show that this computation occurs in the fan-shaped body in the brain of Drosophila melanogaster. We identify two cell types, PFNd and PFNv3-5, that conjunctively encode translational velocity and heading as a fly walks. In these cells, velocity signals are acquired from locomotor brain regions6 and are multiplied with heading signals from the compass system. PFNd neurons prefer forward-ipsilateral movement, whereas PFNv neurons prefer backward-contralateral movement, and perturbing PFNd neurons disrupts idiothetic path integration in walking flies7. Downstream, PFNd and PFNv neurons converge onto hΔB neurons, with a connectivity pattern that pools together heading and translation direction combinations corresponding to the same movement in world-centric space. This network motif effectively performs a rotation of the brain's representation of body-centric translational velocity according to the current heading direction. Consistent with our predictions, we observe that hΔB neurons form a representation of translational velocity in world-centric coordinates. By integrating this representation over time, it should be possible for the brain to form a working memory of the path travelled through the environment8-10.


Quantitative Photo-crosslinking Mass Spectrometry Revealing Protein Structure Response to Environmental Changes.
Protein structures respond to changes in their chemical and physical environment. However, studying such conformational changes is notoriously difficult, as many structural biology techniques are also affected by these parameters. Here, the use of photo-crosslinking, coupled with quantitative crosslinking mass spectrometry (QCLMS), offers an opportunity, since the reactivity of photo-crosslinkers is unaffected by changes in environmental parameters. In this study, we introduce a workflow combining photo-crosslinking using sulfosuccinimidyl 4,4'-azipentanoate (sulfo-SDA) with our recently developed data-independent acquisition (DIA)-QCLMS. This novel photo-DIA-QCLMS approach is then used to quantify pH-dependent conformational changes in human serum albumin (HSA) and cytochrome C by monitoring crosslink abundances as a function of pH. Both proteins show pH-dependent conformational changes resulting in acidic and alkaline transitions. 93% and 95% of unique residue pairs (URP) were quantifiable across triplicates for HSA and cytochrome C, respectively. Abundance changes of URPs and hence conformational changes of both proteins were visualized using hierarchical clustering. For HSA we distinguished the N-F and the N-B form from the native conformation. In addition, we observed for cytochrome C acidic and basic conformations. In conclusion, our photo-DIA-QCLMS approach distinguished pH-dependent conformers of both proteins.


Chemical synthesis and characterization of epicatechin glucuronides and sulfates: bioanalytical standards for epicatechin metabolite identification.
The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4'-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans.


Emergency department presentation and management of pediatric heart transplant recipients.
The object of this study was to review and delineate the presenting complaints, signs, symptoms, and Emergency Department (ED) management of pediatric heart transplant recipients who presented to Loma Linda University Medical Center's (LLUMC) Emergency Department. A retrospective chart review was made of all of the pediatric heart transplant patients who presented to the ED at LLUMC from January 1986 through February 1993. The department is part of a 600-bed university hospital with an associated 250-bed children's hospital that includes a pediatric heart transplant center and an ED that sees over 38,000 patients per year. The retrospective review collected information relating to chief complaint, physical findings, laboratory analysis, and diagnoses. Forty-seven patients (23%) presented to the ED for a total of 76 visits. The patients presented a median of 278 days (range 19 days to 6.5 years) after transplantation. The most common chief complaints were related to the respiratory tract, and the most common diagnoses (55%) were related to infectious processes. Fever was present in 21% of the visits. Three of 13 blood cultures obtained were positive. Cardiac symptoms were present in 14% of the visits with two rejection episodes. Hospital admission was required for 22 (29%) of the ED visits. Results showed that pediatric heart transplant recipients are most likely to present to the ED with infections. Although infections from opportunistic organisms and bacteremia must be considered, most infections are similar to those in the nontransplanted child. Life-threatening conditions such as graft rejection are less likely. Nevertheless, the emergency physician should maintain caution in the evaluation of these patients. Close cooperation and consultation with the transplant team will assure the optimal outcome for these patients.


Alternate day fasting for weight loss in normal weight and overweight subjects: a randomized controlled trial.
Alternate day fasting (ADF; ad libitum "feed day", alternated with 25% energy intake "fast day"), is effective for weight loss and cardio-protection in obese individuals. Whether these effects occur in normal weight and overweight individuals remains unknown. This study examined the effect of ADF on body weight and coronary heart disease risk in non-obese subjects. Thirty-two subjects (BMI 20-29.9 kg/m2) were randomized to either an ADF group or a control group for 12 weeks. Body weight decreased (P < 0.001) by 5.2 ± 0.9 kg (6.5 ± 1.0%) in the ADF group, relative to the control group, by week 12. Fat mass was reduced (P < 0.001) by 3.6 ± 0.7 kg, and fat free mass did not change, versus controls. Triacylglycerol concentrations decreased (20 ± 8%, P < 0.05) and LDL particle size increased (4 ± 1 Å, P < 0.01) in the ADF group relative to controls. CRP decreased (13 ± 17%, P < 0.05) in the ADF group relative to controls at week 12. Plasma adiponectin increased (6 ± 10%, P < 0.01) while leptin decreased (40 ± 7%, P < 0.05) in the ADF group versus controls by the end of the study. LDL cholesterol, HDL cholesterol, homocysteine and resistin concentrations remained unchanged after 12 weeks of treatment. These findings suggest that ADF is effective for weight loss and cardio-protection in normal weight and overweight adults, though further research implementing larger sample sizes is required before solid conclusion can be reached.


Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor.
We examined the interfaces of homodimeric triosephosphate isomerase (TIM) from eight different species. The crystal structures of the enzymes showed that a portion of the interface is markedly similar in TIMs from Trypanosoma cruzi (TcTIM), Trypanosoma brucei, and Leishmania mexicana and significantly different from that of TIMs from human, yeast, chicken, Plasmodium falciparum, and Entamoeba histolytica. Since this interfacial region is central in the stability of TcTIM, we hypothesized that it would be possible to find agents that selectively affect the stability of TIMs from the three trypanosomatids. We found that 6,6'-bisbenzothiazole-2,2' diamine in the low micromolar range causes a desirable irreversible inactivation of the enzymes from the three trypanosomatids and has no effect on the other five TIMs. Thus, the data indicate that it is possible to find compounds that induce selective inactivation of the enzymes from three different trypanosomatids.


MCC-134, a single pharmacophore, opens surface ATP-sensitive potassium channels, blocks mitochondrial ATP-sensitive potassium channels, and suppresses preconditioning.
MCC-134 (1-[4-(H-imidazol-1-yl)benzoyl]-N-methylcyclobutane-carbothioamide), a newly developed analog of aprikalim, opens surface smooth muscle-type ATP-sensitive potassium (K(ATP)) channels but inhibits pancreatic K(ATP) channels. However, the effects of MCC-134 on cardiac surface K(ATP) channels and mitochondrial K(ATP) (mitoK(ATP)) channels are unknown. A mixed agonist/blocker with differential effects on the two channel types would help to clarify the role of K(ATP) channels in cardioprotection. To index mitoK(ATP) channels, we measured mitochondrial flavoprotein fluorescence in rabbit ventricular myocytes. MCC-134 alone had little effect on basal flavoprotein fluorescence. However, MCC-134 inhibited diazoxide-induced flavoprotein oxidation in a dose-dependent manner (EC(50)=27 micro mol/L). When ATP was included in the pipette solution, MCC-134 slowly activated surface K(ATP) currents with some delay (>10 minutes). These results indicate that MCC-134 is a mitoK(ATP) channel inhibitor and a surface K(ATP) channel opener in native cardiac cells. In cell-pelleting ischemia assays, coapplication of MCC-134 with diazoxide abolished the cardioprotective effect of diazoxide, whereas MCC-134 alone did not alter cell death. These results were reproducible in both rabbit and mouse myocytes. MCC-134 also attenuated the effect of ischemic preconditioning against myocardial infarction in mice, consistent with the results of cell-pelleting ischemia assays. A single drug, MCC-134, opens surface K(ATP) channels but blocks mitoK(ATP) channels; the fact that this drug inhibits preconditioning reaffirms the primacy of mitoK(ATP) rather than surface K(ATP), channels in the mechanism of cardioprotection.


Selective Removal of Natural Occlusal Caries by Coupling Near-infrared Imaging with a CO(2) Laser.
Laser removal of dental hard tissue can be combined with optical, spectral or acoustic feedback systems to selectively ablate dental caries and restorative materials. Near-infrared (NIR) imaging has considerable potential for the optical discrimination of sound and demineralized tissue. Last year we successfully demonstrated that near-IR images can be used to guide a CO(2) laser ablation system for the selective removal of artificial caries lesions on smooth surfaces. The objective of this study was to test the hypothesis that two-dimensional near-infrared images of natural occlusal caries can be used to guide a CO(2) laser for selective removal. Two-dimensional NIR images were acquired at 1310-nm of extracted human molar teeth with occlusal caries. Polarization sensitive optical coherence tomography (PS-OCT) was also used to acquire depth-resolved images of the lesion areas. An imaging processing module was developed to analyze the NIR imaging output and generate optical maps that were used to guide a CO(2) laser to selectively remove the lesions at a uniform depth. Post-ablation NIR images were acquired to verify caries removal. Based on the analysis of the NIR images, caries lesions were selectively removed with a CO(2) laser while sound tissues were conserved. However, the removal rate varied markedly with the severity of decay and multiple passes were required for caries removal. These initial results are promising but indicate that the selective removal of natural caries is more challenging than the selective removal of artificial lesions due to varying tooth geometry, the highly variable organic/mineral ratio in natural lesions and more complicated lesion structure.


Disentangling collective motion and local rearrangements in 2D and 3D cell assemblies.
The accurate quantification of cellular motility and of the structural changes occurring in multicellular aggregates is critical in describing and understanding key biological processes, such as wound repair, embryogenesis and cancer invasion. Current methods based on cell tracking or velocimetry either suffer from limited spatial resolution or are challenging and time-consuming, especially for three-dimensional (3D) cell assemblies. Here we propose a conceptually simple, robust and tracking-free approach for the quantification of the dynamical activity of cells via a two-step procedure. We first characterise the global features of the collective cell migration by registering the temporal stack of the acquired images. As a second step, a map of the local cell motility is obtained by performing a mean squared amplitude analysis of the intensity fluctuations occurring when two registered image frames acquired at different times are subtracted. We successfully apply our approach to cell monolayers undergoing a jamming transition, as well as to monolayers and 3D aggregates that exhibit a cooperative unjamming-via-flocking transition. Our approach is capable of disentangling very efficiently and of assessing accurately the global and local contributions to cell motility.


Science-based and practice-based innovativeness and performance of substance abuse treatment facilities.
The fields of mental health and substance abuse treatment lag significantly behind other health care organizational fields in the adoption, implementation, and dissemination of evidence-based practices. Innovative organizational practices may be science based or practice based. The implementation of innovative practices requires considerable organizational resources. Whether this organizational investment actually pays off in terms of superior performance is unclear. This issue in the context of substance abuse treatment facilities (SATFs) in the United States is examined in this study. The purpose of this study is to examine the influence of the use of innovative organizational practices, both science based (psychosocial interventions) and practice based, on the organizational performance of SATFs. The study uses cross-sectional data on 13,513 SATFs in the United States, obtained from the National Survey of Substance Abuse Treatment Services 2009 database. Multinomial logistic regression models find a positive association between the use of science-based innovations and practice-based innovations and organizational performance, that is, the provision of comprehensive (core and wraparound) services. SATFs that were located in metropolitan areas, those accredited by the Commission on Accreditation of Rehabilitation Facilities and Joint Commission, that had a mixed (Substance Abuse and Mental Health) focus or were recipients of earmark funds also had higher organizational performance. The results signify that substance abuse facilities that are high innovators in terms of implementing science based and practice-based innovative practices have higher organizational performance. Organizations that have institutionalized these practices have invested considerable resources in innovation. The shown higher organizational performance provides justification for the organizational investment in innovation.


Synthesis of Cu₂O nanospheres decorated with TiO₂ nanoislands, their enhanced photoactivity and stability under visible light illumination, and their post-illumination catalytic memory.
A novel Cu2O/TiO2 composite photocatalyst structure of Cu2O nanospheres decorated with TiO2 nanoislands were synthesized by a facile hydrolyzation reaction followed by a solvent-thermal process. In this Cu2O/TiO2 composite photocatalyst, Cu2O served as the main visible light absorber, while TiO2 nanoislands formed heterojunctions of good contact with Cu2O, beneficial to the photoexcited electron transfer between them. Their band structure match and inner electrostatic field from the p-n heterojunction both favored the transfer of photoexcited electrons from Cu2O to TiO2, which effectively separated the electron-hole pairs. Photogenerated holes on Cu2O could react with water or organic pollutants/microorganisms in water to avoid accumulation on Cu2O because of the partial TiO2 nanoislands coverage, which enhanced their stability during the photocatalysis process. Their superior photocatalytic performance under visible light illumination was demonstrated in both the degradation of methyl orange and the disinfection of Escherichia coli bacteria. An interesting post-illumination catalytic memory was also observed for this composite photocatalyst as demonstrated in the disinfection of Escherichia coli bacteria in the dark after the visible light was shut off, which could be attributed to the transfer of photoexcited electrons from Cu2O to TiO2 and their trapping on TiO2 under visible light illumination, and their release in the dark after the visible light was shut off.


Interaction of porcine uterine fluid purple acid phosphatase with vanadate and vanadyl cation.
Uteroferrin, the purple acid phosphatase from porcine uterine fluid, is noncompetitively inhibited by vanadate in a time-dependent manner under both aerobic and anaerobic conditions. This time-dependent inhibition is observed only with the diiron enzyme and is absent when the FeZn enzyme is used. The observations are attributed to the sequential formation of two uteroferrin-vanadium complexes. The first complex forms rapidly and reversibly, while the second complex forms slowly and results in the production of catalytically inactive oxidized uteroferrin and V(IV), which is observed by EPR. The redox reaction can be reversed by treatment of the oxidized enzyme first with (V(IV)) and then EDTA to generate a catalytically active uteroferrin. Multiple inhibition kinetics suggests that vanadate is mutually exclusive with molybdate, tungstate, and vanadyl cation. The binding site for each of these anions is distinct from the site to which the competitive inhibitors phosphate and arsenate bind. The time-dependent inhibition by vanadate of uteroferrin containing the diiron core represents a new type of mechanism by which vanadium can interact with proteins and gives additional insight into the binding of anions to uteroferrin.


Cell-Free Expression of Sodium Channel Domains for Pharmacology Studies. Noncanonical Spider Toxin Binding Site in the Second Voltage-Sensing Domain of Human Nav1.4 Channel.
Voltage-gated sodium (NaV) channels are essential for the normal functioning of cardiovascular, muscular, and nervous systems. These channels have modular organization; the central pore domain allows current flow and provides ion selectivity, whereas four peripherally located voltage-sensing domains (VSDs-I/IV) are needed for voltage-dependent gating. Mutations in the S4 voltage-sensing segments of VSDs in the skeletal muscle channel NaV1.4 trigger leak (gating pore) currents and cause hypokalemic and normokalemic periodic paralyses. Previously, we have shown that the gating modifier toxin Hm-3 from the crab spider Heriaeus melloteei binds to the S3-S4 extracellular loop in VSD-I of NaV1.4 channel and inhibits gating pore currents through the channel with mutations in VSD-I. Here, we report that Hm-3 also inhibits gating pore currents through the same channel with the R675G mutation in VSD-II. To investigate the molecular basis of Hm-3 interaction with VSD-II, we produced the corresponding 554-696 fragment of NaV1.4 in a continuous exchange cell-free expression system based on the Escherichia coli S30 extract. We then performed a combined nuclear magnetic resonance (NMR) and electron paramagnetic resonance spectroscopy study of isolated VSD-II in zwitterionic dodecylphosphocholine/lauryldimethylamine-N-oxide or dodecylphosphocholine micelles. To speed up the assignment of backbone resonances, five selectively 13C,15N-labeled VSD-II samples were produced in accordance with specially calculated combinatorial scheme. This labeling approach provides assignment for ∼50% of the backbone. Obtained NMR and electron paramagnetic resonance data revealed correct secondary structure, quasi-native VSD-II fold, and enhanced ps-ns timescale dynamics in the micelle-solubilized domain. We modeled the structure of the VSD-II/Hm-3 complex by protein-protein docking involving binding surfaces mapped by NMR. Hm-3 binds to VSDs I and II using different modes. In VSD-II, the protruding ß-hairpin of Hm-3 interacts with the S1-S2 extracellular loop, and the complex is stabilized by ionic interactions between the positively charged toxin residue K24 and the negatively charged channel residues E604 or D607. We suggest that Hm-3 binding to these charged groups inhibits voltage sensor transition to the activated state and blocks the depolarization-activated gating pore currents. Our results indicate that spider toxins represent a useful hit for periodic paralyses therapy development and may have multiple structurally different binding sites within one NaV molecule.


Physician-assisted death in psychiatric practice in the Netherlands.
In 1994 the Dutch Supreme Court ruled that in exceptional instances, physician-assisted suicide might be justifiable for patients with unbearable mental suffering but no physical illness. We studied physician-assisted suicide and euthanasia in psychiatric practice in the Netherlands. In 1996, we sent questionnaires to 673 Dutch psychiatrists - about half of all such specialists in the country - and received 552 responses from the 667 who met the study criteria (response rate, 83 percent). We estimated the annual frequencies of requests for physician-assisted suicide by psychiatrists and actual instances of assistance. Of the respondents, 205 (37 percent) had at least once received an explicit, persistent request for physician-assisted suicide and 12 had complied. We estimate there are 320 requests a year in psychiatric practice and 2 to 5 assisted suicides. Excluding those who had ever assisted, 345 of the respondents (64 percent) thought physician-assisted suicide because of a mental disorder could be acceptable, including 241 who said they could conceive of instances in which they themselves would be willing to assist. The most frequent reasons for refusing were the belief that the patient had a treatable mental disorder, opposition to assisted suicide in principle, and doubt that the suffering was unbearable or hopeless. Most, but not all, patients who had been assisted by their psychiatrists in suicide had both a mental disorder and a serious physical illness, often in a terminal phase. Thirty percent of the respondents had been consulted at least once by a physician in another specialty about a patient's request for assisted death. The annual number of such consultations was estimated at 310, about 3 percent of the estimated 9700 requests for euthanasia or physician-assisted suicide in medical practice. Explicit requests for physician-assisted suicide are not uncommon in psychiatric practice in the Netherlands, but these requests are rarely granted. Psychiatric consultation for medical patients who request physician-assisted death is relatively rare.


Reversibility of baroreceptor hyposensitivity during reversal of hypertension.
The extent and characteristics of reversal of baroreceptor resetting after pressure normalization were studied in rats with renal hypertension of 2 months' duration. During the control period, the displacement of the entire baroreceptor function curve was accompanied by a decrease slope, indicating that the gain sensitivity was depressed by 36% in the renal hypertensive rats. In response to changes of +10 and -10 mm Hg in the control pressure, the gain sensitivity was attenuated by 56% and 42%, respectively. Two minutes after unclipping and bleeding when necessary, mean arterial pressure decreased from 171 +/- 11 to 134 +/- 11 mm Hg and remained at approximately the same level for the 2-hour period of observation. The extent of reversal of the mean pressure threshold for activation of the baroreceptors was approximately constant (approximately 60%) in the time range of 2-120 minutes. The extent of reversal was slightly higher when the changes in systolic pressure threshold divided by the total change in control diastolic pressure were calculated (maximal of 83%). During the first 20 minutes, the displacements of the curves were parallel with no change in the depressed gain sensitivity. Complete normalization of gain sensitivity was observed after 90-120 minutes. The data indicate that, within the first 2 hours of pressure normalization of chronic renal hypertensive rats, 1) reversal of the resetting of pressure threshold is pronounced (60-80%) but still incomplete and 2) gain sensitivity returns completely to normal.


Taking NIRS-BCIs outside the lab: towards achieving robustness against environment noise.
This paper reported initial findings on the effects of environmental noise and auditory distractions on the performance of mental state classification based on near-infrared spectroscopy (NIRS) signals recorded from the prefrontal cortex. Characterization of the performance losses due to environmental factors could provide useful information for the future development of NIRS-based brain-computer interfaces that can be taken beyond controlled laboratory settings and into everyday environments. Experiments with a hidden Markov model-based classifier showed that while significant performance could be attained in silent conditions, only chance levels of sensitivity and specificity were obtained in noisy environments. In order to achieve robustness against environment noise, two strategies were proposed and evaluated. First, physiological responses harnessed from the autonomic nervous system were used as complementary information to NIRS signals. More specifically, four physiological signals (electrodermal activity, skin temperature, blood volume pulse, and respiration effort) were collected in synchrony with the NIRS signals as the user sat at rest and/or performed music imagery tasks. Second, an acoustic monitoring technique was proposed and used to detect startle noise events, as both the prefrontal cortex and ANS are known to involuntarily respond to auditory startle stimuli. Experiments with eight participants showed that with a startle noise compensation strategy in place, performance comparable to that observed in silent conditions could be recovered with the hybrid ANS-NIRS system.


JAGUC--a software package for environmental diversity analyses.
The study of microbial diversity and community structures heavily relies on the analyses of sequence data, predominantly taxonomic marker genes like the small subunit of the ribosomal RNA (SSU rRNA) amplified from environmental samples. Until recently, the "gold standard" for this strategy was the cloning and Sanger sequencing of amplified target genes, usually restricted to a few hundred sequences per sample due to relatively high costs and labor intensity. The recent introduction of massive parallel tag sequencing strategies like pyrosequencing (454 sequencing) has opened a new window into microbial biodiversity research. Due to its swift nature and relatively low expense, this strategy produces millions of environmental SSU rDNA sequences granting the opportunity to gain deep insights into the true diversity and complexity of microbial communities. The bottleneck, however, is the computational processing of these massive sequence data, without which, biologists are hardly able to exploit the full information included in these sequence data. The freely available standalone software package JAGUC implements a broad regime of different functions, allowing for efficient and convenient processing of a huge number of sequence tags, including importing custom-made reference data bases for basic local alignment searches, user-defined quality and search filters for analyses of specific sets of sequences, pairwise alignment-based sequence similarity calculations and clustering as well as sampling saturation and rank abundance analyses. In initial applications, JAGUC successfully analyzed hundreds of thousands of sequence data (eukaryote SSU rRNA genes) from aquatic samples and also was applied for quality assessments of different pyrosequencing platforms. The new program package JAGUC is a tool that bridges the gap between computational and biological sciences. It enables biologists to process large sequence data sets in order to infer biological meaning from hundreds of thousands of raw sequence data. JAGUC offers advantages over available tools which are further discussed in this manuscript.


Posterior Superior Temporal Sulcus Responses Predict Perceived Pleasantness of Skin Stroking.
Love and affection is expressed through a range of physically intimate gestures, including caresses. Recent studies suggest that posterior temporal lobe areas typically associated with visual processing of social cues also respond to interpersonal touch. Here, we asked whether these areas are selective to caress-like skin stroking. We collected functional magnetic resonance imaging data from 23 healthy participants and compared brain responses to skin stroking and vibration. We did not find any significant differences between stroking and vibration in the posterior temporal lobe; however, right posterior superior temporal sulcus (pSTS) responses predicted healthy participant's perceived pleasantness of skin stroking, but not vibration. These findings link right pSTS responses to individual variability in perceived pleasantness of caress-like tactile stimuli. We speculate that the right pSTS may play a role in the translation of tactile stimuli into positively valenced, socially relevant interpersonal touch and that this system may be affected in disorders associated with impaired attachment.


The effect of corticosteroid therapy on lysosomal enzymes and protein and lipid metabolism in rabbit lung after administration of Freund's adjuvant.
The effect of corticosteroid therapy on the broncho-alveolar cell response, the changes in activity of some lysosomal enzymes and the protein and lipid biosynthesis rates in lung tissue of normal rabbits and of rabbits after induction of an acute inflammation by the intravenous injection of complete Freund's adjuvant (CFA) 0,2 ml/kg body weight was investigated. Three intramuscular injections of methylprednisolone acetate (Depo-Medrol) 1,2 mg/kg over a period of 8 days reduced the mean total broncho-alveolar free cell yields significantly. The percentages of lymphocytes and granulocytes were decreased. The increase in the macrophage percentage was associated with a significant increase in the acid phosphatase activity of the broncho-alveolar cells. The beta-glucuronidase activity, on the other hand, was lowered in alveolar cells and even significantly suppressed in lung tissue. Protein and lipid biosynthesis was significantly retarded in lung tissue 8 days after the start of therapy. Administration of a single dose of CFA 0,2 ml/kg evoked an acute lung inflammation and a significant increase in total alveolar free cell yields. The macrophage percentage was reduced and the lymphocyte numbers doubled, whereas the granulocyte percentage increased more than sevenfold. The change in the percentage distribution of granulocytes may be associated with the marked increase in beta-glucuronidase activity of the cells as well as of the lung tissue. In the inflammatory phase, protein biosynthesis was significantly increased but lipid synthesis was not affected. Corticosteroid therapy in animals treated with adjuvant reversed all the effects of CFA. It has very pronounced anti-inflammatory action and a catabolic effect on protein and lipid metabolism.


Executive attention impairment in first-episode schizophrenia.
We compared the attention abilities of a group of first-episode schizophrenia (FES) patients and a group of healthy participants using the Attention Network Test (ANT), a standard procedure that estimates the functional state of three neural networks controlling the efficiency of three different attentional behaviors, i.e., alerting (achieving and maintaining a state of high sensitivity to incoming stimuli), orienting (ability to select information from sensory input), and executive attention (mechanisms for resolving conflict among thoughts, feelings, and actions). We evaluated 22 FES patients from 17 to 29 years of age with a recent history of a single psychotic episode treated only with atypical neuroleptics, and 20 healthy persons matched with FES patients by sex, age, and educational level as the control group. Attention was estimated using the ANT in which participants indicate whether a central horizontal arrow is pointing to the left or the right. The central arrow may be preceded by spatial or temporal cues denoting where and when the arrow will appear, and may be flanked by other arrows (hereafter, flankers) pointing in the same or the opposite direction. The efficiency of the alerting, orienting, and executive networks was estimated by measuring how reaction time was influenced by congruency between temporal, spatial, and flanker cues. We found that the control group only demonstrated significantly greater attention efficiency than FES patients in the executive attention network. FES patients are impaired in executive attention but not in alerting or orienting attention, suggesting that executive attention deficit may be a primary impairment during the progression of the disease.


Initiating insulin therapy in children and adolescents with type 1 diabetes mellitus.
The primary clinical goals to be achieved with insulin initiation are elimination of ketosis and hyperglycemia with prevention of chronic complications. Insulin therapy is the mainstay in management of type 1 diabetes, which should be aimed at achieving good glycemic control, with achievement of hemoglobin A1c (HbA1c) <7.5%, pre-meal self-monitored blood glucose (SMBG) of 90-130 mg/dL, bed time SMBG of 100-140 mg/dL, mean blood glucose level of 120-160 mg/dL and no ketonuria. Two classes of insulin are available for use in T1DM viz. bolus/prandial insulins (rapid-acting insulins and short-acting insulins) and basal insulins (intermediate-acting insulin and long-acting insulin). Insulin glargine and glulisine can be used in children above 6 years, lispro in children above 3 years and detemir and aspart in children above 2 years. The caution for hypoglycemia should be exercised while prescribing them. Degludec is currently not approved for pediatric use. The initial insulin regimen should comprise of ≥2 daily bolus and ≥1 basal insulin injections. Insulin intensification would be required if the initial regimen fails, which can be achieved by increasing frequency of long and rapid acting insulin analogues. The American Diabetes Association guidelines recommend HbA1c targets of <8.0% for children <6 years of age, ≤7.5% for children 6 to 12 years of age, and ≤7.0% for adolescents, 12-18 years of age. However, the evidence is now in favor of a single target HbA1c of ≤7.5% for all children and adolescents <19 years of age.


Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.


Analgesic effects of branding in treatment of headaches.
The effect of branding--that is, the labelling and marketing--of a well-known proprietary analgesic used to treat headaches was studied in a sample of women given a branded or unbranded form with either an inert or an active formulation. The sample was also divided according to whether the subjects were regular users of the brand or users of other brands. The findings showed that branded tablets were overall significantly more effective than unbranded tablets in relieving headaches. Differential effects were observed: the effects of branding were more noticeable one hour after the tablets were taken compared with 30 minutes; in the women given the placebo; and in the users of the brand compared with the users of other brands. It is hypothesised that these effects are due to increased confidence in obtaining relief with a well-known brand, and that branding has an analgesic effect that interacts with the analgesic effects of placebos and active ingredients.


Design principles for rapid folding of knotted DNA nanostructures.
Knots are some of the most remarkable topological features in nature. Self-assembly of knotted polymers without breaking or forming covalent bonds is challenging, as the chain needs to be threaded through previously formed loops in an exactly defined order. Here we describe principles to guide the folding of highly knotted single-chain DNA nanostructures as demonstrated on a nano-sized square pyramid. Folding of knots is encoded by the arrangement of modules of different stability based on derived topological and kinetic rules. Among DNA designs composed of the same modules and encoding the same topology, only the one with the folding pathway designed according to the 'free-end' rule folds efficiently into the target structure. Besides high folding yield on slow annealing, this design also folds rapidly on temperature quenching and dilution from chemical denaturant. This strategy could be used to design folding of other knotted programmable polymers such as RNA or proteins.


European Position Statement on Diagnosis, and Treatment of Meniere's Disease.
Meniere Disease keeps challenges in its diagnosis and treatment since was defined by Prosper Meniere at the beginning of 19th Century. Several classifications and definition were made until now and speculations still exist on its etiology. As the etiology remains speculative the treatment models remain in discussion also. The European Academy of Otology and Neurotology Vertigo Guidelines Study Group intended to work on the diagnosis and treatment of Meniere's disease and created the European Positional Statement Document also by resuming the consensus studies on it. The new techniques on diagnosis are emphasized as well as the treatment models for each stage of the disease are clarified by disregarding the dilemmas on its treatment. The conservative, noninvasive and invasive therapeutic models are highlighted.


Typology of alcohol consumers in five Australian nighttime entertainment districts.
Understanding how types of alcohol consumers differ is important for public policy targeted at reducing adverse events. The aims of the present study were to identify typologies of alcohol consumers in Australian nighttime entertainment districts based on risk factors for harm and to examine variation between the identified groups in drinking setting and harms. Street-intercept surveys were conducted with 5556 alcohol consumers in and around licensed venues in five Australian cities between November 2011 and June 2012. Latent class analysis identified groups based on age and sex, and blood alcohol concentration, pre-drinking, energy drink use and illicit drug use during that night. Four classes were identified: general patron group (33%), young pre-drinker group (27%), intoxicated male pre-drinker group (31%) and intoxicated illicit drug male group (9%). The proportion of the general patron group interviewed decreased over the night, while the other groups increased (particularly in regional cities). As compared with the general patron group, the remaining three groups reported increased odds of being involved in aggression and any alcohol-related injuries in the past 3 months, with highest rates of harm amongst the intoxicated illicit drug male group. Alcohol consumers in nighttime entertainment districts are not a homogeneous group. One-third have a low likelihood of risky consumption practices; however, representation of this consumer class diminishes throughout the night. Elevated harms amongst groups characterised by certain risk factors (e.g. pre-drinking and illicit drug use) emphasise the importance of addressing these behaviours in public policy. [Peacock A, Norman T, Bruno B, Pennay, Droste N, Jenkinson R, Quinn B, Lubman DI, Miller P. Typology of alcohol consumers in five Australian nighttime entertainment districts. Drug Alcohol Rev 2016;35:539-548].