Acute consumption of p-synephrine does not enhance performance in sprint athletes.
P-Synephrine is a protoalkaloid widely used as an ergogenic aid in sports. This substance has been included in the World Anti-Doping Agency monitoring program, although scientific information about its effects on performance and athletes' well-being is scarce. The purpose of this investigation was to determine the effectiveness of p-synephrine to increase performance in sprint athletes. In a randomized and counterbalanced order, 13 experienced sprinters performed 2 acute experimental trials after the ingestion of p-synephrine (3 mg·kg(-1)) or after the ingestion of a placebo (control trial). Forty-five minutes after the ingestion of the substances, the sprinters performed a squat jump, a countermovement jump, a 15-s repeated jump test, and subsequently performed 60-m and 100-m simulated sprint competitions. Self-reported questionnaires were used to assess side-effect prevalence. In comparison with the control trial, the ingestion of p-synephrine did not change countermovement jump height (37.4 ± 4.2 vs 36.7 ± 3.3 cm, respectively; P = 0.52), squat jump height (34.4 ± 3.6 vs 33.9 ± 3.7 cm; P = 0.34), or average 15-s repeated jumps height (31.8 ± 4.1 vs 32.2 ± 3.6 cm; P = 0.18). P-Synephrine did not modify maximal running speed during the 60-m (9.0 ± 0.5 vs 9.0 ± 0.4 m·s(-1), respectively; P = 0.55) and 100-m sprint competitions (8.8 ± 0.5 vs 8.8 ± 0.5 m·s(-1), respectively; P = 0.92). The ingestion of p-synephrine did not alter the prevalence of headache, gastrointestinal discomforts, muscle pain, or insomnia during the hours following the tests. Acute consumption of 3 mg·kg(-1) of p-synephrine was ineffective to increase performance in competitive sprint athletes. Moreover, p-synephrine did not increase the occurrence of side effects after the competition.


Regulation of megakaryocyte ploidy in vivo in the rat.
The relationship between the bone marrow (BM) megakaryocyte and the circulating platelet was explored. Incremental changes in platelet count were made in rats by infusion of antiplatelet antibody or by platelet transfusion, and the response of megakaryocytes was measured by flow cytometry. Proportional changes in megakaryocyte ploidy were demonstrated: As the platelet count declined, ploidy increased; as the platelet count increased, ploidy decreased. Even moderate degrees of thrombocytopenia and thrombocytosis (48% and 177% of the normal platelet count) were associated with changes in ploidy. These changes were not the results of the technique used to alter the platelet count because reinfusion of platelets after 3 hours of thrombocytopenia prevented any ploidy change. These studies proved that the circulating platelet and the megakaryocyte constitute a classic feedback loop whose activity can be measured by the degree of ploidization of the megakaryocyte. The minimal duration of thrombocytopenia necessary to promote megakaryocyte ploidy changes was approximately 10 hours. Using a BM culture assay, we identified a plasma factor which induced alterations in megakaryocyte ploidy and whose level is inversely proportional to the platelet count.


The Tangibility of Personalized 3D-Printed Feedback May Enhance Youths' Physical Activity Awareness, Goal Setting, and Motivation: Intervention Study.
In the United Kingdom, most youth fail to achieve the government guideline of 60 min of moderate to vigorous physical activity (MVPA) daily. Reasons that are frequently cited for the underachievement of this guideline include (1) a lack of awareness of personal physical activity levels (PALs) and (2) a lack of understanding of what activities and different intensities contribute to daily targets of physical activity (PA). Technological advances have enabled novel ways of representing PA data through personalized tangible three-dimensional (3D) models. The purpose of this study was to investigate the efficacy of 3D-printed models to enhance youth awareness and understanding of and motivation to engage in PA. A total of 39 primary school children (22 boys; mean age 7.9 [SD 0.3] years) and 58 secondary school adolescents (37 boys; mean age 13.8 [SD 0.3] years) participated in a 7-week fading intervention, whereby participants were given 3D-printed models of their previous week's objectively assessed PALs at 4 time points. Following the receipt of their 3D model, each participant completed a short semistructured video interview (children, 4.5 [SD 1.2] min; adolescents, 2.2 [SD 0.6] min) to assess their PA awareness, understanding, and motivation. Data were transcribed verbatim and thematically analyzed to enable key emergent themes to be further explored and identified. Analyses revealed that the 3D models enhanced the youths' awareness of and ability to recall and self-evaluate their PA behaviors. By the end of the study, the youths, irrespective of age, were able to correctly identify and relate to the government's PA guideline represented on the models, despite their inability to articulate the government's guideline through time and intensity. Following the fourth 3D model, 72% (71/97) of the youths used the models as a goal-setting strategy, further highlighting such models as a motivational tool to promote PA. The results suggest that 3D-printed models of PA enhanced the youths' awareness of their PA levels and provided a motivational tool for goal setting, potentially offering a unique strategy for future PA promotion.


In vitro Determination of Rapamycin-triggered FKBP-FRB Interactions Using a Molecular Tension Probe.
As protein-protein interactions (PPI) have been mostly investigated in cellulo or in vivo, it is unclear whether the PPI-based imaging schemes are practically valid in a bioanalytical means in vitro. The present study exemplifies the PPI in vitro inside a unique single-chain probe, named TP2.4, which carries a full-length artificial luciferase (ALuc) sandwiched in between two model proteins of interest, e.g., FKBP and FRB, expressed in E. coli, and purified. We found that the TP2.4 efficiently recognizes its ligand in vitro and varies its molecular kinetics: i.e., rapamycin boosts the enzymatic affinities (Km) of TP2.4 to its substrates, but does not or only weakly influences the turnover rates (Kcat) and the maximal velocity (Vmax). The corresponding circular dichroism (CD) study shows that rapamycin weakly contributes to the enhancement of the α-helical contents in TP2.4. Kinetic constants according to the substrates revealed that a coelenterazine derivative, 6-N3-CTZ, exerted the best catalytic efficiency and the greatest variance in the total photon counts. The present study is the first in vitro example that demonstrates how intramolecular PPI works in a purified single-chain bioluminescent probe and what factors practically influence the biochemistry.


Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors.
There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. On the basis of previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pretreatment with XL765 resulted in superior antitumor effects as compared with either agent alone. Together, preclinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST.


The evaluation of the impact of a stand-biased desk on energy expenditure and physical activity for elementary school students.
Due to the increasing prevalence of childhood obesity, the association between classroom furniture and energy expenditure as well as physical activity was examined using a standing-desk intervention in three central-Texas elementary schools. Of the 480 students in the 24 classrooms randomly assigned to either a seated or stand-biased desk equipped classroom, 374 agreed to participate in a week-long data collection during the fall and spring semesters. Each participant's data was collected using Sensewear® armbands and was comprised of measures of energy expenditure (EE) and step count. A hierarchical linear mixed effects model showed that children in seated desk classrooms had significantly lower (EE) and fewer steps during the standardized lecture time than children in stand-biased classrooms after adjusting for grade, race, and gender. The use of a standing desk showed a significant higher mean energy expenditure by 0.16 kcal/min (p < 0.0001) in the fall semester, and a higher EE by 0.08 kcal/min (p = 0.0092) in the spring semester.


TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses.
In this work, the effects of bacterial LPS, TNF-alpha, and IFN-gamma on gap junctional communication (dye coupling) and on the expression of connexin43 (immunofluorescence, immunoblotting, and RT-PCR) in monocytes/macrophages were studied. Freshly isolated human monocytes plated at high density and treated either with LPS plus IFN-gamma or TNF-alpha plus IFN-gamma became transiently dye coupled (Lucifer yellow) within 24 h. Cells treated with LPS, TNF-alpha, or IFN-gamma alone remained dye uncoupled. In dye-coupled cells, the spread of Lucifer yellow to neighboring cells was reversibly blocked with 18 alpha-glycyrrhetinic acid, a gap junction blocker, but it was unaffected by oxidized ATP or probenecid, which block ionotropic ATP-activated channels and organic anion transporters, respectively. Abs against TNF-alpha significantly reduced the LPS plus IFN-gamma-induced increase in dye coupling. In dye-coupled monocytes/macrophages, but not in control cells, both connexin43 protein and mRNA were detected, and their levels were higher in cells with an elevated incidence of dye coupling. In dye-coupled cells, the localization of connexin43 immunoreactivity was diffuse at perinuclear regions and thin cell processes. The addition of 18-alpha-glycyrrhetinic acid induced a profound reduction of monocyte/macrophage transmigration across a blood brain barrier model. It also induced a significant reduction in the secretion of metalloproteinase-2 in cells treated with TNF-alpha plus IFN-gamma. We propose that some monocyte/macrophage responses are coordinated by connexin-formed membrane channels expressed transiently at inflammatory sites in which these cells form aggregates.


CAUTION! Consider cancer: common symptoms and signs for early detection of cancer in young adults.
Because young adults frequently have longer delays in diagnosis of their cancers than younger or older persons, healthcare providers who encounter this age group should become more aware of diagnostic clues for early detection. The spectrum of cancer types and their relative frequencies is distinctly different in young adults than the array in younger and older persons, such that the symptoms and signs in aggregate are distinctly different. Of potential value in recognizing manifestations of cancer in young adults is a mnemonic-friendly list of seven symptoms each represented by a letter in CAUTION, and seven sites of signs starting with the letter B. These aids have the potential of assisting in early detection, accurate diagnosis, longer survival, and a reduced risk of premature death.


The progression of noise-induced hearing loss. A survey of workers in selected industries in Canada.
An in-depth investigation of the progression of noise induced hearing loss is reported for individuals working in three major Canadian industries. The particular approach taken was to select occupational groups within each industry, who had the same noise exposure for a continuous period, and on whom standard hearing tests were undertaken at regular intervals. Two methods of evaluating the audiometric data were used. The first was a cross-sectional design, in which one audiogram was analyzed for each employee. The second focused on the rate of hearing loss over time within individuals. The results confirmed previous reports that the effect of continuous noise exposure was maximal in the region of 2-6 kHz. Significant differences in hearing loss were noted across job types. Over a 10 year period the rate of loss within exposed individuals was on the average 1.5 dB per year for 4 kHz, as compared with 0.5 dB for control subjects who held office jobs. The absolute difference between hearing thresholds measured at the beginning and end of this period ranged widely from a slight improvement in hearing to losses often as great as 55 dB. In general the greatest loss occurred at 4 kHz. The number of frequencies at which there was a risk of exceeding a 25 dB fence increased with the number of years of exposure.


Amygdala-orbitofrontal resting-state functional connectivity is associated with trait anger.
An important distinction in research on the neural mechanisms of emotion regulation involves the relatively limited duration of emotional states versus emotional traits that are defined as the stable tendency to experience particular emotions in daily life. Neuroimaging investigations of the regulation of anger states point to the involvement of reciprocal changes in the prefrontal cortex and amygdala activity, but the neural substrate of trait anger has received less attention. We used resting-state functional MRI to determine whether the variation in the strength of functional connectivity between the amygdala and the orbitofrontal cortex is associated with trait anger. Sixteen healthy men completed the Spielberger State-Trait Anger Expression Inventory. Correlational analysis for resting-state functional connectivity (RSFC) was carried out with the left and the right amygdala as separate seed regions. Anger measures were correlated to RSFC involving the right and the left amygdala on a voxel-by-voxel basis across all individuals. We found that Trait Anger was inversely associated with the strength of RSFC between the amygdala and the contralateral middle orbitofrontal cortex. The association was stronger for the right amygdala-left orbitofrontal connection. Anger Control, the tendency to try to control expressions of anger, showed the opposite pattern of being positively correlated with amygdala-orbitofrontal connectivity. The present study provides evidence that RSFC in a corticolimbic circuit might subserve stable differences in anger regulation. Our findings also suggest that RSFC may prove valuable as a trait marker for disorders characterized by emotional dysregulation such as depression, anxiety, and personality disorders.


CO2 reduction over NaNbO3 and NaTaO3 perovskite photocatalysts.
The activity of NaNbO3 and NaTaO3 perovskites for the photocatalytic reduction of CO2 is studied in this work. For this purpose, sodium niobate and tantalate have been prepared using solid-state reactions, extensively characterised by means of powder X-ray diffraction, UV-vis, photoluminescence and Raman spectroscopies and N2 adsorption isotherms, and tested in the gas-phase reduction of CO2 under UV light in a continuous flow photoreactor. NaNbO3 is constituted of an orthorhombically distorted perovskite structure, while a ca. 4.5 : 1 combination of the orthorhombic and monoclinic modifications is found in the tantalate. Both catalysts exhibit interesting intrinsic activities, with the tantalate material giving rise to a slightly higher performance. This is attributed to a compromise situation between electron-hole recombination and the reducing potential of conduction band electrons. In addition, a decrease in the competition of water protons for photogenerated electrons is observed with both catalysts with respect to TiO2.


Diagnostic efficacy of serum and urinary netrin-1 in the early detection of diabetic nephropathy.
This study aimed to assess the diagnostic value of serum and urinary netrin-1 in patients with type 2 diabetes mellitus (T2DM) at different stages of diabetic nephropathy (DN) and to compare its efficacy of estimation in serum with that in the urine. This study was carried out on 135 patients with T2DM and 45 healthy subjects. The patients with diabetes were divided according to urinary albumin creatinine ratio (UACR) into: T2DM with normoalbuminuria, incipient DN with microalbuminuria, and overt DN with macroalbuminuria groups. Serum and urinary levels of netrin-1 were measured by ELISA. The mean levels of serum and urinary netrin-1 were significantly higher in the microalbuminuric and macroalbuminuric patients with DN than those in the normoalbuminuric patients with T2DM, with the highest values detected in macroalbuminuric patients with DN. Urinary netrin-1 level was significantly higher in the normoalbuminuric T2DM group than control group, whereas no significant difference existed regarding serum netrin-1 level. In T2DM groups, the urinary and serum netrin-1 correlated with each other and were independently related to fasting blood glucose, UACR, and estimated glomerular filtration rate. Receiver operating characteristic curve analysis showed that the area under the curve of urinary netrin-1 was 0.916 which is significantly higher than that of serum netrin-1 (0.812) for the detection of incipient DN and reached 0.938 on coestimation of both urinary and serum netrin-1. In conclusion, netrin-1 is a potential diagnostic marker for early detection of DN with its estimation in urine has higher accuracy than that of serum.


Introduction of a New Surgical Method to Improve Bone Healing in a Large Bone Defect by Replacement of the Induced Membrane by a Human Decellularized Dermis Repopulated with Bone Marrow Mononuclear Cells in Rat.
The Masquelet technique for the treatment of large bone defects is a two-stage procedure based on an induced membrane. We eliminate the first surgical step by using a decellularized dermal skin graft (Epiflex®) populated with bone marrow mononuclear cells (BMC), as a replacement for the induced membrane. The aim of this study was to demonstrate the feasibility of this technology and provide evidence of equivalent bone healing in comparison to the induced membrane-technique. Therefore, 112 male Sprague-Dawley rats were allocated in six groups and received a 10 mm femoral defect. Defects were treated with either the induced membrane or decellularized dermis, with or without the addition of BMC. Defects were then filled with a scaffold (β-TCP), with or without BMC. After a healing time of eight weeks, femurs were taken for histological, radiological and biomechanical analysis. Defects treated with Epiflex® showed increased mineralization and bone formation predominantly in the transplanted dermis surrounding the defect. No significant decrease of biomechanical properties was found. Vascularization of the defect could be enhanced by addition of BMC. Considering the dramatic reduction of a patient's burden by the reduced surgical stress and shortened time of treatment, this technique could have a great impact on clinical practice.


Proteasome inhibition is partially effective in attenuating pre-existing immunity against recombinant adeno-associated viral vectors.
Pre-existing immunity against adeno-associated virus (AAV) remains a major challenge facing the clinical use of systemic administration of recombinant AAV vectors for the treatment of genetic and acquired diseases using gene therapy. In this study, we evaluated the potential of bortezomib (marketed under trade name Velcade) to abrogate a pre-existing immunity to AAV in mice, thereby allowing subsequent transduction by a recombinant AAV vector of the same serotype. We demonstrate that bortezomib efficiently reduces AAV-specific IgG titres and moderates the cytotoxic T cell response in mice that have a pre-existing immunity to AAV2/8. Significant depletion of AAV2/8-specific IgG-producing plasma cells in secondary lymphoid organs and bone marrow was observed. However, this inhibition of the immune response by bortezomib was insufficient to allow subsequent re-infection with a recombinant AAV vector of a similar serotype. We show that this shortcoming is probably due to the combination of residual antibody levels and the inability of bortezomib to completely deplete the memory B cells that are re-activated in response to a repeated infection with a recombinant AAV vector. Taken together, the results of this study argue for the use of immunosuppressive therapies that target both plasma and memory B cells for the efficient elimination of pre-existing immunity against AAV2/8 vectors.


Craniofacial anomalies: from development to molecular pathogenesis.
Advances in developmental biology combined with progress in human genetics are helping us decipher how the craniofacial region develops and how the consequences of misdirected development result in malformation. This review describes the molecular etiology of a number of craniofacial developmental anomalies. The more common craniofacial anomalies cleft lip and palate and craniosynostosis, as well as cleidocranial dysplasia, hemifacial microsomia, holoprosencephaly, enlarged parietal foramina, Treacher Collins syndrome and cherubism are discussed.


Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
Patients with progressive supranuclear palsy (PSP) and patients with Parkinson disease frequently manifest signs of dry eyes, yet many remain asymptomatic. In this study, we established the relationships between blink rate, corneal sensitivity, and corneal nerve density in patients with ocular surface disease associated with PSP and Parkinson disease. Fourteen eyes of 7 patients with PSP, 8 eyes of 4 patients with Parkinson disease, and 10 eyes of 5 age-matched controls were examined for meibomian dysfunction, ocular surface staining, and blink rate. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer, and corneal subbasal nerve density was measured by using confocal microscopy in vivo. Comparisons between variables were assessed by using generalized estimating equation models to account for possible correlation between fellow eyes of the same subject. Abnormal ocular surface staining and meibomian disease were present in most subjects with PSP and Parkinson disease, but in none of the controls. Patients with PSP and Parkinson disease had lower blink rates (P < 0.001) and decreased corneal sensitivity (P < 0.001) compared with controls, whereas subbasal nerve density did not differ between groups. Blink rate was correlated with corneal sensitivity (r = 0.83, P < 0.001), but corneal sensitivity was not correlated with subbasal nerve density (r = -0.16, P = 0.78). Patients with ocular surface disease associated with PSP and Parkinson disease might be asymptomatic because of decreased corneal sensitivity. Decreased corneal sensitivity was not explained by loss of corneal nerves but was associated with decreased blink rate.


Harmonization of initial estimates of shale gas life cycle greenhouse gas emissions for electric power generation.
Recent technological advances in the recovery of unconventional natural gas, particularly shale gas, have served to dramatically increase domestic production and reserve estimates for the United States and internationally. This trend has led to lowered prices and increased scrutiny on production practices. Questions have been raised as to how greenhouse gas (GHG) emissions from the life cycle of shale gas production and use compares with that of conventionally produced natural gas or other fuel sources such as coal. Recent literature has come to different conclusions on this point, largely due to differing assumptions, comparison baselines, and system boundaries. Through a meta-analytical procedure we call harmonization, we develop robust, analytically consistent, and updated comparisons of estimates of life cycle GHG emissions for electricity produced from shale gas, conventionally produced natural gas, and coal. On a per-unit electrical output basis, harmonization reveals that median estimates of GHG emissions from shale gas-generated electricity are similar to those for conventional natural gas, with both approximately half that of the central tendency of coal. Sensitivity analysis on the harmonized estimates indicates that assumptions regarding liquids unloading and estimated ultimate recovery (EUR) of wells have the greatest influence on life cycle GHG emissions, whereby shale gas life cycle GHG emissions could approach the range of best-performing coal-fired generation under certain scenarios. Despite clarification of published estimates through harmonization, these initial assessments should be confirmed through methane emissions measurements at components and in the atmosphere and through better characterization of EUR and practices.


Comparative analysis of biotin intranuclear inclusions of gestational endometrium using the APAAP, ABC and the PAP immunodetection systems.
Intranuclear inclusions have been observed in gestational endometrial glands. Although resembling Herpes simplex virus infected cells, these nuclei have been shown to contain endogenous biotin. Hence, immunohistochemical systems using the avidin-biotin complex will result in cross reaction and false positivity. This study investigates a series of 10 gestational endometria (formalin fixed and paraffin wax embedded) with intranuclear inclusions using three different immunodetection systems with primary anti-biotin. Both the alkaline phosphatase anti-alkaline phosphatase (APAAP) and peroxidase anti-peroxidase (PAP) systems confirmed that the intranuclear inclusions were endogenous biotin. The streptavidin biotin complex (StreptABC) system produced a positive reaction in both test sections and controls (omitting primary anti-biotin) in the presence of prior blocking with free avidin and biotin. In addition, aberrant immunoreactivity was observed in adjacent nuclei/cytoplasm of endometrial glands and decidualised stroma in the negative control of the PAP system. This was subsequently eliminated using microwave pretreatment prior to immunohistochemistry. The use of either the APAAP or PAP immunodetection systems (the latter with microwave pretreatment) is recommended for any immunohistochemical or non-isotopic in situ hybridisation investigation undertaken on gestational endometria.


Does bromodomain flexibility influence histone recognition?
Bromodomains are protein modules that selectively recognize histones by binding to acetylated lysines. Here, we have carried out multiple molecular dynamics simulations of 20 human bromodomains to investigate the flexibility of their binding site. Some bromodomains show alternative side chain orientations of three evolutionarily conserved residues: the Asn involved in acetyl-lysine binding and two conserved aromatic residues. Furthermore, for the BAZ2B and CREBBP bromodomains we observe occlusion of the binding site which is coupled to the displacement of the two aromatic residues. In contrast to available structures, the simulations reveal large variability of the binding site accessibility. The simulations suggest that the flexibility of the bromodomain binding site and presence of self-occluded metastable states influence the recognition of acetyl-lysine on histone tails.


Exercise and Parkinson Disease: Comparing Tango, Treadmill, and Stretching.
Impaired gait, balance, and motor function are common in Parkinson disease (PD) and may lead to falls and injuries. Different forms of exercise improve motor function in persons with PD, but determining which form of exercise is most effective requires a direct comparison of various approaches. In this prospective, controlled trial, we evaluated the impact of tango, treadmill walking, and stretching on gait, balance, motor function, and quality of life. We hypothesized tango and treadmill would improve forward walking and motor symptom severity, and tango would also improve backward walking, balance, and quality of life. Ninety-six participants (age: 67.2 ± 8.9 years, 42% female) with mild to moderate idiopathic PD were serially assigned to tango, treadmill walking, or stretching (active control group) and attended 1-hour classes twice weekly for 12 weeks. Assessments occurred OFF anti-PD medication before and after the intervention and at follow-up 12 weeks after the intervention. Forward velocity and backward velocity improved for the treadmill group from baseline to posttest and improvements persisted at follow-up. Backward velocity and motor functioning improved for the stretching group from baseline to posttest, but results did not persist at follow-up. There were no significant changes in the tango group across time points. Contrary to our hypotheses, only treadmill improved forward walking, while backward walking improved with treadmill and stretching. Future research should examine combinations of exercises with a focus on optimizing dosing and examining whether specific characteristics of people with PD correlate with different types of exercise.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A237).


The 13 world congress on medical and health informatics, Cape Town, South Africa: Partnerships for effective e-Health solutions.
The 13(th) World Congress on Medical and Health Informatics (Medinfo) was held in 2010 between 12 and 15 September in Cape Town, South Africa. This triennial international gathering is the official conference of the International Medical Informatics Association (IMIA) and brings together leading health informatics leaders, scientists, clinicians, researchers, vendors, developers and government and health care planners from around the globe. The conference attracted 905 submissions and resulted in a program that included 260 oral presentations, 349 posters presentations and 21 scientific demonstrations representing contributions from 58 countries. The Medinfo program covered all aspects of health informatics from traditional areas, such as hospital information systems, patient registries, nursing informatics, data integration, standards, interoperability issues and decision support, to innovative topics, such as translational bioinformatics, text mining, intelligent data analysis, emerging technologies, quality, social networking, workflow and organizational issues. The outgoing President of the IMIA, Professor Reinhold Haux, presented on health informatics challenges into the future, reinforcing that today and in the future, health care has to be considered as part of a continuous and coordinated life-time journey and not just as episodes of disease. Medical informatics has a key role to play in this paradigm shift. The new IMIA President, Professor Antoine Geissbuhler, was announced at the closing ceremony. The next Medinfo congress will take place in Copenhagen, Denmark, in September 2013.


Genotypic variation of the glucosinolate profile in pak choi (Brassica rapa ssp. chinensis).
Thirteen different pak choi (Brassica rapa ssp. chinensis) cultivars were characterized regarding their glucosinolate profile analyzed by HPLC-DAD-MS. The identified glucosinolates were subjected to principal component analysis, and three distinct groups of pak choi sprouts were identified. Group differences were marked mainly by variations in the aliphatic glucosinolate profile such as differing levels of 3-butenyl glucosinolate and 2-hydroxy-3-butenyl glucosinolate as well as by their varying proportional ratios. In addition, the three groups of pak choi sprouts varied by the presence or absence of 2-hydroxy-4-pentenyl glucosinolate and in level and composition of butyl glucosinolates. This classification is reflected by relative mRNA expression level of 2-oxoacid-dependent dioxygenase. As in sprouts, the major glucosinolates in mature leaves were found to be the aliphatic glucosinolates. However, unlike in sprouts, an additional aliphatic glucosinolate, 5-methylsulfinylpentyl glucosinolate, was detected as characteristic ontogenetic variation in mature leaves in 12 of the 13 pak choi cultivars analyzed.


The supporting alliance in child and adolescent treatment: enhancing collaboration among therapists, parents, and teachers.
Research indicates that the therapeutic alliance between therapist and pediatric patient is most effective in the context of a productive supporting alliance--an alliance encompassing the network of relationships among therapists, parents and teachers. In this essay, we develop a model of the supporting alliance, arguing that the child's primary relationships with various parties (therapists, teachers, and parents) imply a set of secondary relationships among those parties (parent-therapist, therapist-teacher, parent-teacher). We review the literature on these secondary relationships, focusing on their nature and discussing the benefits of and obstacles to establishing productive collaborations in each case. We also describe three sorts of pathology that can afflict the supporting alliance as a whole, and discuss the importance of patient autonomy and therapist-patient confidentiality relative to the supporting alliance. Finally, we identify directions for future research and highlight implications for practice.


Flow visualization with stereo shadowgraphs of stratified fluid.
Water stratified thermally or with dissolved material has a refractive index that varies with height. The stratification has no obvious visual effect until the fluid is disturbed, for example by a fish, but then it marks the creature's wake with a jump in refractive index that is visible in shadowgraphic projection. Two shadowgraphs in stereo display the wake in three dimensions. For a permanent record, or for analysing events too quick for the eye to follow, movies can be taken of the shadowgraphs.


Prison suicide in England and Wales, 1972-87.
The case notes of 295 suicides (98.3% of the total) in prisons in England and Wales between 1972 and 1987 were studied. This period has witnessed an increase in the suicide rate far in excess of the rate of rise in the prison population. The most common method of suicide was by hanging, usually at night. There was a frequent past history of psychiatric treatment and self-injury. People charged or convicted of violent or sexual offences were over-represented, as were those serving life sentences. There was an association between suicide and both guilt for the offence and being charged or convicted of a homicide offence. Some suicides occurred many years after reception into prison. Routine enquiry about previous suicide attempts must be implemented, along with better, ongoing, active communication between staff and inmates.


Membrane binding of human immunodeficiency virus type 1 matrix protein in vivo supports a conformational myristyl switch mechanism.
The interaction of the human immunodeficiency virus (HIV) Gag protein with the plasma membrane of a cell is a critical event in the assembly of HIV particles. The matrix protein region (MA) of HIV type 1 (HIV-1) Pr55Gag has previously been demonstrated to confer membrane-binding properties on the precursor polyprotein. Both the myristic acid moiety and additional determinants within MA are essential for plasma membrane binding and subsequent particle formation. In this study, we demonstrated the myristylation-dependent membrane interaction of MA in an in vivo membrane-binding assay. When expressed within mammalian cells, MA was found both in association with cellular membranes and in a membrane-free form. In contrast, the intact precursor Pr55Gag molecule analyzed in an identical manner was found almost exclusively bound to membranes. Both membrane-bound and membrane-free forms of MA were myristylated and phosphorylated. Differential membrane binding was not due to the formation of multimers, as dimeric and trimeric forms of MA were also found in both membrane-bound and membrane-free fractions. To define the requirements for membrane binding of MA, we analyzed the membrane binding of a series of MA deletion mutants. Surprisingly, deletions within alpha-helical regions forming the globular head of MA led to a dramatic increase in overall membrane binding. The stability of the MA-membrane interaction was not affected by these deletions, and no deletion eliminated membrane binding of the molecule. These results establish that myristic acid is a primary determinant of the stability of the Gag protein-membrane interaction and provide support for the hypothesis that a significant proportion of HIV-1 MA molecules may adopt a conformation in which myristic acid is hidden and unavailable for membrane interaction.


Gamma Irradiation Influences the Survival and Regrowth of Antibiotic-Resistant Bacteria and Antibiotic-Resistance Genes on Romaine Lettuce.
Contamination of romaine lettuce with human pathogens, antibiotic-resistant bacteria (ARB), and antibiotic resistance genes (ARGs) occurs during production. Post-harvest interventions are emplaced to mitigate pathogens, but could also mitigate ARB and ARGs on vegetables. The objective of this research was to determine changes to lettuce phyllosphere microbiota, inoculated ARB, and the resistome (profile of ARGs) following washing with a sanitizer, gamma irradiation, and cold storage. To simulate potential sources of pre-harvest contamination, romaine lettuce leaves were inoculated with compost slurry containing antibiotic-resistant strains of pathogenic (Escherichia coli O157:H7) and representative of spoilage bacteria (Pseudomonas aeruginosa). Various combinations of washing with sodium hypochlorite (50 ppm free chlorine), packaging under modified atmosphere (98% nitrogen), irradiating (1.0 kGy) and storing at 4°C for 1 day versus 14 days were compared. Effects of post-harvest treatments on the resistome were profiled by shotgun metagenomic sequencing. Bacterial 16S rRNA gene amplicon sequencing was performed to determine changes to the phyllosphere microbiota. Survival and regrowth of inoculated ARB were evaluated by enumeration on selective media. Washing lettuce in water containing sanitizer was associated with reduced abundance of ARG classes that confer resistance to glycopeptides, β-lactams, phenicols, and sulfonamides (Wilcoxon, p < 0.05). Washing followed by irradiation resulted in a different resistome chiefly due to reductions in multidrug, triclosan, polymyxin, β-lactam, and quinolone ARG classes (Wilcoxon, p < 0.05). Irradiation followed by storage at 4°C for 14 days led to distinct changes to the β-diversity of the host bacteria of ARGs compared to 1 day after treatment (ANOSIM, R = 0.331; p = 0.003). Storage of washed and irradiated lettuce at 4°C for 14 days increased the relative abundance of Pseudomonadaceae and Carnobacteriaceae (Wilcoxon, p < 0.05), two groups whose presence correlated with detection of 10 ARG classes on the lettuce phyllosphere (p < 0.05). Irradiation resulted in a significant reduction (∼3.5 log CFU/g) of inoculated strains of E. coli O157:H7 and P. aeruginosa (ANOVA, p < 0.05). Results indicate that washing, irradiation and storage of modified atmosphere packaged lettuce at 4°C are effective strategies to reduce antibiotic-resistant E. coli O157:H7 and P. aeruginosa and relative abundance of various ARG classes.


Renal cell carcinoma in the solitary kidney: an analysis of complications and outcome after nephron sparing surgery.
We evaluated surgical techniques, pathological features and extended outcomes in patients with renal cell carcinoma in a solitary kidney treated with surgical excision. Between 1970 and 1998, 76 patients underwent nephron sparing surgery for sporadic renal cell carcinoma in a solitary kidney, including 63 with tissue specimens available for pathological review who comprised the cohort. Six (9.5%) patients had a congenitally absent kidney and 57 (90.5%) had previously undergone contralateral nephrectomy for renal cell carcinoma. The clinical and pathological features examined were patient age at nephron sparing surgery, sex, type of nephron sparing surgery (enucleation, partial nephrectomy or ex vivo resection), tumor size, nuclear grade, histological subtype and 1997 tumor stage. Overall cancer specific, local recurrence-free and metastasis-free survival as well as early (within 30 days of nephron sparing surgery) and late (30 days to 1 year after nephron sparing surgery) complications were assessed. Univariate and multivariate analyses were done to test for the associations of clinical and pathological features with outcome. Most patients were treated with enucleation (36.5%), standard partial nephrectomy (38.1%) or the 2 procedures (11.1%) and in 8 (12.7%) ex vivo tumor resection was done. The renal cell carcinoma histological subtypes were clear cell in 82.5% of cases, papillary in 15.9% and chromophobe in 1.6%. Grade was 1 to 3 in 10 (15.9%), 42 (66.7%) and 10 (15.9%) tumors, respectively. At 5 and 10 years the overall survival rate was 74.7% and 45.8%, the cancer specific survival rate was 80.7% and 63.7%, the local recurrence-free survival rate was 89.2% and 80.3%, and the metastasis-free survival rate was 69% and 50.4%, respectively. Tumor stage and nuclear grade were significantly associated with death from any cause, death from renal cell carcinoma and distant metastases on multivariate analysis. Notably no patient with papillary or chromophobe renal cell carcinoma died of renal cell carcinoma, or had recurrence or metastasis. The type of nephron sparing surgery was not significantly associated with outcome, although there were too few patients with recurrence to assess the association of the type of nephron sparing surgery with local recurrence. The most common early complication was acute renal failure in 12.7% of cases, while the most common late complications were proteinuria in 15.9% and renal insufficiency in 12.7%. The 1997 tumor stage and nuclear grade were significant predictors of death from any cause, death from renal cell carcinoma and distant metastases in patients treated with nephron sparing surgery for renal cell carcinoma involving a solitary kidney. Nephron sparing surgery in a solitary kidney can be performed safely and with minimal morbidity.


Autoantibodies of various specificities encoded by genes from the VH J558 family bind to foreign antigens and share idiotopes of antibodies specific for self and foreign antigens.
We examined the binding to foreign antigens and the expression of crossreactive idiotypes by a panel of 20 murine monoclonal autoantibodies encoded by V genes from the VH J558 family. 9 of 20 antibodies bound to foreign antigens such as bacterial polysaccharides, poly(Glu50, Tyr50), poly(Glu54,Lys37,Phe9), arsonate, and lysozyme, known to interact with antibodies encoded by genes from the VH J558 family. A high proportion of our panel of autoantibodies expressed crossreactive idiotypes originally borne by monoclonal rheumatoid factors, anti-Sm, and anti-DNA antibodies, all encoded by V genes from the VH J558 family. Some of these VH J558+ autoantibodies shared crossreactive idiotypes with VH J558+ antibodies directed against foreign antigens such as influenza virus hemagglutinin, poly(Glu60,Ala30,Tyr10), arsonate, and dextran. The implications of these findings are discussed with respect to the process of activation of self-reactive clones.


Video-rate computational heterodyne holography.
We present a versatile computational image rendering software of optically acquired holograms. The reported software can process 4 Megapixel 8-bit raw frames from a sensor array acquired at a sustained rate of 80 Hz. Video-rate image rendering is achieved by streamline image processing with commercial computer graphics hardware. For time-averaged holograms acquired in off-axis optical configuration with a frequency-shifted reference beam, wide-field imaging of one tunable spectral component is permitted. This software is validated by phase-stepped hologram rendering, and noncontact monitoring of surface acoustic waves by single and dual sideband hologram rendering. It demonstrates the suitability of holography for video-rate computational laser Doppler imaging in a heterodyne optical configuration.


Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes.
Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.


ArrayPitope: Automated Analysis of Amino Acid Substitutions for Peptide Microarray-Based Antibody Epitope Mapping.
Identification of epitopes targeted by antibodies (B cell epitopes) is of critical importance for the development of many diagnostic and therapeutic tools. For clinical usage, such epitopes must be extensively characterized in order to validate specificity and to document potential cross-reactivity. B cell epitopes are typically classified as either linear epitopes, i.e. short consecutive segments from the protein sequence or conformational epitopes adapted through native protein folding. Recent advances in high-density peptide microarrays enable high-throughput, high-resolution identification and characterization of linear B cell epitopes. Using exhaustive amino acid substitution analysis of peptides originating from target antigens, these microarrays can be used to address the specificity of polyclonal antibodies raised against such antigens containing hundreds of epitopes. However, the interpretation of the data provided in such large-scale screenings is far from trivial and in most cases it requires advanced computational and statistical skills. Here, we present an online application for automated identification of linear B cell epitopes, allowing the non-expert user to analyse peptide microarray data. The application takes as input quantitative peptide data of fully or partially substituted overlapping peptides from a given antigen sequence and identifies epitope residues (residues that are significantly affected by substitutions) and visualize the selectivity towards each residue by sequence logo plots. Demonstrating utility, the application was used to identify and address the antibody specificity of 18 linear epitope regions in Human Serum Albumin (HSA), using peptide microarray data consisting of fully substituted peptides spanning the entire sequence of HSA and incubated with polyclonal rabbit anti-HSA (and mouse anti-rabbit-Cy3). The application is made available at: www.cbs.dtu.dk/services/ArrayPitope.


Reactivity of the geminal phosphinoborane tBu2PCH2BPh2 towards alkynes, nitriles, and nitrilium triflates.
The reactivity of the geminal phosphinoborane tBu2PCH2BPh2 towards terminal alkynes, nitriles and nitrilium salts is investigated. Terminal alkynes react via C-H bond splitting (deprotonation) resulting in the formation of phosphonium borates. In contrast, both nitriles and nitrilium salts undergo addition reactions resulting in the formation of five-membered heterocycles. All compounds were characterized by multinuclear NMR spectroscopy, and single-crystal X-ray structure determinations. Insight into the reaction mechanisms was gained by DFT calculations.


Writing for international publication in nursing journals: a personal perspective (Part 2).
The number of printed and electronic (Internet) academic nursing publications in Brazil and around the world highlight the importance attached to publishing in the field of nursing. Internationally, journals are ranked according to their professional merits and peer review orientations. Financial institutions increasingly value publications in renowned journals as one criterion for granting funds for research. One important reason why many scientific articles do not meet the requirements from international journal reviewers, especially those submitted English, is the result of poor and literal translation of the text. The challenge we are facing in Latin America is to encourage the development of articles for publication in internationally reviewed journals. Co-authorship is a potentially stimulating model for researchers and postgraduate students to publish. This task can be undertaken through the help of international supervisors and researchers, supervisors or postgraduate students with good command of the English language. This article aims to demystify the publication process and present some guidelines on how to publish in international journals.


Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway.
Hexavalent chromium [Cr(VI)] is commonly used in industry, and is a proven toxin and carcinogen. However, the information regarding its neurotoxic mechanism is not completely understood. The present study was designed to scrutinize the possible protective effects of caffeic acid phenethyl ester (CAPE), a bioactive phenolic of propolis extract, on Cr(VI)-induced brain injury in rats, with an emphasis on the JAK/STAT signaling pathway. Rats received 2mg/kgK2CrO4 and concurrently treated with 20mg/kg CAPE for 30 days. Cr(VI)-induced rats showed a significant increase in cerebral lipid peroxidation, nitric oxide and pro-inflammatory cytokines, with concomitantly declined antioxidants and acetylcholinesterase. CAPE attenuated oxidative stress and inflammation and enhanced antioxidant defenses in the cerebrum of rats. Cr(VI) significantly up-regulated JAK2, STAT3 and SOCS3, an effect that was reversed by CAPE. In conclusion, CAPE protects the brain against Cr(VI) toxicity through abrogation of oxidative stress, inflammation and down-regulation of JAK2/STAT3 signaling in a SOCS3-independent mechanism.


Socioeconomic variation in the burden of chronic conditions and health care provision--analyzing administrative individual level data from the Basque Country, Spain.
Chronic diseases are posing an increasing challenge to society, with the associated burden falling disproportionally on more deprived individuals and geographical areas. Although the existence of a socioeconomic health gradient is one of the main concerns of health policy across the world, health information systems commonly do not have reliable data to detect and monitor health inequalities and inequities. The objectives of this study were to measure the level of socioeconomic-related inequality in prevalence of chronic diseases and to investigate the extent and direction of inequities in health care provision. A dataset linking clinical and administrative information of the entire population living in the Basque Country, Spain (over 2 million individuals) was used to measure the prevalence of 52 chronic conditions and to quantify individual health care costs. We used a concentration-index approach to measure the extent and direction of inequality with respect to the deprivation of the area of residence of each individual. Most chronic diseases were found to be disproportionally concentrated among individuals living in more deprived areas, but the extent of the imbalance varies by type of disease and sex. Most of the variation in health care utilization was explained by morbidity burden. However, even after accounting for differences in morbidity, pro-poor horizontal inequity was present in specialized outpatient care, emergency department, prescription, and primary health care costs and this fact was more apparent in females than males; inpatient costs exhibited an equitable distribution in both sexes. Analyses of comprehensive administrative clinical information at the individual level allow the socioeconomic gradient in chronic diseases and health care provision to be measured to a level of detail not possible using other sources. This frequently updated source of information can be exploited to monitor trends and evaluate the impact of policy reforms.


"The world is upside down" - The Innsbruck Goggle Experiments of Theodor Erismann (1883-1961) and Ivo Kohler (1915-1985).
The "Innsbruck Goggle Experiments" on long-term wearing of reversing mirrors, prismatic and half prismatic goggles, and colored half goggles represent a milestone in research on adaptation (adapting to the introduced "disturbance") and after-effects (after removal of the "disturbance"). By means of these goggles it is, for example, possible to invert or distort the visual field (such as flipping top and bottom or left and right), as well as to observe how individuals learn to change the image back to vertical or recognize left and right. The Innsbruck Experiments gave decisive momentum to further international research on the ontogenetic development of perception, special perception, color perception, perceptual constancy, sensorimotor coordination, as well as to the development of theories. In the current paper, aside from presenting the history and results of selected studies, we will give an introduction to the life and work of the protagonists of these studies in Innsbruck, namely Theodor Erismann (1883-1961) and Ivo Kohler (1915-1985). Furthermore, we will propose ideas for future research on cognition and neuroscience.


Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults.
On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.


Interdisciplinary spasticity management clinic outcomes using the Goal Attainment Scale: A retrospective chart review.
To generate practice-based evidence of outcomes in an interdisciplinary spasticity management clinic using practical application of the Goal Attainment Scale (GAS). Retrospective chart review. A total of 225 adult patients who were referred for spasticity management at a tertiary rehabilitation hospital and returned for follow-up between 2010 and 2013. GAS scores were determined for all patients. GAS T-scores were evaluated based on age; sex; diagnosis; International Classification of Functioning, Disability and Health (ICF) domain; body region affected; and site of botulinum neurotoxin injection. The distribution of GAS outcomes did not vary by age, sex or diagnosis. The overall GAS T-score for the clinic was 47.7, which is consistent with appropriate goal setting. GAS T-scores did not vary by diagnosis or ICF domain. Significant intervention effects were identified for botulinum neurotoxin, with improvements in GAS T-scores for treatment targeted to both upper and lower limb muscles, compared with no botulinum neurotoxin, across diagnoses and ICF domains. The GAS is a useful patient-centred outcome measure that can be practically applied in the clinical setting for a heterogeneous population with diverse goals. Botulinum neurotoxin treatment in this setting was associated with improved goal attainment relating to multiple ICF domains.


I Brazilian guidelines for respiratory physiotherapy in pediatric and neonatal intensive care units.
Developing guidelines for the role of the physiotherapist in neonatal and pediatric intensive care units is essential because these professionals are responsible for the rehabilitation of critically ill patients. Rehabilitation includes the evaluation and prevention of functional kinetic alterations, application of treatment interventions (respiratory and/or motor physiotherapy), control and application of medical gases, care of mechanical ventilation, weaning and extubation, tracheal gas insufflation, inflation/deflation of the endotracheal cuff protocol, and surfactant application, aiming to allow patients to have a full recovery and return to their functional activities. In this article, we present guidelines that are intended to guide the physiotherapist in some of the prevention/treatment interventions in respiratory therapy (airway clearance, lung expansion, position in bed, airway suction, drug inhalation, and cough assist), which help in the rehabilitation process of newborns and children in intensive care units during mechanical ventilation and up to 12 hours following extubation.


Retinal oedema in central retinal artery occlusion develops as a function of time.
Time is the key criterion in the management of non-arteritic central retinal artery occlusion (NA-CRAO). However, the precise onset of vision loss is often difficult to determine. This study aimed to evaluate the temporal changes of retinal thickness in acute NA-CRAO and the potential of this parameter to be used as a surrogate marker to estimate the onset of retinal ischaemia. Optical coherence tomography was used to continuously assess retinal thickness and oedema progression rate in six porcine eyes. Additionally, a retrospective analysis of 12 patients with acute NA-CRAO was performed to determine association strength and progression rate between retinal thickness and onset of ischaemia. All Optical coherence tomography (OCT) scans (pigs and NA-CRAO patients) were performed within an ischaemic time frame of up to 9 hr. Retinal oedema progression rate in pigs was 25.32 µm/hr [CI 95%: 24.24-26.40 µm/hr]. Retrospective analysis of the patients revealed a strong correlation between retinal oedema and duration of ischaemia (Spearman's rho = 0.77, p = 0.004) with an estimated progression rate of 10.02 µm/hr [CI 95%: 3.30-16.74 µm/hr]. Retinal thickness increases with oedema formation, and ischaemia onset is strongly correlated with this structural biomarker in both, pigs and NA-CRAO patients. Prospective clinical trials will have to determine the clinical feasibility of retinal thickness measurements as a biomarker to support clinical management of NA-CRAO.


NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study).
Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative trends (P<0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG


Increased posterior hippocampal volumes in children with lower increase in body mass index: a 3-year longitudinal MRI study.
People are generally lean during childhood and show more variability in body sizes and shapes later in life. Cortical development generally correlates with body growth. However, in children cortical growth may be impaired with oversized body growth. Inverse correlations between body mass index (BMI) and brain volumes suggest that lean bodies may be associated with increased cortical volume. To clarify the positive effects of a lean body on a child's cortical development, we used MRI to measure brain structures longitudinally in 107 children and adolescents aged 5-16 years. The relationships between changes in BMI and cortical volumes during 3 years of development were investigated, while controlling for age, gender and intracranial volume changes. Voxel-based morphometry analyses revealed that an increase in the volume of the right posterior medial temporal lobe – including the hippocampus and parahippocampal gyrus – was associated with lower BMI increases. No correlations were observed between higher BMI increases and cortical volumes. Our results suggest that keeping a lean body – or not getting fat – during childhood can induce an increase in regional cortical volume rather than impair growth. This is the first longitudinal study showing positive effects of a lean body on cortical development in children.


Pastoralism may have delayed the end of the green Sahara.
The climate deterioration after the most recent African humid period (AHP) is a notable past example of desertification. Evidence points to a human population expansion in northern Africa prior to this, associated with the introduction of pastoralism. Here we consider the role, if any, of this population on the subsequent ecological collapse. Using a climate-vegetation model, we estimate the natural length of the most recent AHP. The model indicates that the system was most susceptible to collapse between 7 and 6 ka; at least 500 years before the observed collapse. This suggests that the inclusion of increasing elements of pastoralism was an effective adaptation to the regional environmental changes. Pastoralism also appears to have slowed the deterioration caused by orbitally-driven climate change. This supports the view that modern pastoralism is not only sustainable, but beneficial for the management of the world's dryland environments.


Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling.
Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike many GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.


A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing.
The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical "handles" to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.


Social network analysis of stakeholder networks from two community-based obesity prevention interventions.
Studies of community-based obesity prevention interventions have hypothesized that stakeholder networks are a critical element of effective implementation. This paper presents a quantitative analysis of the interpersonal network structures within a sub-sample of stakeholders from two past successful childhood obesity prevention interventions. Participants were recruited from the stakeholder groups (steering committees) of two completed community-based intervention studies, Romp & Chomp (R&C), Australia (2004-2008) and Shape Up Somerville (SUS), USA (2003-2005). Both studies demonstrated significant reductions of overweight and obesity among children. Members of the steering committees were asked to complete a retrospective social network questionnaire using a roster of other committee members and free recall. Each participant was asked to recall the people with whom they discussed issues related to childhood obesity throughout the intervention period, along with providing the closeness and level of influence of each relationship. Networks were reported by 13 participants from the SUS steering committee and 8 participants from the R&C steering committee. On average, participants nominated 16 contacts with whom they discussed issues related to childhood obesity through the intervention, with approximately half of the relationships described as 'close' and 30% as 'influential'. The 'discussion' and 'close' networks had high clustering and reciprocity, with ties directed to other steering committee members, and to individuals external to the committee. In contrast, influential ties were more prominently directed internal to the steering committee, with higher network centralization, lower reciprocity and lower clustering. Social network analysis provides a method to evaluate the ties within steering committees of community-based obesity prevention interventions. In this study, the network characteristics between a sub-set of stakeholders appeared to be supportive of diffused communication. Future work should prospectively examine stakeholder network structures in a heterogeneous sample of community-based interventions to identify elements most strongly associated with intervention effectiveness.


Modulation of interleukin-1β-induced inflammatory responses by a synthetic cationic innate defence regulator peptide, IDR-1002, in synovial fibroblasts.
Innate defence regulator (IDR) peptides are synthetic cationic peptides, variants of naturally occurring innate immune effector molecules known as host defence peptides. IDR peptides were recently demonstrated to limit infection-associated inflammation selectively without compromising host innate immune functions. This study examined the impact of a 12-amino acid IDR peptide, IDR-1002, in pro-inflammatory cytokine interleukin (IL)-1β-induced responses in synovial fibroblasts, a critical cell type in the pathogenesis of inflammatory arthritis. Human fibroblast-like synoviocytes (FLS) were stimulated with IL-1β in the presence and absence of IDR-1002. Production of enzyme matrix metalloproteinase-3 (MMP-3) and IL-1-receptor antagonist (IL-1RA) was monitored by enzyme-linked immunosorbent assay (ELISA), and various chemokines were evaluated by using multiplex cytometric bead array. Transcriptional responses were analyzed by quantitative real-time PCR. The impact on IL-1β-induced proteome was investigated by quantitative proteomics by using isobaric tags. IL-1β-induced pathways altered by IDR-1002 implicated by the proteomics analyses were further investigated by using various immunochemical assays. Cellular uptake of the peptide was monitored by using a biotinylated IDR-1002 peptide followed by microscopy probing with streptavidin-Alexa Fluor. This study demonstrated that IDR-1002 suppressed the production of IL-1β-induced MMP-3 and monocyte chemotactic protein-1 (MCP-1); in contrast, IDR-1002 enhanced the production of IL-1RA, without neutralizing all chemokine responses. IDR-1002 altered the IL-1β-induced proteome primarily by altering the expression of members of nuclear factor kappa-B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. The proteomics data also suggested that IDR-1002 was altering the transcription factor HNF-4α-mediated responses, known to be critical in metabolic regulation. With various immunochemical assays, it was further demonstrated that IL-1β-induced NF-κB, JNK, and p38 mitogen-activated protein kinase (MAPK) activations were significantly suppressed by IDR-1002. This study demonstrates the ability of an innate immune-modulatory IDR-peptide to influence the IL-1β-induced regulatory pathways and selectively to suppress inflammatory responses in synovial fibroblasts. The results of this study provide a rationale for examining the use of IDR-peptides as potential therapeutic candidates for chronic inflammatory diseases such as inflammatory arthritis.


A Systems Biology Approach in Therapeutic Response Study for Different Dosing Regimens-a Modeling Study of Drug Effects on Tumor Growth using Hybrid Systems.
Motivated by the frustration of translation of research advances in the molecular and cellular biology of cancer into treatment, this study calls for cross-disciplinary efforts and proposes a methodology of incorporating drug pharmacology information into drug therapeutic response modeling using a computational systems biology approach. The objectives are two fold. The first one is to involve effective mathematical modeling in the drug development stage to incorporate preclinical and clinical data in order to decrease costs of drug development and increase pipeline productivity, since it is extremely expensive and difficult to get the optimal compromise of dosage and schedule through empirical testing. The second objective is to provide valuable suggestions to adjust individual drug dosing regimens to improve therapeutic effects considering most anticancer agents have wide inter-individual pharmacokinetic variability and a narrow therapeutic index. A dynamic hybrid systems model is proposed to study drug antitumor effect from the perspective of tumor growth dynamics, specifically the dosing and schedule of the periodic drug intake, and a drug's pharmacokinetics and pharmacodynamics information are linked together in the proposed model using a state-space approach. It is proved analytically that there exists an optimal drug dosage and interval administration point, and demonstrated through simulation study.


Differences in gray matter structure correlated to nationalism and patriotism.
Nationalism and patriotism both entail positive evaluations of one's nation. However, the former inherently involves derogation of other nations, whereas the latter is independent of comparisons with other nations. We used voxel-based morphometry and psychological measures and determined nationalism and patriotism's association with gray matter density (rGMD) and their cognitive nature in healthy individuals (433 men and 344 women; age, 20.7 ± 1.9 years) using whole-brain multiple regression analyses and post hoc analyses. We found higher nationalism associated with greater rGMD in (a) areas of the posterior cingulate cortex and greater rGMD in (b) the orbitofrontal cortex, and smaller rGMD in (c) the right amygdala area. Furthermore, we found higher patriotism associated with smaller rGMD in the (d) rostrolateral prefrontal cortex. Post hoc analyses revealed the mean rGMD of the cluster (a) associated with compassion, that of (b) associated with feeling of superiority, that of (c) associated with suicide ideation, and that of (d) associated with quality of life. These results indicate that individual nationalism may be mediated by neurocognitive mechanisms in social-related areas and limbic neural mechanisms, whereas patriotism may be mediated by neurocognitive mechanisms in areas related to well-being.


Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective.
Many psychiatric patients smoke, and are believed to be heavier smokers than those without psychiatric disorders. Cigarette smoking is one of the environmental factors that contributes to interindividual variations in response to an administered drug. Polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke induce hepatic aryl hydrocarbon hydroxylases, thereby increasing metabolic clearance of drugs that are substrates for these enzymes. PAHs have been shown to induce 3 hepatic cytochrome P450 (CYP) isozymes, primarily CYP1A1, 1A2 and 2E1. Drug therapy can also be affected pharmacodynamically by nicotine. The most common effect of smoking on drug disposition in humans is an increase in biotransformation rate, consistent with induction of drug-metabolising enzymes. Induction of hepatic enzymes has been shown to increase the metabolism and to decrease the plasma concentrations of imipramine, clomipramine, fluvoxamine and trazodone. The effect of smoking on the plasma concentrations of amitriptyline and nortriptyline is variable. Amfebutamone (bupropion) does not appear to be affected by cigarette smoking. Smoking is associated with increased clearance of tiotixene, fluphenazine, haloperidol and olanzapine. Plasma concentrations of chlorpromazine and clozapine are reduced by cigarette smoking. Clinically, reduced drowsiness in smokers receiving chlorpromazine, and benzodiazepines, compared with nonsmokers has been reported. Increased clearance of the benzodiazepines alprazolam, lorazepam, oxazepam, diazepam and demethyl-diazepam is found in cigarette smokers, whereas chlordiazepoxide does not appear to be affected by smoking. Carbamazepine appears to be minimally affected by cigarette smoke, perhaps because hepatic enzymes are already stimulated by its own autoinductive properties. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many psychotropic drugs. Clinicians should consider smoking as an important factor in the disposition of these drugs.


The expectations of pregnant women regarding antenatal care.
From a feminist perspective, research on childbirth and women's health is a means to a positive change that is conducted in partnership with women for their benefit. A patient-led National Health System (NHS) (Hillan, 1999) also calls for consultation with patients and the wider public for shaping the current and future health services. This study was aimed at exploring and describing the expectations that pregnant women have regarding antenatal care service by the midwife practitioner. In-depth interviews were conducted in an antenatal unit of an Academic Hospital in Gauteng Povince. Data saturation was reached with a sample of eighteen pregnant women who were conveniently selected. Data analysis ran concurrently with data collection. A manual content analysis as described by Tesch was used. Lincoln and Guba's method of ensuring trustworthiness was adopted (Lincoln & Guba, 1985:328) Literature was undertaken to compare the findings of this study with those of other previous studies. Women displayed several common expectations that led to the saturation of data. It also became apparent from the findings that each woman had varied expectations. There were also some commonalities within the women's expectations. Health care, as the major expectation and a basic human right, appeared to be basically fulfilled, with the exception of interactional characteristics such as the communication of information, guidance, involvement, the understanding and explanation of aspects, freedom of choice, punctuality, individualized care and continuity of care. The conclusions that were reached let to recommendations for nursing practice, education, research and the formulation of guidelines for the midwife practitioner for the implementation of effective antenatal care, based on the identified expectations.


Development of quality measures for the care of patients with gastroesophageal reflux disease.
Gastroesophageal reflux disease (GERD) is a common and costly disorder. Symptoms attributed to GERD have a wide spectrum of presentations and complications that have led to complex diagnostic and management algorithms. As such, there is considerable variation in clinical approaches to GERD. In contrast to multiple published guidelines for the management of GERD, there are few validated GERD quality measures. The objective of this study was to use a well-described, formal methodology to develop valid, physician-led quality measures for all aspects of care for patients with GERD. Quality measures were identified from the literature, consensus guidelines, and GERD experts. Eight clinical experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. Of the 52 proposed quality measures, 24 were rated as valid, and 1 new measure was developed. These valid measures were related to initial diagnosis and management (9), monitoring (3), further diagnostic testing (4), proton pump inhibitor refractory symptoms (2), symptoms of chest pain (1), erosive esophagitis (3), esophageal stricture or ring (1), and surgical therapy (2). Fifteen of these measures were ranked with the highest validity. Twenty-seven measures were determined to be equivocal; 89% of these were extracted from guidelines that were based on low or moderate level evidence. We used RAND/University of California, Los Angeles Appropriateness Methodology to develop quality measures for GERD care. By examining performance on these valid, formally developed quality measures, clinical practices and individual providers can assess their adherence with them and direct quality improvement efforts accordingly.


Spatiotemporal selective extrapolation for 3-D signals and its applications in video communications.
In this paper, we derive a spatiotemporal extrapolation method for 3-D discrete signals. Extending a discrete signal beyond a limited number of known samples is commonly referred to as discrete signal extrapolation. Extrapolation problems arise in many applications in video communications. Transmission errors in video communications may cause data losses which are concealed by extrapolating the surrounding video signal into the missing area. The same principle is applied for TV logo removal. Prediction in hybrid video coding is also interpreted as an extrapolation problem. Conventionally, the unknown areas in the video sequence are estimated from either the spatial or temporal surrounding. Our approach considers the spatiotemporal signal including the missing area in a volume and replaces the unknown samples by extrapolating the surrounding signal from spatial, as well as temporal direction. By exploiting spatial and temporal correlations at the same time, it is possible to inherently compensate motion. Deviations in luminance occurring from frame to frame can be compensated, too.


Effects of glucosinolates on a generalist and specialist leaf-chewing herbivore and an associated parasitoid.
Glucosinolates (GLS) are secondary plant metabolites that as a result of tissue damage, for example due to herbivory, are hydrolysed into toxic compounds that negatively affect generalist herbivores. Specialist herbivores have evolved specific adaptations to detoxify GLS or inhibit the formation of toxic hydrolytic products. Although rarely studied, GLS and their breakdown products may also affect parasitoids. The objectives were to test the effects of GLS in a multitrophic system consisting of the generalist herbivore Spodoptera exigua, the specialist herbivore Pieris rapae, and the endoparasitoid Hyposoter ebeninus. Three ecotypes of Arabidopsis thaliana that differ in their GLS composition and concentrations and one transformed line that constitutively produces higher concentrations of aliphatic GLS were used, the latter allowing a direct assessment of the effects of aliphatic GLS on insect performance. Feeding by the generalist S. exigua and the specialist P. rapae induced both higher aliphatic and indole GLS concentrations in the A. thaliana ecotypes, although induction was stronger for indole than aliphatic GLS. For both herbivores a negative correlation between performance and aliphatic GLS concentrations was observed. This suggests that the specialist, despite containing a nitrile-specifier protein (NSP) that diverts GLS degradation from toxic isothiocyanates to less toxic nitriles, cannot completely inhibit the formation of toxic GLS hydrolytic products, or that the costs of this mechanism are higher at higher GLS concentrations. Surprisingly, performance of the parasitoid was positively correlated with higher concentrations of aliphatic GLS in the plant, possibly caused by negative effects on host immune responses. Our study indicates that GLS can not only confer resistance against herbivores directly, but also indirectly by increasing the performance of the parasitoids of these herbivores.


The evolution of social networks through the implementation of evidence-informed decision-making interventions: a longitudinal analysis of three public health units in Canada.
We studied the evolution of information-seeking networks over a 2-year period during which an organization-wide intervention was implemented to promote evidence-informed decision-making (EIDM) in three public health units in Ontario, Canada. We tested whether engagement of staff in the intervention and their EIDM behavior were associated with being chosen as information source and how the trend of inter-divisional communications and the dominance of experts evolved over time. Local managers at each health unit selected a group of staff to get engage in Knowledge Broker-led workshops and development of evidence summaries to address local public health problems. The staff were invited to answer three online surveys (at baseline and two annual follow-ups) including name generator questions eliciting the list of the staff they would turn to for help integrating research evidence into practice. We used stochastic actor-oriented modeling to study the evolution of networks. We tested the effect of engagement in the intervention, EIDM behavior scores, organizational divisions, and structural dynamics of social networks on the tendency of staff to select information sources, and the change in its trend between year 1 and year 2 of follow-up. In all the three health units, and especially in the two units with higher levels of engagement in the intervention, the network evolved towards a more centralized structure, with an increasing significance of already central staff. The staff showed greater tendencies to seek information from peers with higher EIDM behavior scores. In the public health unit that had highest engagement and stronger leadership support, the engaged staff became more central. In all public health units, the engaged staff showed an increasing tendency towards forming clusters. The staff in the three public health units showed a tendency towards limiting their connections within their divisions. The longitudinal analysis provided us with a means to study the microstructural changes in public health units, clues to the sustainability of the implementation. The hierarchical transformation of networks towards experts and formation of clusters among staff who were engaged in the intervention show how implementing organizational interventions to promote EIDM may affect the knowledge flow and distribution in health care communities, which may lead to unanticipated consequences.


Empagliflozin/linagliptin single-pill combination therapy for patients with type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is typically progressive, with sequential addition of therapies often needed to address increasing hyperglycemia over the disease course. Using treatments in combination may be preferred to sequential addition, as a means of providing a more rapid clinical response and potentially avoiding clinical inertia. In such cases, a single-pill combination can help to reduce pill burden. Although various single-pill combinations of oral glucose-lowering agents are available, empagliflozin/linagliptin was the first approved combination of a sodium glucose co-transporter 2 (SGLT2) inhibitor with a dipeptidyl peptidase 4 (DPP-4) inhibitor in the United States. Areas covered: Two publications of the clinical trial investigating the efficacy and safety of single-pill combinations of empagliflozin/linagliptin in treatment-naive or metformin-treated patients with T2DM (NCT01422876) are reviewed, and their potential impact on clinical practice is discussed. Expert opinion: The study discussed provides evidence for the efficacy and safety of empagliflozin/linagliptin single pills. Addition of an empagliflozin/linagliptin single pill may be considered in patients with inadequate glycemic control on metformin, or as an alternative to first-line treatment with empagliflozin or linagliptin when metformin is not suitable, particularly in patients with very poor glycemic control, or those who need to achieve target more quickly.


RhoC and ROCKs regulate cancer cell interactions with endothelial cells.
RhoC is a member of the Rho GTPase family that is implicated in cancer progression by stimulating cancer cell invasiveness. Here we report that RhoC regulates the interaction of cancer cells with vascular endothelial cells (ECs), a crucial step in the metastatic process. RhoC depletion by RNAi reduces PC3 prostate cancer cell adhesion to ECs, intercalation between ECs as well as transendothelial migration in vitro. Depletion of the kinases ROCK1 and ROCK2, two known RhoC downstream effectors, similarly decreases cancer interaction with ECs. RhoC also regulates the extension of protrusions made by cancer cells on vascular ECs in vivo. Transient RhoC depletion is sufficient to reduce both early PC3 cell retention in the lungs and experimental metastasis formation in vivo. Our results indicate RhoC plays a central role in cancer cell interaction with vascular ECs, which is a critical event for cancer progression.


Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.
Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2(-/-) embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2(+/-)) can support the development of double-mutant (Aldh2(-/-)Fancd2(-/-)) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2(-/-)Fancd2(-/-) mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.


Online division of labour: emergent structures in Open Source Software.
The development Open Source Software fundamentally depends on the participation and commitment of volunteer developers to progress on a particular task. Several works have presented strategies to increase the on-boarding and engagement of new contributors, but little is known on how these diverse groups of developers self-organise to work together. To understand this, one must consider that, on one hand, platforms like GitHub provide a virtually unlimited development framework: any number of actors can potentially join to contribute in a decentralised, distributed, remote, and asynchronous manner. On the other, however, it seems reasonable that some sort of hierarchy and division of labour must be in place to meet human biological and cognitive limits, and also to achieve some level of efficiency. These latter features (hierarchy and division of labour) should translate into detectable structural arrangements when projects are represented as developer-file bipartite networks. Thus, in this paper we analyse a set of popular open source projects from GitHub, placing the accent on three key properties: nestedness, modularity and in-block nestedness -which typify the emergence of heterogeneities among contributors, the emergence of subgroups of developers working on specific subgroups of files, and a mixture of the two previous, respectively. These analyses show that indeed projects evolve into internally organised blocks. Furthermore, the distribution of sizes of such blocks is bounded, connecting our results to the celebrated Dunbar number both in off- and on-line environments. Our conclusions create a link between bio-cognitive constraints, group formation and online working environments, opening up a rich scenario for future research on (online) work team assembly (e.g. size, composition, and formation). From a complex network perspective, our results pave the way for the study of time-resolved datasets, and the design of suitable models that can mimic the growth and evolution of OSS projects.


All-Trans Retinoic Acid Induces TGF-β2 in Intestinal Epithelial Cells via RhoA- and p38α MAPK-Mediated Activation of the Transcription Factor ATF2.
We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently-transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. AtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation. AtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.


Relevance theory: pragmatics and cognition.
Relevance Theory is a cognitively oriented theory of pragmatics, i.e., a theory of language use. It builds on the seminal work of H.P. Grice(1) to develop a pragmatic theory which is at once philosophically sensitive and empirically plausible (in both psychological and evolutionary terms). This entry reviews the central commitments and chief contributions of Relevance Theory, including its Gricean commitment to the centrality of intention-reading and inference in communication; the cognitively grounded notion of relevance which provides the mechanism for explaining pragmatic interpretation as an intention-driven, inferential process; and several key applications of the theory (lexical pragmatics, metaphor and irony, procedural meaning). Relevance Theory is an important contribution to our understanding of the pragmatics of communication.