Induction of adult human bone marrow mesenchymal stromal cells into functional astrocyte-like cells: potential for restorative treatment in Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder with its motor phenomena due mostly to loss of dopamine-producing neurons in the substantia nigra. Pharmacological treatments aimed to increase the deficient dopaminergic neurotransmission are effective in ameliorating the cardinal symptoms, but none of these therapies is curative. It has been suggested that treatment with neurotrophic factors (NTFs) might protect and prevent death of the surviving dopaminergic neurons and induce proliferation of their axonal nerve terminals with reinnervations of the deafferented striatum. However, long-term delivery of such proteins into the CNS is problematic. We therefore aimed to differentiate ex vivo human bone marrow-derived mesenchymal stromal cells into astrocyte-like cells, capable of generating NTFs for future transplantation into basal ganglia of PD patients. Indeed, mesenchymal stromal cells treated with our novel astrocyte differentiation medium, present astrocyte-like morphology and express the astrocyte markers S100beta, glutamine synthetase and glial fibrillary acidic protein. Moreover, these astrocyte-like cells produce and secrete significant amounts of glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor as indicated by messenger RNA, real-time polymerase chain reaction, ELISA, and Western blot analyses. Such NTF-producing cells transplanted into the striatum of 6-hydroxydopamine-lesioned rats, a model of PD, produced a progressive reduction in the apomorphine-induced contralateral rotations as well as behavioral improvement in rotor-rod and the "sunflower seeds" eating motor tests. Histological assessments revealed that the engrafted cells survived and expressed astrocyte and human markers and acted to regenerate the damaged dopaminergic nerve terminal system. Findings indicate that our novel procedure to induce NTF-producing astrocyte-like cells derived from human bone marrow stromal cells might become a promising and feasible autologous transplantation strategy for PD.


Glutamine is required for persistent epileptiform activity in the disinhibited neocortical brain slice.
The neurotransmitter glutamate is recycled through an astrocytic-neuronal glutamate-glutamine cycle in which synaptic glutamate is taken up by astrocytes, metabolized to glutamine, and transferred to neurons for conversion back to glutamate and subsequent release. The extent to which neuronal glutamate release is dependent upon this pathway remains unclear. Here we provide electrophysiological and biochemical evidence that in acutely disinhibited rat neocortical slices, robust release of glutamate during sustained epileptiform activity requires that neurons be provided a continuous source of glutamine. We demonstrate that the uptake of glutamine into neurons for synthesis of glutamate destined for synaptic release is not strongly dependent on the system A transporters, but requires another unidentified glutamine transporter or transporters. Finally, we find that the attenuation of network activity through inhibition of neuronal glutamine transport is associated with reduced frequency and amplitude of spontaneous events detected at the single-cell level. These results indicate that availability of glutamine influences neuronal release of glutamate during periods of intense network activity.


[The fate of injured motor neurons and the behavior of surrounding glial cells].
The fate of injured motor neurons could be determined by the balance of the protection and death signals, which expressed in the injured motor neuron. However recent studies implied the significances of surrounding non-neuronal cells for the protection of motor neurons in degenerative diseases and nerve injury. In periphery Schwann cell, macrophage and endoneurial fibroblast play crucial roles for the proper nerve regeneration. Schwann cell promotes infiltration of macrophage to remove debris of degenerated myelin and provides a scaffold and several growth factors for axon to elongate. The macrophage phagocytoses myelin debris and stocks lipids, which is re-used for re-myelination by Schwann cell. The fibroblast controls the localization of axon and Schwann cells during nerve regeneration. For those cellular functions several mediators among those cells are expressed. In CNS microglia and astrocytes would be the major players for the protection of motor neurons after injury. After nerve injury the activated microglia adhered to the injured motor neurons for a while and then the astrocyte took over, whereas in the dying motor neurons the initial behavior of the microglia was not observed. Glial behavior in CNS may be associated with the fate of injured motor neurons.


Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells.
The retinoids, the natural or synthetic derivatives of Vitamin A (retinol), are essential for the normal development of prostate and have been shown to modulate prostate cancer progression in vivo as well as to modulate growth of several prostate cancer cell lines. 9-cis-retinoic acid and all-trans-retinoic acid are the two most important metabolites of retinol. Gap junctions, formed of proteins called connexins, are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells. Gap junctional communication is instrumental in the control of cell growth. We examined the effect of 9-cis-retinoic acid and all-trans retinoic acid on the formation and degradation of gap junctions as well as on junctional communication in an androgen-responsive prostate cancer cell line, LNCaP, which expressed retrovirally introduced connexin32, a connexin expressed by the luminal cells and well-differentiated cells of prostate tumors. Our results showed that 9-cis-retinoic acid and all-trans retinoic acid enhanced the assembly of connexin32 into gap junctions. Our results further showed that 9-cis-retinoic acid and all-trans-retinoic acid prevented androgen-regulated degradation of gap junctions, post-translationally, independent of androgen receptor mediated signaling. Finally, our findings showed that formation of gap junctions sensitized connexin32-expressing LNCaP cells to the growth modifying effects of 9-cis-retinoic acid, all-trans-retinoic acid and androgens. Thus, the effects of retinoids and androgens on growth and the formation and degradation of gap junctions and their function might be related to their ability to modulate prostate growth and cancer.


Impact of membrane partitioning on the spatial structure of an S-type cobra cytotoxin.
Cobra cytotoxins (CTs) belong to the three-fingered protein family. They are classified into S- and P-types, the latter exhibiting higher membrane-perturbing capacity. In this work, we investigated the interaction of CTs with phospholipid bilayers, using coarse-grained (CG) and full-atom (FA) molecular dynamics (MD). The object of this work is a CT of an S-type, cytotoxin I (CT1) from N.oxiana venom. Its spatial structure in aqueous solution and in the micelles of dodecylphosphocholine (DPC) were determined by 1H-NMR spectroscopy. Then, via CG- and FA MD-computations, we evaluated partitioning of CT1 molecule into palmitoyloleoylphosphatidylcholine (POPC) membrane, using the toxin spatial models, obtained either in aqueous solution, or detergent micelle. The latter model exhibits minimal structural changes upon partitioning into the membrane, while the former deviates from the starting conformation, loosing the tightly bound water molecule in the loop-2. These data show that the structural changes elicited by CT1 molecule upon incorporation into DPC micelle take place likely in the lipid membrane, although the mode of the interaction of this toxin with DPC micelle (with the tips of the all three loops) is different from its mode in POPC membrane (primarily with the tip of the loop-1 and both the tips of the loop-1 and loop-2).


Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning.
Defining the three body axes is a central event of vertebrate morphogenesis. Establishment of left-right (L-R) asymmetry in development follows the determination of dorsal-ventral and anterior-posterior (A-P) body axes, although the molecular mechanism underlying precise L-R symmetry breaking in reference to the other two axes is still poorly understood. Here, by removing both Vangl1 and Vangl2, the two mouse homologues of a Drosophila core planar cell polarity (PCP) gene Van Gogh (Vang), we reveal a previously unrecognized function of PCP in the initial breaking of lateral symmetry. The leftward nodal flow across the posterior notochord (PNC) has been identified as the earliest event in the de novo formation of L-R asymmetry. We show that PCP is essential in interpreting the A-P patterning information and linking it to L-R asymmetry. In the absence of Vangl1 and Vangl2, cilia are positioned randomly around the centre of the PNC cells and nodal flow is turbulent, which results in disrupted L-R asymmetry. PCP in mouse, unlike what has been implicated in other vertebrate species, is not required for ciliogenesis, cilium motility, Sonic hedgehog (Shh) signalling or apical docking of basal bodies in ciliated tracheal epithelial cells. Our data suggest that PCP acts earlier than the unidirectional nodal flow during bilateral symmetry breaking in vertebrates and provide insight into the functional mechanism of PCP in organizing the vertebrate tissues in development.


Headache characteristics of uncomplicated intracranial vertebral artery dissection and validation of ICHD-3 beta diagnostic criteria for headache attributed to intracranial artery dissection.
Headache may be a warning sign of subsequent stroke in patients with vertebral artery dissection (VAD). Even though the headache characteristics of VAD have been described predominantly in patients with extracranial VAD and neurological complications, headache semiology is not well known in patients with uncomplicated intracranial vertebral artery dissection (ICVAD). In the present study, we attempt to identify the headache semiology that characterizes ICVAD and validate the revised version of the International Classification of Headache Disorders (ICHD-3 beta) criteria for headache attributed to intracranial artery dissection. Six patients with neurologically uncomplicated ICVAD presented at a participating medical center, and eight similar patients were reviewed in the literature. Combining these data, we analyzed headache characteristics of patients with uncomplicated ICVAD according to their pain onset and duration, nature, intensity, location, aggravating and relieving factors, associated symptoms, response to medication, and prognosis. Headache in uncomplicated ICVAD usually has an acute mode of onset (11/14) and persistent (10/14) temporal feature. Pain that has a throbbing quality (nine of 14) and severe intensity (13/14) on the ipsilesional (10/14) and occipitonuchal area (12/14) is a headache prototype in ICVAD. Additionally, headache was intensified by head flexion and rotation (three of six), and relieved by head extension and supine positioning (five of six). Headache of all patients in the present study fulfilled the ICHD-3 beta criteria. Headache semiology of uncomplicated ICVAD is mostly homogenous in the present study. These characteristics may be helpful in the diagnosis of uncomplicated ICVAD.


Parental love pills: some ethical considerations.
It may soon be possible to develop pills that allow parents to induce in themselves more loving behaviour, attitudes and emotions towards their children. In this paper, I consider whether pharmacologically induced parental love can satisfy reasonable conditions of authenticity; why anyone would be interested in taking such parental love pills at all, and whether inducing parental love pharmacologically promotes narcissism or results in self-instrumentalization. I also examine how the availability of such pills may affect the duty to love a child.


2015 Beers Criteria and STOPP v2 for detecting potentially inappropriate medication in community-dwelling older people: prevalence, profile, and risk factors.
To comparatively assess the prevalence rates of potentially inappropriate medications (PIMs) obtained by the former and latest versions of American Geriatrics Society Beers Criteria (AGS BC) and screening tool of older person's potentially inappropriate prescriptions (STOPP), and analyze the factors of influence on PIM. Cross-sectional study including 582 community-dwelling older adults over the age of 65. Sociodemographic, clinical, functional, and comprehensive drug therapy data were collected. The primary endpoint was the percentage of patients receiving at least one PIM. A total of 3626 prescriptions were analyzed. PIMs were detected in 35.4% and 47.9% of patients according to the STOPP v1 and the 2012 AGS BC, respectively. This percentage rose to 54% when 2015 AGS BC were used and reached 66.8% with STOPP v2. The kappa coefficient between STOPP v2 and its former version was lower than the one between the updated Beers Criteria and their former version (0.41 vs 0.85). The agreement was good (0.65) between both latest criteria. The number of medications, psychological disorders, and insomnia were predictors of PIM. A novel finding was that bone and joint disorders increased the odds for PIM by 78%. The 2015 AGS BC showed high sensitivity and good applicability to the European older patients. Both updated tools identified some pharmacological groups (benzodiazepines, PPIs, and opioids, among others) and certain health problems (insomnia, psychological disorders, and osteoarticular diseases) as factors of influence on PIM. Based on these findings, interventions aimed at promoting appropriate use of medications should be developed.


Efficacy evaluation of 2D, 3D U-Net semantic segmentation and atlas-based segmentation of normal lungs excluding the trachea and main bronchi.
This study aimed to examine the efficacy of semantic segmentation implemented by deep learning and to confirm whether this method is more effective than a commercially dominant auto-segmentation tool with regards to delineating normal lung excluding the trachea and main bronchi. A total of 232 non-small-cell lung cancer cases were examined. The computed tomography (CT) images of these cases were converted from Digital Imaging and Communications in Medicine (DICOM) Radiation Therapy (RT) formats to arrays of 32 × 128 × 128 voxels and input into both 2D and 3D U-Net, which are deep learning networks for semantic segmentation. The number of training, validation and test sets were 160, 40 and 32, respectively. Dice similarity coefficients (DSCs) of the test set were evaluated employing Smart SegmentationⓇ Knowledge Based Contouring (Smart segmentation is an atlas-based segmentation tool), as well as the 2D and 3D U-Net. The mean DSCs of the test set were 0.964 [95% confidence interval (CI), 0.960-0.968], 0.990 (95% CI, 0.989-0.992) and 0.990 (95% CI, 0.989-0.991) with Smart segmentation, 2D and 3D U-Net, respectively. Compared with Smart segmentation, both U-Nets presented significantly higher DSCs by the Wilcoxon signed-rank test (P < 0.01). There was no difference in mean DSC between the 2D and 3D U-Net systems. The newly-devised 2D and 3D U-Net approaches were found to be more effective than a commercial auto-segmentation tool. Even the relatively shallow 2D U-Net which does not require high-performance computational resources was effective enough for the lung segmentation. Semantic segmentation using deep learning was useful in radiation treatment planning for lung cancers.


Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis.
Sipuleucel-T is a novel active cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). It is assumed to be associated with less adverse events than conventional docetaxel-based chemotherapy. A systematic review of literature published between January, 1 1966 and February, 6 2012 was performed to assess the efficacy and safety of sipuleucel-T in patients with mCRPC. Databases were searched: Medline, EMBASE, Cochrane, CancerLit as well as ASCO and ESCO websites. Three randomized clinical trials with a total of 737 participants fulfilled established criteria. The overall survival of patients who received sipuleucel-T in comparison to the control group was significantly longer with a hazard ratio (HR) of 0.73 (95% CI: 0.61-0.88; p = 0.001). Time to disease progression was not prolonged using sipuleucel-T compared to placebo, HR = 0.89 (95% CI: 0.75-1.05; p = 0.18). Relative benefit (RB) of serum PSA level reduction of at least 50% for sipuleucel-T compared to placebo did not meet statistical significance, RB = 1.97 (95% CI: 0.48-8.14; p = 0.38). The safety population consisted of 729 patients with mCRPC. Compared to the control group, the pooled relative risks (RR) of all adverse events - RR = 1.03 (95% CI: 1.00-1.05; p = 0.06), grade 3 to 5 adverse events - RR = 0.98 (95% CI: 0.79-1.22; p = 0.86) and cerebrovascular events - RR = 1.93 (95% CI: 0.73-5.09; p = 0.18) were not significantly higher for men treated with sipuleucel-T. The use of sipuleucel-T prolonged the overall survival among men with mCRPC. No effect on time to disease progression was observed and the safety profile was acceptable.


Involvement of ethylene biosynthesis and signalling in fruit set and early fruit development in zucchini squash (Cucurbita pepo L.).
We have identified a kind of parthenocarpy in zucchini squash which is associated with an incomplete andromonoecy, i.e. a partial conversion of female into bisexual flowers. Given that andromonoecy in this and other cucurbit species is caused by a reduction of ethylene production in the female flower, the associated parthenocarpic development of the fruit suggested the involvement of ethylene in fruit set and early fruit development. We have compared the production of ethylene as well as the expression of 13 ethylene biosynthesis and signalling genes in pollinated and unpollinated ovaries/fruits of two cultivars, one of which is parthenocarpic (Cavili), while the other is non-parthenocarpic (Tosca). In the latter, unpollinated ovaries show an induction of ethylene biosynthesis and ethylene signal transduction pathway genes three days after anthesis, which is concomitant with the initiation of fruit abortion and senescence. Fruit set and early fruit development in pollinated flowers of both cultivars and unpollinated flowers of Cavili is coupled with low ethylene biosynthesis and signalling, which would also explain the partial andromonoecy in the parthenocarpic genotype. The reduction of ethylene production in the ovary cosegregates with parthenocarpy and partial andromonoecy in the selfing progeny of Cavili. Moreover, the induction of ethylene in anthesis (by ethephon treatments) reduced the percentage of bisexual parthenocarpic flowers in Cavili, while the inhibition of ethylene biosynthesis or response (by AVG and STS treatments) induces not only andromonoecy but also the parthenocarpic development of the fruit in both cultivars. Results demonstrate that a reduction of ethylene production or signalling in the zucchini flower is able to induce fruit set and early fruit development, and therefore that ethylene is actively involved in fruit set and early fruit development. Auxin and TIBA treatments, inducing fruit set and early fruit development in this species, also inhibit ethylene production and the expression of ethylene biosynthesis and response genes. A model is presented that discusses the crosstalk between ethylene and auxin in the control of fruit set and early fruit development in zucchini squash.


The absence of alternative oxidase AOX1A results in altered response of photosynthetic carbon assimilation to increasing CO(2) in Arabidopsis thaliana.
In higher plants, the mitochondrial electron transport chain has non-phosphorylating alternative pathways that include the alternative terminal oxidase (AOX). This alternative pathway has been suggested to act as a sink for dissipating excess reducing power, minimizing oxidative stress and possibly optimizing photosynthesis in response to changing conditions. The expression patterns of the AOX genes have been well characterized under different growth conditions, particularly in response to light and temperature stress. Additionally, it has been suggested that mitochondrial electron transport is important for avoiding chloroplast over-reduction and balancing energy partitioning among photosynthesis, photorespiration and respiration. Nonetheless, the role AOX plays in optimizing photosynthetic carbon metabolism is unclear. Therefore, the response of photosynthesis to the disruption of AOX was investigated in the Arabidopsis thaliana T-DNA mutant aox1a (SALK_084897). Gas exchange analysis revealed a lower net CO(2) assimilation rate (A) at high CO(2) concentrations in the aox1a mutant compared to wild type. This decrease in A was accompanied by a lower maximum electron transport rate and quantum yield of PSII, and higher excitation pressure on PSII and non-photochemical quenching. The aox1a mutant also exhibited a lower estimated rate of ribulose 1,5-bisphosphate regeneration, and the ribulose 1,5-bisphosphate content was lower at high CO(2) concentrations, suggesting an ATP limitation of the Calvin-Benson cycle. Additionally, the activity of the malate-oxaloacetate shuttle was lower in the mutant compared to wild type. These results indicate that AOX is important for optimizing rates of photosynthetic CO(2) assimilation in response to rising CO(2) concentration by balancing the NAD(P)H/ATP ratio and rates of ribulose 1,5-bisphosphate regeneration within the chloroplast.


Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study.
A healthy lifestyle is the first-line treatment in non-alcoholic fatty liver disease (NAFLD), but specific dietary recommendations are lacking. Therefore, we aimed to determine whether dietary macronutrient composition is associated with NAFLD. Participants from the Rotterdam Study were assessed on (1) average intake of macronutrients (protein, carbohydrate, fat, fibre) using a Food Frequency Questionnaire and (2) NAFLD presence using ultrasonography, in absence of excessive alcohol, steatogenic drugs and viral hepatitis. Macronutrients were analysed using the nutrient density method and ranked (Q1-Q4). Logistic regression analyses were adjusted for sociodemographic, lifestyle and metabolic covariates. Moreover, analyses were adjusted for and stratified by body mass index (BMI) (25 kg/m2). Also, substitution models were built. In total, 3882 participants were included (age 70±9, 58% female). NAFLD was present in 1337 (34%) participants of whom 132 were lean and 1205 overweight. Total protein was associated with overweight NAFLD after adjustment for sociodemographic and lifestyle covariates (ORQ4vsQ1 1.40; 95% CI 1.11 to 1.77). This association was driven by animal protein (ORQ4vsQ1 1.54; 95% CI 1.20 to 1.98). After adjustment for metabolic covariates, only animal protein remained associated with overweight NAFLD (ORQ4vsQ1 1.36; 95% CI 1.05 to 1.77). Monosaccharides and disaccharides were associated with lower overall NAFLD prevalence (ORQ4vsQ1 0.66; 95% CI 0.52 to 0.83) but this effect diminished after adjustment for metabolic covariates and BMI. No consistent associations were observed for fat subtypes or fibre. There were no substitution effects. This large population-based study shows that high animal protein intake is associated with NAFLD in overweight, predominantly aged Caucasians, independently of well-known risk factors. Contrary to previous literature, our results do not support a harmful association of monosaccharides and disaccharides with NAFLD.


Long-term trends in the longevity of scientific elites: evidence from the British and the Russian academies of science.
National science academies represent intellectual elites and vanguard groups in the achievement of longevity. We estimated life expectancy (LE) at age 50 of members of the British Royal Society (RS) for the years 1670-2007 and of members of the Russian Academy of Sciences (RAS) for the years 1750-2006. The longevity of academicians was higher than that of their corresponding national populations, with the gap widening from the 1950s. Since the 1980s, LE in the RS has been higher than the maximum LE among all high-income countries. In each period, LE in the RS was greater than in the RAS, although since the 1950s it has risen in parallel in the two academies. This steep increase shared by academicians in Britain and Russia suggests that general populations have the potential for a substantial increase in survival to high ages.


An integrated model of cognitive control in task switching.
A model of cognitive control in task switching is developed in which controlled performance depends on the system maintaining access to a code in episodic memory representing the most recently cued task. The main constraint on access to the current task code is proactive interference from old task codes. This interference and the mechanisms that contend with it reproduce a wide range of behavioral phenomena when simulated, including well-known task-switching effects, such as latency and error switch costs, and effects on which other theories are silent, such as with-run slowing and within-run error increase. The model generalizes across multiple task-switching procedures, suggesting that episodic task codes play an important role in keeping the cognitive system focused under a variety of performance constraints.


Factors associated with reduction in use of neoadjuvant androgen suppression therapy before radical prostatectomy.
To determine whether the prescribing patterns for nonindicated androgen suppression therapy (AST), using neoadjuvant AST as the model, changed according to the prevailing clinical evidence, changes in reimbursement, or evidence of increased harm from treatment. We identified 34,976 men with prostate cancer who had undergone radical prostatectomy within 12 months of diagnosis from the Surveillance, Epidemiology, and End Results-Medicare data set (1992-2007), and their clinical and demographic parameters were assessed. We measured the Medicare claims for receipt of AST before radical prostatectomy and calculated the annual rates of neoadjuvant AST, which were adjusted for confounding variables using multivariate logistic regression analysis, and compared them with the prevailing published clinical data on the outcomes of neoadjuvant AST, changes in reimbursement, or published data on clinical harm from treatment. The use of neoadjuvant AST increased from 7.8% in 1992 to a peak of 17.6% in 1996 and then decreased steadily to 4.6% in 2007. This rate change was significant on multivariate regression analysis, with a single join point in 1996 (P <.001), and corresponded to published data showing improved surgical margin rates and pathologic downstaging in the early 1990s and data showing no improvement in disease recurrence or overall survival beginning in 1997. Changes in reimbursement and evidence of harm from AST were not associated with the decreased use of neoadjuvant AST. Using neoadjuvant AST as the model for the nonindicated use of AST, physicians reduced AST use in response to high-level evidence showing a lack of benefit, despite the high reimbursement. This suggests that physicians adapt to emerging evidence and use evidence-based practice.


Rationale for pertussis booster vaccination throughout life in Europe.
Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection.


Automated drusen segmentation and quantification in SD-OCT images.
Spectral domain optical coherence tomography (SD-OCT) is a useful tool for the visualization of drusen, a retinal abnormality seen in patients with age-related macular degeneration (AMD); however, objective assessment of drusen is thwarted by the lack of a method to robustly quantify these lesions on serial OCT images. Here, we describe an automatic drusen segmentation method for SD-OCT retinal images, which leverages a priori knowledge of normal retinal morphology and anatomical features. The highly reflective and locally connected pixels located below the retinal nerve fiber layer (RNFL) are used to generate a segmentation of the retinal pigment epithelium (RPE) layer. The observed and expected contours of the RPE layer are obtained by interpolating and fitting the shape of the segmented RPE layer, respectively. The areas located between the interpolated and fitted RPE shapes (which have nonzero area when drusen occurs) are marked as drusen. To enhance drusen quantification, we also developed a novel method of retinal projection to generate an en face retinal image based on the RPE extraction, which improves the quality of drusen visualization over the current approach to producing retinal projections from SD-OCT images based on a summed-voxel projection (SVP), and it provides a means of obtaining quantitative features of drusen in the en face projection. Visualization of the segmented drusen is refined through several post-processing steps, drusen detection to eliminate false positive detections on consecutive slices, drusen refinement on a projection view of drusen, and drusen smoothing. Experimental evaluation results demonstrate that our method is effective for drusen segmentation. In a preliminary analysis of the potential clinical utility of our methods, quantitative drusen measurements, such as area and volume, can be correlated with the drusen progression in non-exudative AMD, suggesting that our approach may produce useful quantitative imaging biomarkers to follow this disease and predict patient outcome.


A Framework for Local Mechanical Characterization of Atherosclerotic Plaques: Combination of Ultrasound Displacement Imaging and Inverse Finite Element Analysis.
Biomechanical models have the potential to predict plaque rupture. For reliable models, correct material properties of plaque components are a prerequisite. This study presents a new technique, where high resolution ultrasound displacement imaging and inverse finite element (FE) modeling is combined, to estimate material properties of plaque components. Iliac arteries with plaques were excised from 6 atherosclerotic pigs and subjected to an inflation test with pressures ranging from 10 to 120 mmHg. The arteries were imaged with high frequency 40 MHz ultrasound. Deformation maps of the plaques were reconstructed by cross correlation of the ultrasound radiofrequency data. Subsequently, the arteries were perfusion fixed for histology and structural components were identified. The histological data were registered to the ultrasound data to construct FE model of the plaques. Material properties of the arterial wall and the intima of the atherosclerotic plaques were estimated using a grid search method. The computed displacement fields showed good agreement with the measured displacement fields, implying that the FE models were able to capture local inhomogeneities within the plaque. On average, nonlinear stiffening of both the wall and the intima was observed, and the wall of the atheroslcerotic porcine iliac arteries was markedly stiffer than the intima (877 ± 459 vs. 100 ± 68 kPa at 100 mmHg). The large spread in the data further illustrates the wide variation of the material properties. We demonstrated the feasibility of a mixed experimental-numerical framework to determine the material properties of arterial wall and intima of atherosclerotic plaques from intact arteries, and concluded that, due to the observed variation, plaque specific properties are required for accurate stress simulations.


Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration.
Golgi anti-apoptotic proteins (GAAPs) are multitransmembrane proteins that are expressed in the Golgi apparatus and are able to homo-oligomerize. They are highly conserved throughout eukaryotes and are present in some prokaryotes and orthopoxviruses. Within eukaryotes, GAAPs regulate the Ca(2+) content of intracellular stores, inhibit apoptosis, and promote cell adhesion and migration. Data presented here demonstrate that purified viral GAAPs (vGAAPs) and human Bax inhibitor 1 form ion channels and that vGAAP from camelpox virus is selective for cations. Mutagenesis of vGAAP, including some residues conserved in the recently solved structure of a related bacterial protein, BsYetJ, altered the conductance (E207Q and D219N) and ion selectivity (E207Q) of the channel. Mutation of residue Glu-207 or -178 reduced the effects of GAAP on cell migration and adhesion without affecting protection from apoptosis. In contrast, mutation of Asp-219 abrogated the anti-apoptotic activity of GAAP but not its effects on cell migration and adhesion. These results demonstrate that GAAPs are ion channels and define residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion, and migration independently.


Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation.
Boric acid (BA), an essential plant micronutrient, occurs naturally in fruits, vegetables, and other foods. It is widely used in the manufacture of glass, ceramics, and other products. In a prior study, gestational exposure to BA was associated with developmental toxicity in the rat, including fetal growth retardation and altered skeletal morphology. In order to establish the developmental toxicity no-observed-adverse-effect level (NOAEL) in the rat, BA (0, 0.025, 0.05, 0.075, 0.1, or 0.2% in feed) was administered to timed-mated rats (60/group) from gestational day (gd) 0 to gd 20. Approximately half the dams were terminated on gd 20, and the remaining dams delivered their litters. Pup growth and viability were monitored until postnatal day (pnd) 21. Dams sacrificed on gd 20 (pnd 21) ingested average doses of 0(0), 19(19), 36(37), 55(56), 76(74), or 143(145) mg BA/kg/day. Maternal clinical signs, body weight, and food and water intake were measured at regular intervals during gestation and lactation. At termination, maternal liver and right kidney were weighed, and live fetuses (gd 20) and pups (pnd 21) were weighed, sexed, and examined for morphological anomalies (external, visceral, skeletal). Maternal effects were limited to increased relative kidney weight at 0.2% BA. Viability of the offspring was unaffected. On gd 20, fetal body weight was 94 and 88% of controls at 0.1 and 0.2% BA, but recovery was complete at birth (approximately gd 22). The incidence of short rib XIII was increased on gd 20 at > or = 0.1% BA, but only at 0.2% on pnd 21. The incidence of wavy rib was increased on gd 20 at > or = 0.1% BA, but the reversibility of this effect was confirmed on pnd 21. A slight decrease in extra lumbar ribs was observed at 0.2% BA on gd 20, and extra lumbar ribs were not found in any pups on pnd 21. Thus, the developmental toxicity NOAEL in the rat was 0.075% BA (55 mg/kg/day) on gd 20 and 0.1% BA (74 mg/kg/day) on pnd 21.


The transfer of knowledge on integrated care among five European regions: a qualitative multi-method study.
To examine how the knowledge transfer processes unfolded within SCIROCCO, a EU funded project (3rd Health Programme (2014-2020)) that aimed to facilitate the process of knowledge sharing across five European regions, to speed up adoption and scaling-up of integrated care initiatives. A qualitative multi-method design was used. Data collection methods included focus groups, project documents and action plans of the regions. The data was analysed using a qualitative content-analysis procedure, which was guided by the frameworks of knowledge exchange and the why, whose, what, how framework for knowledge mobilisers. All five components (including the themes) of knowledge exchange could be identified in the approach developed on the knowledge transfer processes. The four questions and accompanying categories of the framework of knowledge mobilisation were also identified to a large degree. The observed incorporation of distinct forms of knowledge from multiple sources and the observed dynamic and fluid knowledge transfer processes both suggest that SCIROCCO developed a comprehensive knowledge transfer approach aiming to enable the adoption and scaling-up of integrated care. Overall, the multi-method qualitative nature of this research has allowed some new and practical insights in the knowledge transfer activities on integrated care between several European regions. To obtain a clear understanding of the content of the knowledge transfer approaches, which could assist the operationalising of models to support the evaluation of knowledge transfer activities, it is strongly recommended that further research of this type should be conducted in other research settings.


Evaluation of the Start Strong initiative: preventing teen dating violence and promoting healthy relationships among middle school students.
This study reports on an independent evaluation of Start Strong: Building Healthy Teen Relationships, a multicomponent initiative targeting 11- to 14-year-olds. "Start Strong" was designed to focus on the developmental needs of middle school students and to enhance skills and attitudes consistent with promotion of healthy relationships and reduction of teen dating violence (TDV). The quasi-experimental evaluation design included data collection from four Start Strong schools and four comparison schools. Student surveys were collected at four waves of data at the beginning and the end of grades 7 and 8. Multilevel models used repeated observations nested within students who were, in turn, nested within schools to determine whether participation in Start Strong enhanced healthy skills and relationships and decreased TDV-related attitudes and behaviors. Short-term effects from waves 1 to 2 were statistically significant for increased parent-child communication and boy/girlfriend relationship satisfaction and support and decreased gender stereotypes and attitudes supporting TDV. Findings for acceptance of TDV and gender stereotypes persisted longitudinally. Results are promising and illustrate that a multicomponent, community-based initiative reduced risk factors predictive of TDV. Start Strong is innovative in its focus on early adolescence, which is a critical period in the transition to dating. The results inform future intervention efforts and underscore the need for further study of middle school students.


Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines.
Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N(epsilon)-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.


IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46.
The potent tumoricidal activity of interleukin 12 (IL-12) is thought to be mediated by the activation and polarization of natural killer (NK) cells and T helper type 1 (T(H)1) cells, respectively. By systematic analysis of the IL-12-induced immune response to subcutaneous melanoma (B16), we found that tumor suppression was mediated independently of T lymphocytes or NK cells. IL-12 initiated local antitumor immunity by stimulating a subset of NKp46(+) lymphoid tissue-inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46(+) LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion. Thus, this innate cell type is responsive to IL-12 and is a powerful mediator of tumor suppression.


A meta-analysis of prior corticosteroid use and fracture risk.
The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD. The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk. We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD. We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.


Extracellular Lactate: A Novel Measure of T Cell Proliferation.
Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [3H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze-thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro.


Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer.
To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC). Targeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes. The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance. Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.


A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders.
Epstein-Barr virus (EBV) encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). In this study, we tried to find series in which data of EBER and onset time of post-transplant lymphoproliferative disorder (PTLD) for patients have been documented to conduct a meta-analysis. A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered "early onset" when it develops within the first post-transplant year. Finally, 265 patients from 15 studies have been included in the meta-analysis. The overall meta-analysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001]. The i2 index was 49.8%. Our study suggests that PTLD lesions with positive EBER test are more likely to develop within the early post-transplant period. Since early-onset PTLD is supposed to have better prognosis, having a positive EBER test might not be a bad news. However, for having a precise conclusion, prospective studies are needed to be conducted.


Telehealthcare for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a disease of irreversible airways obstruction in which patients often suffer exacerbations. Sometimes these exacerbations need hospital care: telehealthcare has the potential to reduce admission to hospital when used to administer care to the pateint from within their own home. To review the effectiveness of telehealthcare for COPD compared with usual face-to-face care. We searched the Cochrane Airways Group Specialised Register, which is derived from systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO; last searched January 2010. We selected randomised controlled trials which assessed telehealthcare, defined as follows: healthcare at a distance, involving the communication of data from the patient to the health carer, usually a doctor or nurse, who then processes the information and responds with feedback regarding the management of the illness. The primary outcomes considered were: number of exacerbations, quality of life as recorded by the St George's Respiratory Questionnaire, hospitalisations, emergency department visits and deaths. Two authors independently selected trials for inclusion and extracted data. We combined data into forest plots using fixed-effects modelling as heterogeneity was low (I(2) < 40%). Ten trials met the inclusion criteria. Telehealthcare was assessed as part of a complex intervention, including nurse case management and other interventions. Telehealthcare was associated with a clinically significant increase in quality of life in two trials with 253 participants (mean difference -6.57 (95% confidence interval (CI) -13.62 to 0.48); minimum clinically significant difference is a change of -4.0), but the confidence interval was wide. Telehealthcare showed a significant reduction in the number of patients with one or more emergency department attendances over 12 months; odds ratio (OR) 0.27 (95% CI 0.11 to 0.66) in three trials with 449 participants, and the OR of having one or more admissions to hospital over 12 months was 0.46 (95% CI 0.33 to 0.65) in six trials with 604 participants. There was no significant difference in the OR for deaths over 12 months for the telehealthcare group as compared to the usual care group in three trials with 503 participants; OR 1.05 (95% CI 0.63 to 1.75). Telehealthcare in COPD appears to have a possible impact on the quality of life of patients and the number of times patients attend the emergency department and the hospital. However, further research is needed to clarify precisely its role since the trials included telehealthcare as part of more complex packages.


The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation.
Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1β and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1β secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1β release. MBZ-induced IL-1β release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.


Massive remobilization of permafrost carbon during post-glacial warming.
Recent hypotheses, based on atmospheric records and models, suggest that permafrost carbon (PF-C) accumulated during the last glaciation may have been an important source for the atmospheric CO2 rise during post-glacial warming. However, direct physical indications for such PF-C release have so far been absent. Here we use the Laptev Sea (Arctic Ocean) as an archive to investigate PF-C destabilization during the last glacial-interglacial period. Our results show evidence for massive supply of PF-C from Siberian soils as a result of severe active layer deepening in response to the warming. Thawing of PF-C must also have brought about an enhanced organic matter respiration and, thus, these findings suggest that PF-C may indeed have been an important source of CO2 across the extensive permafrost domain. The results challenge current paradigms on the post-glacial CO2 rise and, at the same time, serve as a harbinger for possible consequences of the present-day warming of PF-C soils.


Smartphones as multimodal communication devices to facilitate clinical knowledge processes: randomized controlled trial.
Despite the widespread use and advancements of mobile technology that facilitate rich communication modes, there is little evidence demonstrating the value of smartphones for effective interclinician communication and knowledge processes. The objective of this study was to determine the effects of different synchronous smartphone-based modes of communication, such as (1) speech only, (2) speech and images, and (3) speech, images, and image annotation (guided noticing) on the recall and transfer of visually and verbally represented medical knowledge. The experiment was conducted from November 2011 to May 2012 at the University Hospital Basel (Switzerland) with 42 medical students in a master's program. All participants analyzed a standardized case (a patient with a subcapital fracture of the fifth metacarpal bone) based on a radiological image, photographs of the hand, and textual descriptions, and were asked to consult a remote surgical specialist via a smartphone. Participants were randomly assigned to 3 experimental conditions/groups. In group 1, the specialist provided verbal explanations (speech only). In group 2, the specialist provided verbal explanations and displayed the radiological image and the photographs to the participants (speech and images). In group 3, the specialist provided verbal explanations, displayed the radiological image and the photographs, and annotated the radiological image by drawing structures/angle elements (speech, images, and image annotation). To assess knowledge recall, participants were asked to write brief summaries of the case (verbally represented knowledge) after the consultation and to re-analyze the diagnostic images (visually represented knowledge). To assess knowledge transfer, participants analyzed a similar case without specialist support. Data analysis by ANOVA found that participants in groups 2 and 3 (images used) evaluated the support provided by the specialist as significantly more positive than group 1, the speech-only group (group 1: mean 4.08, SD 0.90; group 2: mean 4.73, SD 0.59; group 3: mean 4.93, SD 0.25; F2,39=6.76, P=.003; partial η(2)=0.26, 1-β=.90). However, significant positive effects on the recall and transfer of visually represented medical knowledge were only observed when the smartphone-based communication involved the combination of speech, images, and image annotation (group 3). There were no significant positive effects on the recall and transfer of visually represented knowledge between group 1 (speech only) and group 2 (speech and images). No significant differences were observed between the groups regarding verbally represented medical knowledge. The results show (1) the value of annotation functions for digital and mobile technology for interclinician communication and medical informatics, and (2) the use of guided noticing (the integration of speech, images, and image annotation) leads to significantly improved knowledge gains for visually represented knowledge. This is particularly valuable in situations involving complex visual subject matters, typical in clinical practice.


Survivorship and improving quality of life in men with prostate cancer.
Long-term survival following a diagnosis of cancer is improving in developed nations. However, living longer does not necessarily equate to living well. To search systematically and synthesise narratively the evidence from randomised controlled trials (RCTs) of supportive interventions designed to improve prostate cancer (PCa)-specific quality of life (QoL). A systematic search of Medline and Embase was carried out from inception to July 2014 to identify interventions targeting PCa QoL outcomes. We did not include nonrandomised studies or trials of mixed cancer groups. In addition to database searches, citations from included papers were hand-searched for any potentially eligible trials. A total of 2654 PCa survivors from 20 eligible RCTs were identified from our database searches and reference checks. Disease-specific QoL was assessed most frequently by the Functional Assessment of Cancer Therapy-Prostate questionnaire. Included studies involved men across all stages of disease. Supportive interventions that featured individually tailored approaches and supportive interaction with dedicated staff produced the most convincing evidence of a benefit for PCa-specific QoL. Much of these data come from lifestyle interventions. Our review found little supportive evidence for simple literature provision (either in booklets or via online platforms) or cognitive behavioural approaches. Physical and psychological health problems can have a serious negative impact on QoL in PCa survivors. Individually tailored supportive interventions such as exercise prescription/referral should be considered by multidisciplinary clinical teams where available. Cost-effectiveness data and an understanding of how to sustain benefits over the long term are important areas for future research. This review of supportive interventions for improving quality of life in prostate cancer survivors found that supervised and individually tailored patient-centred interventions such as lifestyle programmes are of benefit.


Quantitative Comparison of Deep Learning-Based Image Reconstruction Methods for Low-Dose and Sparse-Angle CT Applications.
The reconstruction of computed tomography (CT) images is an active area of research. Following the rise of deep learning methods, many data-driven models have been proposed in recent years. In this work, we present the results of a data challenge that we organized, bringing together algorithm experts from different institutes to jointly work on quantitative evaluation of several data-driven methods on two large, public datasets during a ten day sprint. We focus on two applications of CT, namely, low-dose CT and sparse-angle CT. This enables us to fairly compare different methods using standardized settings. As a general result, we observe that the deep learning-based methods are able to improve the reconstruction quality metrics in both CT applications while the top performing methods show only minor differences in terms of peak signal-to-noise ratio (PSNR) and structural similarity (SSIM). We further discuss a number of other important criteria that should be taken into account when selecting a method, such as the availability of training data, the knowledge of the physical measurement model and the reconstruction speed.


An Assay to Evaluate the Function of Liposomal Platelet Substitutes Delivered to Platelet Aggregates.
Aggregation of liposomal platelet substitutes with activated platelets is the primary endpoint to estimate hemostatic potential. Although light transmission aggregometry is a "gold standard" in assessing platelet aggregation in vitro, this method is less specific and sensitive when tested using liposomal platelet substitutes. In the current study, a new method is developed to evaluate the function of platelet substitutes. By labeling liposomes with a fluorescent dye, DiD, we evaluated their ability to target platelet aggregates using a fluorescence microscope. By incorporating an image-based 96 microtiter microplate, this method was optimized by varying the final lipid concentrations and washing times and validated using unmodified liposomes (e.g., L550 with 0 mol% of carboxylic headgroup lipid; L551 with 9 mol% of carboxylic headgroup lipid) and modified liposomes (e.g., H12-L551 with 9 mol% of carboxylic headgroup lipid and 0.3 mol% of dodecapeptide). Our results showed that 200 μM of H12-L551 liposomes and four washes represent optimal conditions for quantitative fluorescence imaging. This method allowed users to qualitatively observe the fluorescently labeled liposomes involved in platelet aggregates. The imaging analysis tool was sufficiently sensitive to quantitatively determine the significantly enhanced delivery of the modified liposomes to platelet aggregates. This enhancement was achieved using dodecapeptide, which specifically binds to activated platelets. This robust and high-throughput method enables the evaluation of liposome function and should facilitate the development of platelet substitutes with a greater ability to target platelet aggregates.


Skin Sensitization Testing-What's Next?
There is an increasing demand for alternative in vitro methods to replace animal testing, and, to succeed, new methods are required to be at least as accurate as existing in vivo tests. However, skin sensitization is a complex process requiring coordinated and tightly regulated interactions between a variety of cells and molecules. Consequently, there is considerable difficulty in reproducing this level of biological complexity in vitro, and as a result the development of non-animal methods has posed a major challenge. However, with the use of a relevant biological system, the high information content of whole genome expression, and comprehensive bioinformatics, assays for most complex biological processes can be achieved. We propose that the Genomic Allergen Rapid Detection (GARD™) assay, developed to create a holistic data-driven in vitro model with high informational content, could be such an example. Based on the genomic expression of a mature human dendritic cell line and state-of-the-art machine learning techniques, GARD™ can today accurately predict skin sensitizers and correctly categorize skin sensitizing potency. Consequently, by utilizing advanced processing tools in combination with high information genomic or proteomic data, we can take the next step toward alternative methods with the same predictive accuracy as today's in vivo methods-and beyond.


Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up.
Although the hippocampus has been found to be smaller in patients with depression, prospective longitudinal in vivo studies are necessary to investigate whether depression can result in a further diminution of hippocampal volumes or whether a smaller hippocampal volume predisposes an individual to the development of depression. Thirty patients with DSM-IV major depressive disorder as well as 30 healthy control subjects matched for age, gender, and handedness were examined at admission to the hospital and 1 year later using a documentation of the medical history and high-resolution magnetic resonance imaging (MRI) for the presence of depression and to determine changes in hippocampal as well as amygdala volumes. Patients were enrolled from March 2000 to August 2002. No significant hippocampal and amygdala volume changes were observed in patients or controls between baseline and 1-year follow-up investigations. However, the subgroup of patients who were nonremitted at the time of the follow-up investigation showed significantly reduced left and right hippocampal volumes at both baseline and the 1-year follow-up compared with remitted patients. Moreover, the right hippocampal volumes of nonremitted patients were significantly smaller compared with matched healthy controls. These results do not support the hypothesis that hippocampal volumes diminish during the 1-year follow-up period. However, smaller hippocampal volumes may be related to a poor clinical outcome after 1 year.


An analysis of edentulous maxillary arch width and palatal height.
This study involving 500 edentulous patients (250 males, 250 females) was undertaken to introduce a dimensionless factor termed the "palatal height ratio," defined as the ratio of the width of the edentulous maxillary arch to the height of the palate. The authors categorized the height, width, and anteroposterior dimensions of the edentulous maxillae. Measurements were made on diagnostic casts at five defined points. The difference between males and females was statistically analyzed and the variables were categorized. The results of this study may be helpful for a better standardization of the same variables in future studies.


Local and global effects of climate on dengue transmission in Puerto Rico.
The four dengue viruses, the agents of dengue fever and dengue hemorrhagic fever in humans, are transmitted predominantly by the mosquito Aedes aegypti. The abundance and the transmission potential of Ae. aegypti are influenced by temperature and precipitation. While there is strong biological evidence for these effects, empirical studies of the relationship between climate and dengue incidence in human populations are potentially confounded by seasonal covariation and spatial heterogeneity. Using 20 years of data and a statistical approach to control for seasonality, we show a positive and statistically significant association between monthly changes in temperature and precipitation and monthly changes in dengue transmission in Puerto Rico. We also found that the strength of this association varies spatially, that this variation is associated with differences in local climate, and that this relationship is consistent with laboratory studies of the impacts of these factors on vector survival and viral replication. These results suggest the importance of temperature and precipitation in the transmission of dengue viruses and suggest a reason for their spatial heterogeneity. Thus, while dengue transmission may have a general system, its manifestation on a local scale may differ from global expectations.


Viremia Trajectories of HIV in HIV-Positive Women in the United States, 1994-2017.
Viral suppression of HIV is an important treatment goal to decrease morbidity, mortality, and risk of transmission to others. To characterize longitudinal HIV viral load outcomes among women enrolled in the Women's Interagency HIV Study (WIHS). A prospective cohort study of HIV-positive women with semiannual study visits and a minimum of 5 follow-up visits was conducted from 1994 to 2017. The WIHS sites included in this analysis are in Brooklyn and Bronx, New York; Chicago, Illinois; San Francisco, California; and Washington, DC. Women were categorized into groups based on their probability of achieving viral load suppression below 200 copies/mL using logistic trajectory modeling. Multinomial regression analysis was used to identify factors associated with placement in the group with the highest probability of viremia. At baseline, the mean (SD) age of the 1989 women was 36.9 (8.0) years, mean CD4+ T-lymphocyte count was 467/mm3, median (interquartile range) HIV RNA was 6200.0 (384.5-41 678.0) copies/mL, and 1305 women (65.6%) were African American. Three trajectory groups were identified with low (568 [28.6%]), intermediate (784 [39.4%]), and high (637 [32.0%]) probability of viremia above 200 copies/mL. The mean (SD) cumulative years of viral suppression were 18.7 (4.0) years, 12.2 (3.1) years, and 5.8 (2.9) years in the respective groups. Factors associated with high probability of viremia included younger age (odds ratio [OR]. 0.99; 95% CI, 0.98-0.99; P = .03), African American race (odds ratio [OR], 2.43; 95% CI, 1.75-3.37), P < .001), Hispanic race/ethnicity (OR, 1.50; 95% CI, 1.03-2.19; P = .04), increased levels of depressive symptoms (OR, 1.17; 95% CI, 1.01-1.36; P = .03), drug use (OR, 1.23; 95% CI, 1.01-1.51; P = .04), lower CD4+ T-lymphocyte counts (OR, 95% CI, 0.82; 0.80-0.85; P < .001), and unstable housing (OR, 1.25, 95% CI, 1.03-1.50; P = .02). Between 2015 and 2017, 71.2% of women demonstrated sustained viral suppression: 89.6% (310 of 346) of those with low viremia, 83.4% (346 of 415) with intermediate, and 35.2% (112 of 318) with high probability of viremia. This longitudinal approach suggested that the probability of viremia decreased substantially over time for most participants, including among women with earlier histories of incomplete viral suppression. The findings from this study suggest that continued efforts are needed to address mental health, social, behavioral and structural factors that were identified as associated with high probability of HIV viremia over time.


Expression and putative functions of GDF-15, a member of the TGF-beta superfamily, in human glioma and glioblastoma cell lines.
Recent studies have demonstrated growth-inhibiting effects of growth differentiation factor-15 (GDF-15) on different cancer cell lines invitro and on tumor growth in vivo. Here, we present data concerning expression of GDF-15 in glioblastoma. We found low levels of GDF-15 transcripts in primary glioblastoma. Thus, GDF-15 expression might be exploited as a useful indicator for distinguishing primary from other glial derived tumors. In contrast to the documented proapoptotic and anti-tumorigenic activities of GDF-15 in several cancer cell lines, our data suggest that GDF-15 does not decrease proliferation of glioblastoma cell lines, while its effects on invasiveness are not consistent.


Polymersome Formation by Amphiphilic Polyglycerol-b-polydisulfide-b-polyglycerol and Glutathione-Triggered Intracellular Drug Delivery.
This article reports the synthesis, spontaneous self-assembly, highly efficient drug encapsulation, and glutathione (GSH)-triggered intracellular sustained drug delivery of an ABA-type amphiphilic triblock copolymer, namely, polyglycerol-b-poly(disulfide)-b-polyglycerol (PG-b-PDS-b-PG). The bioreducible PDS block with reactive pyridyldisulfide groups present at the chain terminals was attached to thiol-terminated heterotelechelic PG by a thiol-disulfide exchange reaction producing the amphiphilic PG-b-PDS-b-PG. It formed a stable polymersome in aqueous medium with a critical aggregation concentration of 0.02 mg/mL and average hydrodynamic diameter (Dh) of 230 nm and showed highly efficient and stable encapsulation of doxorubicin (Dox) with a remarkably high drug loading efficiency (DLE) and drug loading content (DLC) of 54% and 16%, respectively. Fluorescence spectroscopy studies revealed GSH-triggered drug release and strong dependence of the release kinetics on the GSH concentration due to degradation of the amphiphilic block copolymer and disassembly of the polymersome. MTT assay indicated excellent biocompatibility of the block copolymer as >90% cells (HeLa or MDA-MB-231) were found to be alive after 96 h of incubation with a polymer concentration of up to 1.0 mg/mL, which was further validated by the hemolysis assay. Cytotoxicity assay of the Dox-loaded polymersome exhibited time and dose-dependent sustained killing of HeLa as well as MDA-MB-231 cells wherein after 48 h of incubation >50% cell killing was noticed with a Dox concentration of ∼4.0 and ∼8.7 μg/mL, respectively, while the free Dox showed faster cell killing. Flow cytometry and live cell fluorescence microscopy studies revealed time-dependent cellular uptake of the drug-loaded polymersome followed by diffusion of the drug to the nucleus. Cells with artificially enhanced GSH were killed at a much faster rate indicating that intracellular GSH-triggered disassembly is the key drug release mechanism.


A prospective study of diet and benign breast disease.
Much attention has been paid to the relation between diet and breast cancer risk. Because benign breast disease (BBD), particularly atypical hyperplasia (AH), is a marker of increased breast cancer risk, studies of diet and BBD may provide evidence about the effect of diet at an early stage in the process of breast carcinogenesis. We evaluated the relationship between fat, fiber, antioxidant and caffeine intake and incidence of non-proliferative BBD, proliferative BBD without atypia and AH in the Nurses' Health Study II. We calculated rate ratios (RR) and 95% confidence intervals (95% CI) for each quartile of energy-adjusted intake using the lowest quartile as reference. There was no increase in risk of BBD with increasing fat intake, rather increasing vegetable fat was associated with a significant reduction in the rate of proliferative BBD without atypia. There was no significant association between any type of BBD and micronutrient intake. High caffeine consumption was positively associated (RR = 2.46, 95% CI 1.11-5.49 for the highest quartile), and use of multivitamin supplements inversely associated (RR = 0.57, 95% CI 0.33-0.98) with risk of AH although these analyses were based on small numbers. These data do not support the hypothesis that higher fat consumption increases risk of BBD, with or without atypia, and also provide little evidence for a major role of antioxidants in the development of breast disease. They do, however, raise the possibility that high caffeine intake may increase, and use of vitamin supplements may decrease risk of developing AH.


Evolution of CRISPs associated with toxicoferan-reptilian venom and mammalian reproduction.
Cysteine-rich secretory proteins (CRISPs) are glycoproteins found exclusively in vertebrates and have broad diversified functions. They are hypothesized to play important roles in mammalian reproduction and in reptilian venom, where they disrupt homeostasis of the prey through several mechanisms, including among others, blockage of cyclic nucleotide-gated and voltage-gated ion channels and inhibition of smooth muscle contraction. We evaluated the molecular evolution of CRISPs in toxicoferan reptiles at both nucleotide and protein levels relative to their nonvenomous mammalian homologs. We show that the evolution of CRISP gene in these reptiles is significantly influenced by positive selection and in snakes (ω = 3.84) more than in lizards (ω = 2.33), whereas mammalian CRISPs were under strong negative selection (CRISP1 = 0.55, CRISP2 = 0.40, and CRISP3 = 0.68). The use of ancestral sequence reconstruction, mapping of mutations on the three-dimensional structure, and detailed evaluation of selection pressures suggests that the toxicoferan CRISPs underwent accelerated evolution aided by strong positive selection and directional mutagenesis, whereas their mammalian homologs are constrained by negative selection. Gene and protein-level selection analyses identified 41 positively selected sites in snakes and 14 sites in lizards. Most of these sites are located on the molecular surface (nearly 76% in snakes and 79% in lizards), whereas the backbone of the protein retains a highly conserved structural scaffold. Nearly 46% of the positively selected sites occur in the cysteine-rich domain of the protein. This directional mutagenesis, where the hotspots of mutations are found on the molecular surface and functional domains of the protein, acts as a diversifying mechanism for the exquisite biological targeting of CRISPs in toxicoferan reptiles. Finally, our analyses suggest that the evolution of toxicoferan-CRISP venoms might have been influenced by the specific predatory mechanism employed by the organism. CRISPs in Elapidae, which mostly employ neurotoxins, have experienced less positive selection pressure (ω = 2.86) compared with the "nonvenomous" colubrids (ω = 4.10) that rely on grip and constriction to capture the prey, and the Viperidae, a lineage that mostly employs haemotoxins (ω = 4.19). Relatively lower omega estimates in Anguimorph lizards (ω = 2.33) than snakes (ω = 3.84) suggests that lizards probably depend more on pace and powerful jaws for predation than venom.


Granzyme B-induced apoptosis in cancer cells and its regulation (review).
The granzyme B-induced cell death has been traditionally viewed as a primary mechanism that is used by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to eliminate harmful target cells including allogeneic, virally infected and tumour cells. Granzyme B (GrB) is the most abundant serine protease which is stored in secretory granules of CTLs and NK cells. After recognition of the target cell, the engaged CTLs and NK cells vectorially secrete GrB along with other granule proteins including perforin into the immunological synapse. From this submicroscopic intercellular cleft GrB translocates into the cytoplasm of the target cell. Although several models have been proposed to explain the GrB delivery mechanism, conclusive understanding of this process remains still elusive. Once in the cytoplasm, GrB cleaves and activates, or inactivates, multiple protein substrates, resulting eventually into apoptotic demise of the target cell. This review is focused on the gene structure and expression of GrB, its biosynthesis and activation, delivery mechanisms into the target cell cytoplasm, direct proteolytic involvement in activation of several pro-apoptotic pathways, and on regulation of its activity in cancer cells. Moreover, emphasis is given to the GrB-mediated anticancer effects and future clinical applications of the GrB-based and tumour-targeted recombinant fusion constructs.


Comparison of patient outcomes in periarticular and intraarticular local anaesthetic infiltration techniques in total knee arthroplasty.
The use of local infiltration analgesia in the setting of knee arthroplasty is well established. There are no studies to date which have directly compared differences in infiltration techniques. The purpose of this study is to establish if a difference in patient outcomes exists when the infiltrate is injected into the periarticular tissues or directly into the joint. One hundred and forty-two consecutive patients waitlisted for primary total knee arthroplasty were enrolled after primary exclusion criteria were applied. These included the following: allergy to study drugs, inability to receive spinal anaesthesia, and planned bilateral surgery. Patients were divided into two groups, a periarticular infiltration group (group A) and an intraarticular infiltration group (group B). Secondary exclusion criteria of regular opioid use, psychiatric illness, and serious medical comorbidity left a total of 47 patients in group A and 54 patients in group B. Both groups received a combination of 30 mg ketorolac, 500 μg of adrenaline, and 300 mg of ropivacaine, and normal saline. This was either injected into the periarticular tissues during surgery (group A) or intraarticularly after closure of the wound (group B). Primary outcome measures included opioid consumption during the first 24 h postoperatively and over the total admission, and visual analogue scales (VAS) on postoperative day 1 and at discharge. Secondary measures included Oxford Knee Score, knee flexion, length of stay, haemoglobin drop, and transfusion requirement. Ethics approval was granted by the hospital review board. The trial is registered in the Australian New Zealand Clinical Trials Registry, registration ACTRN12615000488505 . No statistically significant differences in postoperative analgesic use were observed between the two groups. However, there was a trend toward decreased postoperative patient-controlled analgesia use in the periarticular group (mean 53.1 vs 68.3 mg morphine equivalents; p = 0.093), as well as a statistically significant reduction in postoperative visual analogue pain scores. No statistically significant differences were observed for haemoglobin drop, range of motion, or pre- to 6-week postoperative Oxford Score difference. Our study is the first we are aware of to directly compare a periarticular to intraarticular injection technique when using local infiltration analgesia for total knee arthroplasty. Our results show no clear statistically significant benefit with either technique. The periarticular group showed a statistically significant reduction in postoperative VAS pain scores alongside a trend in that group toward reduced overall opioid use.


Differential effects of two fermentable carbohydrates on central appetite regulation and body composition.
Obesity is rising at an alarming rate globally. Different fermentable carbohydrates have been shown to reduce obesity. The aim of the present study was to investigate if two different fermentable carbohydrates (inulin and β-glucan) exert similar effects on body composition and central appetite regulation in high fat fed mice. Thirty six C57BL/6 male mice were randomized and maintained for 8 weeks on a high fat diet containing 0% (w/w) fermentable carbohydrate, 10% (w/w) inulin or 10% (w/w) β-glucan individually. Fecal and cecal microbial changes were measured using fluorescent in situ hybridization, fecal metabolic profiling was obtained by proton nuclear magnetic resonance ((1)H NMR), colonic short chain fatty acids were measured by gas chromatography, body composition and hypothalamic neuronal activation were measured using magnetic resonance imaging (MRI) and manganese enhanced MRI (MEMRI), respectively, PYY (peptide YY) concentration was determined by radioimmunoassay, adipocyte cell size and number were also measured. Both inulin and β-glucan fed groups revealed significantly lower cumulative body weight gain compared with high fat controls. Energy intake was significantly lower in β-glucan than inulin fed mice, with the latter having the greatest effect on total adipose tissue content. Both groups also showed an increase in the numbers of Bifidobacterium and Lactobacillus-Enterococcus in cecal contents as well as feces. β-Glucan appeared to have marked effects on suppressing MEMRI associated neuronal signals in the arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus, periventricular nucleus and the nucleus of the tractus solitarius, suggesting a satiated state. Although both fermentable carbohydrates are protective against increased body weight gain, the lower body fat content induced by inulin may be metabolically advantageous. β-Glucan appears to suppress neuronal activity in the hypothalamic appetite centers. Differential effects of fermentable carbohydrates open new possibilities for nutritionally targeting appetite regulation and body composition.


Automatic construction of correspondences for tubular surfaces.
Statistical shape modeling is an established technique and is used for a variety of tasks in medical image processing, such as image segmentation and analysis. A challenging task in the construction of a shape model is establishing a good correspondence across the set of training shapes. Especially for shapes of cylindrical topology, very little work has been done. This paper describes an automatic method to obtain a correspondence for a set of cylindrical shapes. The method starts from an initial correspondence which is provided by cylindrical parameterization. The quality of the obtained correspondence, measured in terms of the description length, is then improved by deforming the parameterizations using cylindrical b-spline deformations and by optimization of the spatial alignment of the shapes. In order to allow efficient gradient-guided optimization, an analytic expression is provided for the gradient of this quality measure with respect to the parameters of the parameterization deformation and the spatial alignment. A comparison is made between models obtained from the correspondences before and after the optimization. The results show that, in comparison with parameterization-based correspondences, this new method establishes correspondences that generate models with significantly increased performance in terms of reconstruction error, generalization ability, and specificity.


Artificial fish schools: collective effects of school size, body size, and body form.
Individual-based models of schooling in fish have demonstrated that, via processes of self-organization, artificial fish may school in the absence of a leader or external stimuli, using local information only. We study for the first time how body size and body form of artificial fish affect school formation in such a model. For a variety of group sizes we describe how school characteristics (i.e., group form, spread, density, polarization, turning rate, and speed) depend on body characteristics. Furthermore, we demonstrate that the nearest neighbor distance and turning rate of individuals are different for different regions in the group, although the agents are completely identical. Our approach shows the significance of both self-organization and embodiment in modeling of schools of artificial fish and, probably, in structuring schools of real fish.


Dual-Functional Multichannel Carbon Framework Embedded with CoS2 Nanoparticles: Promoting the Phase Transformation for High-Loading Li-S Batteries.
Lithium-sulfur batteries have been considered as one of the most promising energy storage devices due to their high theoretical capacity and low cost. They go through complicated multistep electrochemical reactions from solid (sulfur)-liquid (soluble polysulfide) to liquid (soluble polysulfide)-solid (Li2S) during the discharge process. Actually, during this process, the transition from liquid phase (Li2S4) to solid phase (Li2S) at 2.1 V plateau is a difficult step with sluggish kinetics, thus leading to low sulfur utilization and discharge capacity. To promote the transition processes and enhance the sulfur utilization, CoS2@multichannel carbon nanofiber composites (CoS2@MCNFs) serving as sulfur host were successfully synthesized. Herein, CoS2 catalysts are proven to be beneficial not only for enhancing the phase-transition kinetics but also for adsorbing soluble polysulfide. Besides, unlike other carbon materials, MCNFs have plenty of hollow channels and thus enhance sulfur loading and conductivity. Accordingly, the discharge capacity increases 32% more than that of electrode without CoS2. And a very low capacity fade rate of 0.03% per cycle (over 450 cycles) is obtained at a 0.5C rate. This work has opened up new ideas for enhancing sulfur utilization for high sulfur-loading electrode.


The role of FGF and VEGF in angioblast induction and migration during vascular development.
The embryonic vasculature forms by the processes of vasculogenesis and angiogenesis. Angioblasts (endothelial cell precursors) appear to be induced by fibroblast growth factor 2 (FGF-2). The angioblasts contributing to the dorsal aortae arise by an epithelial to mesenchymal transformation of cells originating from the splanchnic mesoderm. QH-l and vascular endothelial growth factor receptor 2 (VEGFR-2) both appear to label these cells as they adopt a mesenchymal morphology. Since VEGFR-2 is the earliest known VEGF receptor this suggests that VEGF is not involved in angioblast induction. VEGF does appear to be critical, however, for growth and morphogenesis of angioblasts into the initial vascular pattern. Controlled delivery of FGF-2 from beads and aggregates of cells transfected with quail VEGF have been used in our laboratory to study the role of these growth factors in angioblast induction and migration. We have induced cells from the epithelial quail somite to differentiate into angioblasts with FGF-2 both in the embryo and in culture. This is a useful model system to study the origins of endothelial cells that are normally more diffusely induced during gastrulation by an obscure process probably involving signals from the embryonic endoderm. The origins of arterial versus venous endothelial cells is also poorly understood but recent findings on the distribution of ephrins and Eph receptors suggest that molecular differences exist prior to the onset of circulation. Finally, studies on the role of growth factors in such diverse phenomena as stem cell biology, angiogenesis, and molecular medicine in addition to vascular development suggest multiple roles for FGF-2 and VEGF in vascular development.


Evaluation of the effects of the Arm Light Exoskeleton on movement execution and muscle activities: a pilot study on healthy subjects.
Exoskeletons for lower and upper extremities have been introduced in neurorehabilitation because they can guide the patient's limb following its anatomy, covering many degrees of freedom and most of its natural workspace, and allowing the control of the articular joints. The aims of this study were to evaluate the possible use of a novel exoskeleton, the Arm Light Exoskeleton (ALEx), for robot-aided neurorehabilitation and to investigate the effects of some rehabilitative strategies adopted in robot-assisted training. We studied movement execution and muscle activities of 16 upper limb muscles in six healthy subjects, focusing on end-effector and joint kinematics, muscle synergies, and spinal maps. The subjects performed three dimensional point-to-point reaching movements, without and with the exoskeleton in different assistive modalities and control strategies. The results showed that ALEx supported the upper limb in all modalities and control strategies: it reduced the muscular activity of the shoulder's abductors and it increased the activity of the elbow flexors. The different assistive modalities favored kinematics and muscle coordination similar to natural movements, but the muscle activity during the movements assisted by the exoskeleton was reduced with respect to the movements actively performed by the subjects. Moreover, natural trajectories recorded from the movements actively performed by the subjects seemed to promote an activity of muscles and spinal circuitries more similar to the natural one. The preliminary analysis on healthy subjects supported the use of ALEx for post-stroke upper limb robotic assisted rehabilitation, and it provided clues on the effects of different rehabilitative strategies on movement and muscle coordination.


Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study.
Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT. We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an 'off-EPT' mammogram from MD of an 'on-EPT' (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline 'on-EPT' MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated 'P values adjusted for correlated tests (P(ACT))' to account for multiple testing within a gene. The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; P(ACT) = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; P(ACT) = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant. Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.


Neoadjuvant Chemotherapy does not Increase Complications in Oncoplastic Breast-Conserving Surgery.
Oncoplastic breast-conserving surgery (OBCS) broadens the indications for breast conservation. Neoadjuvant systemic chemotherapy (NAC) is used increasingly in the treatment of patients with early-stage and locally advanced breast cancer. This study aimed to evaluate the outcomes for patients who received NAC followed by OBCS. A retrospective chart review was performed for all patients who underwent OBCS involving the mastopexy/breast-reduction technique, including synchronous mastopexy/breast reduction for symmetry, at the University of Texas MD Anderson Cancer Center between January 2010 and January 2016. Patients who had received NAC were compared with those who had undergone surgery first. Demographic, treatment, and outcomes data were collected. The study included 429 patients, corresponding to 713 breasts. Of these patients, 122, corresponding to 199 breasts, received NAC. The patients who received NAC were younger (p < 0.001) and had a more advanced cancer stage (p < 0.001). The overall complication rate per patient was 25.9%, with major complications occurring in 9.1% of the patients. After adjustment for risk factors, NAC was not shown to be associated with an increased risk of complications or delayed adjuvant radiation therapy (p = 0.37), irrespective of the chemotherapy regimen used or whether the interval between NAC and surgery was 4 weeks or longer. In a high-volume center, OBCS can be performed safely for carefully selected patients after NAC without an increased risk of complications or delayed adjuvant radiation therapy. An interval of at least 4 weeks between completion of NAC and surgery can be regarded as safe irrespective of the chemotherapy regimen used.


Glycan motif profiling reveals plasma sialyl-lewis x elevations in pancreatic cancers that are negative for sialyl-lewis A.
The sialyl-Lewis A (sLeA) glycan forms the basis of the CA19-9 assay and is the current best biomarker for pancreatic cancer, but because it is not elevated in ∼25% of pancreatic cancers, it is not useful for early diagnosis. We hypothesized that sLeA-low tumors secrete glycans that are related to sLeA but not detectable by CA19-9 antibodies. We used a method called motif profiling to predict that a structural isomer of sLeA called sialyl-Lewis X (sLeX) is elevated in the plasma of some sLeA-low cancers. We corroborated this prediction in a set of 48 plasma samples and in a blinded set of 200 samples. An antibody sandwich assay formed by the capture and detection of sLeX was elevated in 13 of 69 cancers that were not elevated in sLeA, and a novel hybrid assay of sLeA capture and sLeX detected 24 of 69 sLeA-low cancers. A two-marker panel based on combined sLeA and sLeX detection differentiated 109 pancreatic cancers from 91 benign pancreatic diseases with 79% accuracy (74% sensitivity and 78% specificity), significantly better than sLeA alone, which yielded 68% accuracy (65% sensitivity and 71% specificity). Furthermore, sLeX staining was evident in tumors that do not elevate plasma sLeA, including those with poorly differentiated ductal adenocarcinoma. Thus, glycan-based biomarkers could characterize distinct subgroups of patients. In addition, the combined use of sLeA and sLeX, or related glycans, could lead to a biomarker panel that is useful in the clinical diagnosis of pancreatic cancer. Précis: This paper shows that a structural isomer of the current best biomarker for pancreatic cancer, CA19-9, is elevated in the plasma of patients who are low in CA19-9, potentially enabling more comprehensive detection and classification of pancreatic cancers.