Diagnostic ultrasound (DUS) pressures have the ability to induce inertial cavitation (IC) of systemically administered microbubbles; this bioeffect has many diagnostic and therapeutic implications in cardiovascular care. Diagnostically, commercially available lipid-encapsulated perfluorocarbons (LEP) can be utilized to improve endocardial and vascular border delineation as well as assess myocardial perfusion. Therapeutically, the liquid jets induced by IC can alter endothelial function and dissolve thrombi within the immediate vicinity of the cavitating microbubbles. The cavitating LEP can also result in the localized release of any bound therapeutic substance at the site of insonation. DUS-induced IC has been tested in pre-clinical studies to determine what effect it has on acute vascular and microvascular thrombosis as well as nitric oxide (NO) release. These pre-clinical studies have consistently shown that DUS-induced IC of LEP is effective in restoring coronary vascular and microvascular flow in acute ST segment elevation myocardial infarction (STEMI), with microvascular flow improving even if upstream large vessel flow has not been achieved. The initial clinical trials examining the efficacy of short pulse duration DUS high mechanical index impulses in patients with STEMI are underway, and preliminary studies have suggested that earlier epicardial vessel recanalization can be achieved prior to arriving in the cardiac catheterization laboratory. DUS high mechanical index impulses have also been effective in pre-clinical studies for targeting DNA delivery that has restored islet cell function in type I diabetes and restored vascular flow in the extremities downstream from a peripheral vascular occlusion. Improvements in this technique will come from three dimensional arrays for therapeutic applications, more automated delivery techniques that can be applied in the field, and use of submicron-sized acoustically activated LEP droplets that may better permeate the clot prior to DUS activation and cavitation. This article will focus on these newer developments for DUS therapeutic applications.The online version of this article (doi:10.1186/s40349-016-0062-y) contains supplementary material, which is available to authorized users. Although diagnostic ultrasound (DUS) systems and lipid-encapsulated perfluorocarbons (LEP) like Definity  or Sonazoid  have been approved only for imaging applications; these two products have significant therapeutic potential for non-invasive targeted thrombolysis and drug delivery. Ultrasound and microbubbles alone as a method of dissolving thrombi was first introduced in 1997 . SubsequThe potential for intermittent high MI impulses from a DUS transducer was first examined in a canine model of arteriovenous graft thrombosis, where intermittent high MI impulses all <1.9 MI) were applied when low MI imaging detected microbubbles within the risk area . These h.9 MI werThis study prompted subsequent investigations which examined the efficacy of DUS high MI impulses in restoring microvascular and epicardial blood flow in porcine models of acute ST segment elevation myocardial infarction, or STEMI –12. ThesSlight prolongations in pulse duration on a DUS transducer may improve the amount of thrombus dissolution. By increasing pulse duration from <5 to 20 μs on a DUS transducer, a higher epicardial recanalization rate was achieved with DUS-guided therapy added to ½ dose tissue plasminogen activator. Despite the higher epicardial recanalization rate, both short and longer pulse duration high MI impulses were equally effective in ST segment resolution and improvement in wall thickening within the risk area . The guiIn an ischemic stroke, transcranial DUS and intravenous LEP microbubbles, even in the absence of tissue plasminogen activator, have recanalized intravascular and microvascular thrombi in a large porcine animal model . In thisA considerable number of small animal studies have demonstrated the ability of DUS-guided cavitation of LEP to target the delivery of DNA or RNA –22; Tabl2; Tabl2.The use of a commercially available LEP and DUS for targeted thrombolysis is now being tested in the first clinical trials , with prOne problem with microbubbles is that they are confined to intravascular spaces, and inertial cavitation can only increase subendothelial delivery. The LEP can also be formulated into droplets, even for the lower molecular weight fluorocarbons like octafluoropropane . Since tDUS, diagnostic ultrasound; IC, inertial cavitation; LEP, lipid-encapsulated perfluorocarbons; MI, mechanical index; NO, nitric oxide; PWD, pulsed wave Doppler; STEMI, ST segment elevation myocardial infarction


The mere sight of foods may activate the brain’s reward circuitry, and humans often experience difficulties in inhibiting urges to eat upon encountering visual food signals. Imbalance between the reward circuit and those supporting inhibitory control may underlie obesity, yet brain circuits supporting volitional control of appetite and their possible dysfunction that can lead to obesity remain poorly specified. Here we delineated the brain basis of volitional appetite control in healthy and obese individuals with functional magnetic resonance imaging (fMRI). Twenty-seven morbidly obese women (mean BMI = 41.4) and fourteen age-matched normal-weight women (mean BMI = 22.6) were scanned with 1.5 Tesla fMRI while viewing food pictures. They were instructed to inhibit their urge to eat the foods, view the stimuli passively or imagine eating the foods. Across all subjects, a frontal cortical control circuit was activated during appetite inhibition versus passive viewing of the foods. Inhibition minus imagined eating (appetite control) activated bilateral precunei and parietal cortices and frontal regions spanning anterior cingulate and superior medial frontal cortices. During appetite control, obese subjects had lower responses in the medial frontal, middle cingulate and dorsal caudate nuclei. Functional connectivity of the control circuit was increased in morbidly obese versus control subjects during appetite control, which might reflect impaired integrative and executive function in obesity. In our modern society humans are surrounded by food advertisement and palatable visual food cues are readily available and on display in supermarkets and restaurants. Despite complex homeostatic mechanisms that govern eating and appetite , the merThe sight of food cues engages the brain’s reward circuit and it shows greater activation encountering palatable versus bland foods , especiafunctional connectivity of the cognitive control networks and the reward circuit has remained elusive. It is indeed possible that the previously reported elevated reward circuit responses to palatable foods in obese individuals [The evidence of the influence of obesity on the functioning of the fronto cortical appetite control systems remains mixed, nevertheless. Some studies have reported no effects of Body Mass Index (BMI) on cortical inhibitory circuits , while sividuals –6 could Here, we used functional magnetic resonance imaging (fMRI) to study brain circuits supporting cognitive appetite control in normal-weight and morbidly obese individuals. Participants viewed pictures of foods, while their task was to either inhibit their urges to eat, imagine eating the foods or watch the foods passively. We hypothesized that volitional control of appetite would engage the fronto-cortical circuits, and that obese individuals would have lower frontal activations reflecting failure to volitionally inhibit their urges to eat. In line with this, we also predicted that functional connectivity of the control circuit would be lowered in obese individuals.http://www.clinicaltrials.gov). All participants signed an ethical committee-approved, informed consent form prior to scans.The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethical Committee of the Hospital District of South-Western Finland  were recruited for the study  were recruited as a control group  to assess the nutritional state .inhibition condition, they had to inhibit urges to eat the food, during passive viewing condition they had to view the foods passively, and during imaginary eating condition they had to imagine eating the foods. The blocks were presented in a fixed, pseudo-randomized order, which was counterbalanced across participants. Altogether there were twenty blocks of each condition, and total scanning time was approximately 19 minutes. Participants were given written and spoken instructions before entering the scanner, and they practiced the task in the scanner before the experiment began. The participants were also interviewed after the experiment to assure that they had finished the task as instructed.Stimuli and design are summarized in The stimulus presentation and behavioral data collection were controlled with Presentation software . Stimuli were projected from an LCD projector onto a non-magnetic screen mounted at the foot of the bore, and an angled mirror reflected images onto the screen into the participants’ field of vision.3 resolution) were acquired using a T1-weighted sequence .Altogether 380 functional volumes were acquired. Furthermore, four ‘dummy’ volumes were acquired and discarded at the beginning to allow for equilibration effects. The dummy volumes were not included in the analysis. Data were pre-processed and analyzed using SPM8 software (http://www.fil.ion.ucl.ac.uk/spm/) running on Matlab 2011b. The EPI images were realigned to the first scan image by rigid body transformations to correct for head movements. Echoplanar and structural images were co-registered and normalized to the T1 standard template in MNI space  using linear and non-linear transformations, and smoothed with a Gaussian kernel of 8 mm full width at half maximum—FWHM 8 mm.MR imaging was performed with Philips Gyroscan Intera 1.5 T CV Nova Dual scanner at Turku PET centre. Whole-brain functional data were acquired with T2* weighted echo-planar imaging (EPI) sequence, sensitive to the blood-oxygen-level-dependent (BOLD) signal contrast . High-resolution anatomical images  corrected at the cluster level.A whole-brain random effects model was used. This two-stage process (first and second level) assesses effects on the basis of inter-subject variance and thus allows inferences about the population that the participants are drawn from. For each participant, we used a general linear model (GLM) to assess regional effects of task parameters on brain activation. The first level model included all three experimental conditions  as well as the six realignment parameters as effects of no interest. Low-frequency signal drift was removed using a high-pass filter (cut-off 128 s) and we applied autoregressive AR(1) modeling of temporal autocorrelations. The individual contrast images were generated using the t-contrasts i) inhibition minus viewing, ii) imaginary eating minus viewing, and iii) inhibition minus imaginary eating, as well as the opposite contrasts. The contrast images of the voxel-wise difference in beta estimates for the contrasts of interest. The second-level analysis used these contrast images in a new GLM from which generated statistical images, that is, SPM t-maps across all subjects and between subject groups. When the second-level analysis has balanced designs at first level with similar numbers of similar events for each subject it closely approximates a true mixed-effects design, exhibiting within- and between-subject variance. In addition, second-level analysis in SPM is considered to be robust against unequal group sizes, when unequal variances are assumed. The inhibition minus passive viewing and imaginary eating versus passive viewing contrasts were used to delineate the brain regions involved in cognitive control of appetite and mental processing of the hedonic value of the foods. The appetite control contrast (inhibition minus imaginary eating) was considered the main contrast of interest for revealing the neural basis of appetite control, as this enabled contrasting the two active food-related tasks directly against each other, thus accounting for effects of increasing task complexity in the active versus passive viewing conditions . Data weThe connectivity between brain regions can vary as a function of the psychological context . This isSource regions for the brain’s inhibition network were selected from a previous meta-analysis on inhibitory processing in Go/No-Go tasks , 11 and Contrasting the inhibition condition with passive viewing revealed widespread activation in fronto-cortical regions , Table 3In inhibition minus imaginary eating comparison, normal-weight subjects showed stronger activations than obese subjects in bilateral dorsal caudate nuclei and anterior cingulate cortex , Table 5Across all subjects, the right caudate nucleus showed increased task-driven (inhibition versus passive viewing) connectivity with bilateral precunei and cunei and parietal cortices . InferioBetween-group comparisons revealed that obese subjects had stronger functional connectivity between middle frontal cortex and bilateral supplemental motor area (SMA), right putamen and right middle temporal gyrus , Table 6Hunger ratings  did not Here we show that volitional appetite control while viewing visual food cues activates a network of prefrontal, frontal and parietal and inferior cerebellar cortical regions. This confirms that the fronto cortical control system – well known for inhibition and error monitoring ,9 is alsEating and appetite are controlled by complex homeostatic mechanisms . In realThese findings from the task-evoked BOLD responses to cognitive appetite control accord with those made by Yokum et al. They compared the neural responses of three cognitive reappraisal strategies when adolescent subjects viewed visual food cues and thought of the long-term costs or benefits of not eating the food and suppressing cravings for the food. They found increased activation in inhibitory prefrontal and superior frontal regions during these mental tasks, yet in that study participants’ BMI did not modulate the intensity of brain activation . FurtherDuring the inhibition versus imaginary eating condition, normal-weight individuals showed stronger responses than obese individuals in medial frontal and orbitofrontal cortices, as well as in dorsal caudate nucleus . With moenhanced rather than diminished connectivity of the appetite control network in obese versus normal-weight individuals (Against our predictions, functional connectivity analysis revealed ividuals . Obese iAltogether these findings imply that modulating the brain activity of the whole inhibitory circuitry may prove effective to combat our urges to eat excessively. Indeed, most of the currently available anti-obesity pharmaceuticals modulate widespread neurotransmitter systems . InteresWe did not measure blood glucose or insulin levels, which are shown to influence fMRI responses to food pictures . HoweverWe conclude that premotor areas, superior frontal cortices and the precuneus support cognitive control of appetite upon encountering visual food cues. Although these areas seem to function similarly in obese and normal-weight individuals, dorsal striatal responses during volitional appetite control are reduced in obese individuals. This suggests that even though frontal inhibitory function seems to be largely preserved in obesity, altered reward and homeostatic signaling together with heightened functional connectivity within the cognitive control circuit likely play an important role in the pathophysiology of obesity, and drive excessive eating and contribute to development and maintenance of obesity.


Inflammation is the first biological response of the immune system against infection or irritation. However, accumulating epidemiological and clinical study indicates that zealous acute inflammation or chronic inflammatory reaction is a significant risk factor to develop various human diseases. Controlling or modulating inflammation is therefore important to prevent or ameliorate certain diseases, such as organ transplantations, allergic diseases, and autoimmune diseases. T. wilfordii extract in patients with rheumatoid arthritis , cyclosporin A (CsA), rapamycin, tacrolimus (FK506), and fingolimod FTY720) (summarized in review ). In add0 (summarThis special issue will introduce you to the valuable research reports on anti-inflammatory natural products, ranging from basic researches to exploring roles of natural products against inflammatory diseases. We hope this timely special issue will encourage the research and development of valuable natural products and finally lead to the development of novel therapeutic agents to provide better care to patients.Yifu YangYifu YangLifei HouLifei HouAbdelfattah El OuaamariAbdelfattah El OuaamariLijun XinLijun Xin


The primary complication of any available anticoagulant therapy is the risk of bleeding. Rapid reversal of anticoagulation may be necessary in patients requiring emergency treatment due to uncontrolled bleeding. Prothrombin complex concentrates (PCC) are frequently used to reverse the effect of vitamin K antagonists such as warfarin and have also been suggested to be potentially effective in reversing the effects of the new oral anticoagulants. The present study was therefore designed to determine whether the four-factor PCC Beriplex® (25 to 75 IU/kg). Bleeding was assessed based on the time to hemostasis and the total blood loss after induction of a standardized kidney injury. In parallel, the following biomarkers of hemostasis were determined: factor Xa inhibition, prothrombin time (PT), activated partial thromboplastin time (aPTT), whole blood clotting time (WBCT), and thrombin generation (TGA).Rabbits were treated with a high intravenous bolus dose of edoxaban  followed by the administration of Beriplex® resulted in a dose-dependent reversal of edoxaban-induced bleeding as indicated by reduced time to hemostasis and total blood loss. Both parameters achieved statistical significance compared with placebo at the Beriplex® dose of 50 IU/kg under fully blinded study conditions. The biomarkers correlating best with Beriplex®-mediated edoxaban anticoagulation reversal included PT, WBCT and endogenous thrombin potential.The results confirmed increased and prolonged bleeding of edoxaban-treated animals following standardized kidney injury compared with vehicle administration. Parallel monitoring of biomarkers of hemostasis showed a prolongation of PT, aPTT, WBCT, and changes in thrombin generation parameters. Subsequent administration of Beriplex® treatment effectively reversed edoxaban-induced anticoagulation in an animal model of acute bleeding at clinically relevant dose levels.In summary, Beriplex


Post-stroke care after hospital discharge suffers from lack of intersectoral collaboration within the public health sectors. Hence, primary care remains the only option in managing stroke patients in underserved areas in Malaysia. This study aimed to identify the areas, which can be better coordinated to deliver optimal post-stroke care in community setting. A seamless transfer of care model known as integrated Care Pathway for Post Stroke patients (iCaPPS) was designed to address this issue.Expert panel discussions comprising of family physicians, neurologists, rehabilitation physicians and therapists, and nurse managers from both Ministry of Health and the academia were conducted. Modified Delphi technique was employed to resolve practice variations through additional literature support. Care algorithms were designed around existing work schedules and available resources at public health centres.Identified areas for coordinated transfer of care include: identification of patient criteria suitable for long-term stroke management at primary care facilities, information required at transfer of care, stroke risk factors treatment targets, screening for stroke complications and rehabilitation guide for primary care team. Care algorithm including appropriate tools were summarised to identify patients requiring further multidisciplinary rehabilitation interventions i.e. assessment for those uninitiated or missed out on rehabilitation and leisure intervention for those indicated, screening for swallowing disorders as well as mental health disorders (i.e. depression and dementia).The iCaPPS would facilitate coordinated primary care-led post-stroke management for patients residing at home in the community, hence promoting better collaboration within public health sectors. Clinical outcomes and cost effectiveness of iCaPPS can be evaluated for benefit of stakeholders and stroke survivors.


Chronic migraine is a debilitating disease particularly in women and underlying pathophysiology remains unclear. Clinically relevant migraine models are missing.The aim of this study is to mimic chronic migraine model in rats and to test migraine drugs.Study was approved the Institutional Animal Care and Use Committee and care and handling of animals were in accord with National Institute of Health guidelines. Nasociliary nerve (NCN), which is the rat correlate of opthalmic branch of trigeminal nerve is ligated to mimic chronic headache. Glyceroltrinitrate (GTN) was administered to induce acute migraine attack. Sumatriptane and CGRP receptor antagonist were administered. Pain, anxiety related behavior were recorded. Mechanical allodynia, thermal hyperalgesia was tested by VF/ EVF and acetone; anxiety by elevated plus maze (EPM). Activated areas were investigated by c-fos immunoreactivity and plasma extravasation was studied by horse radish peroxidase.NCN ligation, GTN administration model demonstrated mechanical allodynia, thermal hyperalgesia. Anxiety accompanying pain was confirmed by EPM. Extravasation in dura mater was shown by Horse radish peroxidase. Significantly c-fos immunoreactivity was increased in ipsilateral brainstem TNC compared to contralateral and also in cortical structures constituting pain matrix. CGRP antagonists decreased pain related behavior and c-fos positive cells.Mechanical allodynia, thermal hyperalgesia, c-fos staining confirming central and peripheral sensitization is exhibited in NCN ligated rats and pain related anxiety is confirmed. CGRP receptor antagonists are effective for chronic headache treatment. This chronic migraine model is relevant to human migraine and eligible for further drug investigations.No conflict of interest.


Infectious diseases are a major health problem worldwide, causing many serious complications, including autoimmune disorders in unvaccinated populations. The vaccinations represent the most effective method of preventing infectious diseases and cost benefit analysis of vaccination programmes demonstrated their utility. On the basis of Orphanet database, in Italy rare diseases affect almost 2 million people, and 70% of them are children. Among neurodegenerative disorders, children with spinal muscolar atrophy should receive routine immunizations, including influenza and pneumococcal vaccines; for pediatric patients affected by Becker's Muscular Dystrophy influenza and pneumococcal vaccines are indicated in case of severe weakness of respiratory muscles . Immunoc


Plasmodium sporozoites may function as protective immune responses. They cover immune induction quite extensively but discuss virtually nothing on effector mechanisms of antibody responses against sporozoites. Because their review should be balanced by reference to studies describing effector mechanisms, this commentary will confine itself to recounting some of these.Dups et al.  assess hIn vitro exposure to serum from immunized mice results in an antibody-mediated precipitant projecting from sporozoites (In vitro inhibition of sporozoite motility by serum from immune animals subsequently suggested that anti-sporozoite antibodies can function by blocking sporozoite motility (in vitro studies showed that monoclonal antibodies against the CS antigen blocked in vitro invasion by sporozoites into target cells (in vivo inhibition of sporozoite motility and inhibition of sporozoite invasion of dermal blood vessels by antibodies (rozoites . Becausemotility . Furtheret cells , 5. Substibodies . And an tibodies .Plasmodium berghei sporozoites injected by mosquitoes into sporozoite-immunized vs. non-immunized mice showed significantly fewer sporozoites were deposited in immune mice (in vitro (in vitro and in vivo (Anti-sporozoite antibodies act even earlier during challenge by mosquito bite, by inhibiting release of sporozoites from the mosquito proboscis into skin . This apune mice . CS protin vitro  and intoin vitro , 11. Thu in vivo .Some sporozoites injected by mosquitoes into immunized hosts may successfully escape into the blood. Indeed, sporozoites that bypass skin by being injected intravenously by syringe into mice passively immunized with immune serum are cleared effectively from the circulation , indicatIn vitro studies have documented that opsonized sporozoites are prone to phagocytosis (in vivo. Furthermore, antibodies also inhibit invasion and traversal through hepatocytes, events that rely on sporozoite motility (Conceivably, antibody-coated sporozoites may be blocked during attempted passage through Kupffer cells prior to hepatocyte invasion , 14. In ocytosis –17, suggmotility .Thus, anti-sporozoite antibodies can act sequentially against sporozoites at different stages of sporozoite invasion from the skin to invasion of dermal blood vessels, to passage from Kupffer cells into hepatocytes, and subsequent traversal of sporozoites through a series of hepatocytes.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recruiting patients to research and collecting study data in a primary care setting, combined with maximising retention rates from a primary care population can be challenging and requires recruitment and retention methods which are innovative, efficient and transferrable.To apply low resource intensive and rapidly implemented recruitment and retention innovations for use in primary care settings that ensure patient recruitment and follow-up targets are achieved.A range of innovative recruitment and retention strategies are utilised by Keele CTU including; electronic aide-memoires linked to Read codes; physical aide-memoire prompts in consulting rooms; automated referral methods; postcard, repeat, email, SMS and minimum data collection reminder mailings; death and departure auditing.Methods used; sustain routine care whilst simultaneously screening for research data and participants; provide flexible instruments compatible with all general practice infrastructures; increase clinical precision in identifying suitable participants; automates recording of study data collection; ensures minimal impact on consultation time; contribute towards the delivery of excellent retention rates.Recruitment aide-memoires, automated innovations and retention strategies can all be embedded easily into a primary care setting. These tools, without over burdening the busy primary care practitioner, result in simple and effective methods of prompting patient recruitment and retention. Excellent recruitment and retention rates are possible, despite encountering differences in primary care infrastructure. Such methods should be utilised more widely to facilitate primary care research, if this is where many conditions are diagnosed and managed.


Coregonus sardinella) is a bellwether for Arctic lakes as an important consumer and prey resource. To explore the consequences of climate warming, we used a bioenergetics model to simulate changes in Least Cisco production under future climate scenarios for lakes on the Arctic Coastal Plain. First, we used current temperatures to fit Least Cisco consumption to observed annual growth. We then estimated growth, holding food availability, and then feeding rate constant, for future projections of temperature. Projected warmer water temperatures resulted in reduced Least Cisco production, especially for larger size classes, when food availability was held constant. While holding feeding rate constant, production of Least Cisco increased under all future scenarios with progressively more growth in warmer temperatures. Higher variability occurred with longer projections of time mirroring the expanding uncertainty in climate predictions further into the future. In addition to direct temperature effects on Least Cisco growth, we also considered changes in lake ice phenology and prey resources for Least Cisco. A shorter period of ice cover resulted in increased production, similar to warming temperatures. Altering prey quality had a larger effect on fish production in summer than winter and increased relative growth of younger rather than older age classes of Least Cisco. Overall, we predicted increased production of Least Cisco due to climate warming in lakes of Arctic Alaska. Understanding the implications of increased production of Least Cisco to the entire food web will be necessary to predict ecosystem responses in lakes of the Arctic.Lake ecosystems in the Arctic are changing rapidly due to climate warming. Lakes are sensitive integrators of climate-induced changes and prominent features across the Arctic landscape, especially in lowland permafrost regions such as the Arctic Coastal Plain of Alaska. Despite many studies on the implications of climate warming, how fish populations will respond to lake changes is uncertain for Arctic ecosystems. Least Cisco ( Lakes are prominent features across the Arctic landscape, especially in lowland permafrost regions where the landscape comprises thousands of lakes and the lake area fraction (lake area/land area) can exceed 40%, such as on the Arctic Coastal Plain of Alaska  and loons (Gavia spp.). Therefore, changes in growth rates and size structure of Least Cisco could have implications throughout the food web. Least Cisco will likely have strong responses to climate warming as temperatures exceed the optimum temperature of 16.8°C for coregonids  and Alaska blackfish , whereas widely distributed, but found more often in highly connected systems, are Least Cisco, Broad whitefish (Coregonus nasus), and Arctic grayling . Similar to nearby systems in the Brooks Range , Dolly varden , rainbow smelt (Osmerus mordax), Humpback whitefish (Coregonus oidschian), and the top predators Northern pike (Esox lucius) and burbot ]; Seigle To parameterize the Least Cisco model to lakes on the Arctic Coastal Plain, we assumed Least Cisco feed primarily in the water column and their diet remains constant throughout the year. In the model, diets were evenly divided among expected prey groups of bosmina (1674 J/g wet mass), copepods (2792 J/g wet mass), other cladocerans (2514 J/g wet mass), diptera (1763 J/g wet mass), and leptodora (867 J/g wet mass) using previously published values for prey energy density  for different climate scenarios by holding annual ration and pCmax constant at the level determined for current conditions. By holding annual ration and pCmax constant, we can predict growth for future temperature scenarios. Holding feeding rate and food availability constant has been useful in projecting growth differences with climate change predictions in other systems  of Least Cisco indicates growth only occurs during the summer under current temperatures for all age classes  estimated for growth under current temperatures ranged from 0.33 to 0.59 across age classes of Least Cisco  and accumulated biomass (g) of Least Cisco increased under all future scenarios of warmer temperatures with a constant pCmax Figs. , 6A. MorAge classes of Least Cisco responded differently to increasing temperatures. Relative growth shows an exponential decrease from younger to older age classes for all the climate scenarios produced by the SNAP projections Fig. . YoungerThe annual ration estimated for growth under the current temperatures ranged from 5.61% to 3.18%  in Lake Michigan  and Cisco (Coregonus artedii), by reducing suitable habitat with warmer temperatures  in headwater streams of southern British Columbia, Canada in which their growth rates were more sensitive to prey quality than temperature  in Lake Michigan (Madenjian et al. Using the generalized coregonid model for comparing differences in Least Cisco growth on the Arctic Coastal Plain provides relative comparisons of future climate projections and identifies knowledge gaps. We used a value for the respiration parameter (Wohlschag The empirical data available on the physical and biological components of Arctic freshwater systems are increasing; however, our only option was to compile data from a variety of sources and regions. With a spatially focused assessment of Least Cisco, a more robust model could be built as large differences occur across the landscape. For example, climate warming in the winter is expected to affect coastal areas more than inland areas due to the influence of a longer marine ice-free period. In contrast, during the summer, the projected temperature increases are of a lesser magnitude on the coast and more pronounced in inland areas. Within a region, systematic differences in lake size and morphometry can generate differences in both ice phenology and summer water temperatures despite common climate conditions (Shuter et al.


Gender-based differences in the cardiac morphology and function in patients with volume-overload cardiac pathologies has been widely examined. However the relationship between gender and contractility is not well defined.Therefore we evaluate the gender influence on contractile capacity in patients with volume overload, present with severe mitral valve regurgitation and preserved left ventricular function.Right auricle samples from 40 patients  with severe mitral regurgitation, scheduled for elective mitral valve surgery, were obtained before extracorporal circulation (ECC). The fibers were prepared and skinned to remove membrane-dependent properties and exposed to gradual increase of calcium concentration.Female fibers achieve higher force values than male patients at the highest step of calcium concentration . Male and female fibers show an anticyclical course when exposed to increasing steps of calcium concentrations: starting with lower force values at lower calcium concentrations in males, the steepness of pCa-force-curve is flatter compared to female counterparts . At higher force values females achieve higher maximal forces and lower force values for males .Calcium sensitivity, given as half maximal concentration, is achieved at pCa 5.0 in females and between 6 and 5.5 for males (p 0.04).Male and female fibers from patients with severe mitral regurgitation show adverse calcium induced force properties. Male fibers achieve lower maximal force values, starting at higher base values in low calcium concentration condition and might therefore have higher sensitivity to calcium.


Auditing is an integral part of quality assurance in trials. The introduction of risk-based monitoring in industry coupled with reduced funding for academic trials indicates a need to enhance the comprehensive oversight of trials. Generating an internal audit system streamlines quality management across the clinical trials unit. We aimed to pilot a robust in-house process that prioritises patient safety and monitors trial delivery.Ten healthcare professionals within our team voluntarily formed an internal audit group and received appropriate training. Sub-teams were assigned individual trials to audit over a three month period. Quality and SOP compliance data was collated in a comprehensive audit spreadsheet and processes covered included examination of Site Files, Case Report Forms, Serious Adverse Events (SAE), and source data verification (SDV). Findings were amalgamated into a Corrective Action Preventative Action (CAPA) Plan and fed back to the wider team. Team actions were subsequently reviewed after six weeks as a follow-up measure.Preliminary findings of five internal audits highlighted areas for improvement within data and procedural systems including; informed consent, SAE reporting, and SDV. Additionally, the Audit Group proved a useful measure in developing overall quality standards of the team, highlighted by staff learning, improved knowledge and adherence to regulatory standards.In line with upcoming EU legislation and ICH GCP, maintaining rigorous auditing processes and adherence to quality standards is of utmost importance. The ongoing quarterly internal audit cycle will be continuously reviewed, feeding into an evolving quality management system ensuring best practice across the unit.


Plant immunity relies on a complex network of hormone signaling pathways in which jasmonic acid (JA) plays a central role. Successful microbial pathogens or symbionts have developed strategies to manipulate plant hormone signaling pathways to cause hormonal imbalances for their own benefit. These strategies include the production of plant hormones, phytohormone mimics, or effector proteins that target host components to disrupt hormonal signaling pathways and enhance virulence. Here, we describe the molecular details of the most recent and best-characterized examples of specific JA hormonal manipulation by microbes, which exemplify the ingenious ways by which pathogens can take control over the plant’s hormone signaling network to suppress host immunity. Agricultural productivity depends on the capacity of plants to adapt to changing environmental conditions. In nature, plants live in complex environments in which they intimately interact with a broad range of microbial pathogens with different infection strategies. To defend themselves, plants have evolved sophisticated strategies to perceive their attacker during the infection process and to translate this perception into an effective immune response. Recognition of highly conserved microbe-associated molecular patterns (MAMPs) by host cell transmembrane pattern recognition receptors (PRRs) leads to MAMP-triggered immunity (MTI) that restricts pathogen growth . To overBotrytis cinerea, whereas the SA pathway is primarily induced by and effective in mediating resistance against biotrophic and hemi-biotrophic pathogens such as Pseudomonas syringae . . P. syrit manner . Of noteelopment . In combd by COR .P. syringae mutants unable to produce COR show reduced virulence . In. InB. cidefenses . SSITL rdefenses . FurtherLaccaria bicolor, support host growth by providing growth-limiting nutrients to their plant host through a mutualistic symbiotic relationship within the plant roots [L. bicolor. MiSSP7 is an effector protein indispensable for the establishment of mutualism with their host plants [in planta or through transgenic overexpression of the PtJAZ6 gene [Beneficial microbes establish long-term relationships with their host plants to fulfill their life cycles . Ectomycnt roots . In ordet plants . Upon pet plants ,80. In tAZ6 gene . This inThe importance of signaling molecules in plant immunity is a well-established notion in plant biology and the molecular mechanisms regulating the phytohormone-mediated defenses have been extensively studied in the last decades. In this context, the role of hormones in plant immunity is further highlighted by the increasing number of pathogens producing phytohormones or phytohormone mimics and by the identification of a plethora of microbial effectors targeting hormonal pathways to promote disease or establish beneficial interactions. Of note, virulence activities of effectors on specific hormonal components can lead to the identification of novel mechanisms of host hormonal regulation unknown to date. In addition, an improved mechanistic understanding of how pathogenic toxins and effectors manipulate host hormonal components will be instrumental in identifying new defensive hubs and to develop new plant varieties with improved resistance to pathogens.


Pulseless electrical activity cardiac arrest is associated with poor outcomes and the identification of potentially reversible reasons for cardiac arrest is fundamental.We describe the case of a 46-year-old male with the rare coincidental finding of supravalvular aortic stenosis and coronary vasospasm leading to recurrent pulseless electrical activity cardiac arrest. Extracorporeal life support was successfully applied for hemodynamic stabilization. Supravalvular aorticstenosis underwent surgical repair. The patient survived five time resuscitation and was discharged after full neurological recovery.Coronary vasospasm and supravalvular aortic stenosis are rare but potentially reversible causes of pulseless electrical activity cardiac arrest. Extracorporeal life support allows accurate diagnostic and possibly therapy even of uncommon reasons for cardiac arrest.The online version of this article (doi:10.1186/s12872-016-0284-5) contains supplementary material, which is available to authorized users. Cardiac arrest due to pulseless electrical activity (PEA) is associated with poor survival and neurological outcome when compared to a shockable rhythm , 2. To pWe describe here for the first time the case of a patient with the rare coincident finding of coronary vasospasm and supravalvular aortic stenosis leading to recurrent pulseless electrical activity cardiac arrests.A 46-year-old male was successfully resuscitated for out-of-hospital cardiac arrest due to ventricular fibrillation Fig. . CoronarBecause of the development of a severe acute respiratory distress syndrome five days after admission our ECMO team established a veno-venous extra-corporeal membrane oxygenation (vvECMO) system using a 31 Fr bi-caval cannula and transferred the patient to our center  that was confirmed by CT (Fig.The patient has no family history of cardiac death. He underwent patch-repair for supravalvular aortic stenosis during childhood. On day 6 transthoracic and transesophageal echocardiography revealed a remaining supravalvular aortic stenosis (Vy CT Fig..The patient had full neurological recovery and was discharged to follow-up treatment. A cardiac defibrillator was implanted for secondary prevention of the initial VF.We report a case of recurrent cardiac arrests due to coronary vasospasm and supravalvular aortic stenosis.The patient survived five episodes of cardiac arrest, four of them with PEA which is an uncommon complication of vasospastic angina. Patients with vasospastic angina pectoris are at higher risk of sudden cardiac death and most often cardiac arrest occurs due to tachycardic ventricular arrhythmia . NeverthVeno-arterial ECMO is considered as the preferred method for extracorporeal life support to allow further diagnosis and therapeutic measures when standard life support fails to achieve ROSC . PercutaIn conclusion, the coincidence of coronary vasospasm and supravalvular aortic stenosis lead to recurrent pulseless electrical activity cardiac arrest in this case. Unusual causes for refractory cardiac arrest should be considered during and after resuscitation. Extracorporeal life support provides the opportunity for accurate diagnostic and therapy when routine diagnostic measures are not sufficient.CT, computer-assisted tomography; ECLS, extracorporeal life support; ECMO, extracorporeal membrane oxygenation; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation.


It seems that renal tubular damages in acute renal failure involved in gentamicin nephrotoxicity or ischemia/reperfusion mainly induced by increasing of reactive oxygen species (oxidative stress). According to this attitude, many researchers have been used different antioxidant agents in combat with gentamicin nephrotoxicity. Treatment of animal with metformin against gentamicin revealed that gentamicin might be induced renal tubular damages via energy depletion in renal tubular cells besides inducing of oxidative stress. More studies are needed to clarify renal protective effect of adenosine monophosphate-activated protein kinase (AMPK) activator such as metformin in combat with gentamicin nephrotoxicity.In spite of undesirable gentamicin nephrotoxicity, this antibiotic is commonly used versus Gram-negative bacteria and still constitutes the only effective therapeutic alternative against microorganisms-pseudomonas, proteus and serratia – that are insensitive to other antibiotics . MoreoveThe pathological mechanisms involved in gentamicin induced nephrotoxicity include induction of oxidative stress, apoptosis, necrosis, up regulation of transforming growth factor B, elevation of endothelin I , increase of monocyte/macrophages infiltration , phospholipidosis an increase of intracellular sodium ions ,3. GentaGentamicin nephrotoxicity is characterized functionally by an increase of serum creatinine, blood urea nitrogen, and decrease in glomerular filtration rate , which mMore investigations showed that antioxidant agents inhibited or attenuated gentamicinnephrotoxicity in rats. Usage of antioxidants improved histological injuries such as tubular necrosis, tubular cell edema and apoptosis in gentamicin-injected rats -8.Metformin that used by diabetic patients showed oxidative stress inhibitor activity and adenosine monophosphate-activated protein kinase (AMPK) activator. Some researchers evaluated effects of metformin against gentamicin nephrotoxicity. They reported beneficial effect of metformin in combat with renal histopathological changes induced by gentamicin -10.Alterations in epithelial cell polarity and in the subcellular distributions of epithelial ion transport proteins are key molecular consequences of acute kidney injury and intracellular energy depletion. AMPK, a cellular energy sensor, is rapidly activated in response to renal ischemia, and renal epithelial cells subjected to energy depletion .In the study of Baradaran and colleague for the first time combination effect of metformin and garlic extract evaluated against gentamicin nephrotoxicity. They showed that this treatment attenuated renal histopathological injuries including epithelial cell vacuolization, degeneration, tubular cell flattening, hyaline cast, tubular dilatation, and debris materials in tubular lumen- induced by gentamicin . TreatmeThe author wants to thank from the personals of Department of Anatomy, Lorestan University of Medical Sciences.MT is the single author of the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the author.None declared.


Objective: The purpose of this study was to assess central (aortic) vascular dysfunction in post renal transplant patients by high-resolution cardiovascular magnetic resonance imaging (CMR). Background: Renal transplant recipients are at increased risk of cardiovascular (CV) disease. The cardiac phenotype in post-transplant recipients is not well defined. A recent study suggested myocardial perfusion is impaired in renal transplant patients irrespective of the degree of left ventricular hypertrophy.We hypotMethods: Twenty-five asymptomatic renal transplant patients (RT) and 17 hypertensive controls (HT) underwent CMR scanning at 1.5 T. Myocardial function, late enhancement, aortic pulse wave velocity and first-pass perfusion at rest and stress was performed. Myocardial Perfusion Reserve Index (MPRI) was calculated as the ratio of hyperemic to resting myocardial blood flow by dividing the myocardial perfusion at stress by rest perfusion (corrected to rate pressure product). Pulse wave velocity (PWV) was calculated as the ratio between the distance and time from ascending aorta to descending aorta at the level of main pulmonary artery. Statistical analyses were performed using mixed effects modelling for MPRI and linear regression for relationship between MPRI and PWV.Results: Baseline clinical characteristics were similar for RT and HT control groups. Mean inter-ventricular septal thickness and LV mass indexed to body surface area were similar in both RT cases and HT controls. MPRI was significantly lower in the RT group compared to the HT group , globally and in all three coronary artery territories[Conclusions: In our cohort population, there is no evidence of increased aortic stiffness in post renal transplant patients compared to hypertensive patients. Although these patients demonstrate impaired myocardial perfusion reserve, this is not correlated with increased aortic stiffness.None.


Rapidly destructive coxarthrosis (RDC) is a rare syndrome that involves aggressive hip joint destruction within 6–12 months of symptom onset with no single diagnostic laboratory, pathological, or radiographic finding. We report an original case of RDC as an initial presentation of seronegative rheumatoid arthritis (RA) in a 57-year-old Caucasian woman presenting with 6 months of progressive right groin pain and no preceding trauma or chronic steroid use. Over 5 months, she was unable to ambulate and plain films showed complete resorption of the right femoral head and erosion of the acetabulum. There were inflammatory features seen on computed tomography (CT) and magnetic resonance imaging (MRI). She required a right total hip arthroplasty, but arthritis in other joints showed improvement with triple disease modifying antirheumatic drugs (DMARD) therapy and almost complete remission with the addition of adalimumab. We contrast our case of RDC as an initial presentation of RA to 8 RDC case reports of patients with established RA. Furthermore, this case highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration. Rapidly destructive coxarthrosis (RDC) of the hip joint was initially coined in 1970 . The joiA 57-year-old Caucasian woman was referred to our rheumatology outpatient center from the orthopedics service for assessment of a possible inflammatory etiology for her rapidly destructive arthritis. Initial diagnostic work-up was significant for elevated inflammatory markers, weakly positive antinuclear antibody (ANA) and otherwise negative autoimmune markers including both rheumatoid factor (RF) and anticitrullinated peptide (anti-CCP) . All culInitial plain films of her right hip and pelvis showed femoral head lucencies compatible with subchondral cysts (but no definite fracture) and moderate diffuse articular joint space loss with flattening of the femoral head . Over a Three right hip aspirations were attempted with sufficient sample in only one attempt, which showed bloody fluid, 0.6 nucleated cells (17% neutrophils), and presence of only extracellular but not intracellular calcium pyrophosphate dehydrate (CPPD) crystals. Synovial biopsy did not reveal any crystals. Historically, CPPD crystal deposition disease can cause such acutely destructive disease on imaging and pathology , but theThe major differential diagnosis of this atypical case of destructive arthritis is outlined in In order to definitively differentiate between chronic sepsis, malignancy, and a chronic inflammatory process, an open biopsy of the hip was performed by the orthopaedic service, which showed overall morphology with features of chronic inflammation, fibrosis, multinucleated giant cell reaction with dystrophic calcification, and reactive synovial proliferation . CultureAn inflammatory etiology was most likely given multiple swollen joints, elevated inflammatory markers, constitutional symptoms, evidence of inflammatory features on imaging, and other causes excluded. Hence, a diagnosis of seronegative rheumatoid arthritis (RA) was ultimately made, fulfilling 4/7 of the 1987 RA American College of Rheumatology (ACR) classification criteria  and scorInflammatory arthritis is a rare cause of RDC with only 8 case reports of patients with preexisting RA , 9–11. LAnother atypical feature of this patient's presentation was an associated benign soft tissue mass with enhancement involving the articular region, acetabulum, sacroiliac region, and anterior pelvis . A previTotal hip arthroplasties have been used as a treatment modality for severe RDC with good response in a retrospective review of total hip arthroplasties performed on patients with RDC . HoweverTo conclude, rheumatoid arthritis is a rare cause of rapidly destructive coxarthrosis (RDC). We present the first case report of RDC as the initial presentation of seronegative rheumatoid arthritis in a 57-year-old woman who required right total hip arthroplasty, but whose other active joints had a good response to DMARD and biologic therapy. This case also highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration.


Laparoscopic appendectomy is increasingly accepted as the preferred surgical treatment for acute appendicitis and represents one of the most common emergency operations performed in both adult and paediatric populations. However, in patients with perforated appendicitis laparoscopy is associated with an increased incidence of postoperative intraabdominal infections compared to open appendectomy. Nowadays urgent imaging is commonly requested by surgeons when postoperative complications are suspected. Due to the widespread use of laparoscopy, in hospitals with active surgical practices clinicians and radiologists are increasingly faced with suspected postappendectomy complications. This pictorial essay illustrates the normal cross-sectional imaging findings observed shortly after laparoscopic appendectomy and the spectrum of appearances of iatrogenic intraabdominal infections observed in adults and adolescents, aiming to provide radiologists with an increased familiarity with early postoperative imaging. Emphasis is placed on the role of multidetector CT, which according to the most recent World Society of Emergency Surgery (WSES) guidelines is the preferred and most accurate modality to promptly investigate suspected intraabdominal infections and highly helpful for correct therapeutic choice, particularly to identify those occurrences that require in-hospital treatment, drainage or surgical reintervention. In teenagers and young adults MRI represents an attractive alternative modality to detect or exclude iatrogenic abscesses without ionising radiation.Teaching pointsLaparoscopic appendectomy is the preferred surgical treatment for uncomplicated acute appendicitis• In perforated appendicitis laparoscopy results in increased incidence of intraabdominal infections• Multidetector CT promptly assesses suspected iatrogenic intraabdominal infections• Interpretation of early postoperative CT requires knowledge of normal postsurgical imaging findings• Postsurgical infections include right-sided peritonitis, intraabdominal, pelvic or liver abscesses•  Acute appendicitis (AA) represents one of the most common surgical emergencies worldwide and often occurs in young people, adolescents and children. Nowadays laparoscopic appendectomy (LA) has become increasingly accepted as the preferred surgical procedure in adult patients with suspected or documented AA –4.However, despite several published studies it is still unclear whether the classical open appendectomy (OA) remains superior to LA in terms of efficacy and safety. Although with similar overall short-term morbidity and mortality compared to OA, in adults LA is associated with lower incidence of wound infection, postoperative ileus and analgesics use, an earlier resumption of normal diet, shorter hospitalisation and more rapid recovery to normal activities , 5, 6. PSimilarly, in paediatric populations LA currently represents the preferred surgical procedure for most cases of AA and is associated with shorter hospitalisation, earlier resumption of normal diet and activities, and a reduced morbidity including lower incidence of wound infections and postoperative ileus , 10. How2 pneumoperitoneum and a local thermal effect from surgical instrumentation , 2221, 2Exceptionally, intraabdominal infections may seed via a patent processus vaginalis leading to the formation of a scrotal abscess .Furthermore, as with other abdominal surgeries, the portal venous system should be carefully scrutinised for signs of dilatation and filling defects. Following appendectomy pylephlebitis has been occasionally reported to involve the superior mesenteric vein, particularly in patients with underlying coagulopathy or when the operation is performed in advanced stages of the disease with peritonitis .Appendectomy remains one of the most common emergency surgical procedures and is increasingly performed using laparoscopy. Partly due to fear of litigation, urgent diagnostic imaging is increasingly requested by surgeons when postoperative complications are suspected after laparoscopic procedures. Prompt cross-sectional imaging investigation with MDCT and familiarity with the normal postoperative findings and the imaging appearances of IAA are helpful for accurate diagnosis and correct therapeutic choice, particularly to identify those occurrences that require prolonged in-hospital treatment, drainage or surgical reintervention. When available, MRI represents a valuable alternative modality that allows avoiding ionising radiation in young patients and adolescents in good clinical condition , 15.


The incorporation of tidal inundation information and detailed data on landscape features, such as the structure of saltmarsh vegetation at mangrove boundaries, should improve the accuracy of models that are being developed to forecast mangrove distributional shifts in response to sea-level rise.Few studies have empirically examined the suite of mechanisms that underlie the distributional shifts displayed by organisms in response to changing climatic condition. Mangrove forests are expected to move inland as sea-level rises, encroaching on saltmarsh plants inhabiting higher elevations. Mangrove propagules are transported by tidal waters and propagule dispersal is likely modified upon encountering the mangrove-saltmarsh ecotone, the implications of which are poorly known. Here, using an experimental approach, we record landward and seaward dispersal and subsequent establishment of mangrove propagules that encounter biotic boundaries composed of two types of saltmarsh taxa: succulents and grasses. Our findings revealed that propagules emplaced within saltmarsh vegetation immediately landward of the extant mangrove fringe boundary frequently dispersed in the seaward direction. However, propagules moved seaward less frequently and over shorter distances upon encountering boundaries composed of saltmarsh grasses versus succulents. We uniquely confirmed that the small subset of propagules dispersing landward displayed proportionately higher establishment success than those transported seaward. Although impacts of ecotones on plant dispersal have rarely been investigated  Impacts of climate change may be displayed by a variety of responses at the individual population, species, community, or ecosystem level. Populations are predicted to track their niche and shift predictably towards suitable areas , 2, but Although directional dispersal of individuals towards those areas suitable for sustaining populations has often been discussed , 8 and msensu boundary permeability  within the buffer. Conversely, propagules from succulent-grass plots rooted a mean (± se) distance of 6.7 (± 5.1) cm seaward of the starting position. On the last sampling date, we also observed a trend towards greater leaf production by A. germinans seedlings (71% produced leaves) from the grass monoculture treatment compared to leaf production by seedlings (52%) that were emplaced into the succulent-grass ecotone treatment. Finally, A. germinans propagules that had been emplaced into grass monoculture plots produced a slightly higher number of leaves than that recorded for individuals emplaced into succulent-grass plots .The composition of the experimental saltmarsh boundaries into which propagules were emplaced also influenced spatial patterns of mangrove establishment. By 6 weeks, 50.8% of all propagules had successfully rooted . Of the ositions . AdditioFactors influencing an inland niche shift of the black mangrove emerge from our quantification of landward movement of mangrove propagules upon encountering saltmarsh boundaries. Our study demonstrates that biotic boundaries erected by saltmarsh plants play a key role in directing the initial sequence of landward migration of mangroves expected under conditions of increasing sea-level. More specifically, hydrochorous transport vectors  and structural features of saltmarsh plants combine to determine permeability of inland boundaries to dispersing mangrove propagules. By recording both propagule retention and seedling establishment at landward mangrove margins we newly identified processes that contribute to successful mangrove persistence during inland migration. Our work provides empirical assessment of responses by early life-history stages of the black mangrove to the spatial arrangement of co-occurring coastal taxa thereby adding insight into the adaptive capacity for mangroves to respond to challenges from climate change.in situ work on mangrove dispersal [In agreement with ispersal , mangrovispersal , 20. Theispersal . This fiSporobolus virginicus, because both frequency and distance of seaward dispersal of propagules was reduced compared to the boundary containing succulent plants. Where succulents were present, comparatively higher proportions of propagules transported seaward led to a reduced abundance of potential colonizers remaining at the leading edge of mangrove migration. Propagule dispersal through saltmarsh plants  was likely influenced by the physical characteristics of the saltmarsh taxa, such as structural complexity [Although propagules emplaced into either boundary condition, i.e., grass monoculture or succulent-grass, generally moved seaward, the influence of saltmarsh taxa on the inland movement of the remaining propagules varied in a consistent way. Notably, propagule retention was improved at the saltmarsh boundary composed of monocultures of the saltmarsh grass, mplexity , height Rhizophora mangle propagules, which are considerably larger and distinctly different in shape than A. germinans [A. germinans propagules through succulent saltmarsh vegetation at our study site.Various types of saltmarsh-mangrove boundaries occur throughout the Caribbean and Gulf of Mexico , 28, 30.erminans , may becerminans ; whereaspersonal observations), suggest that some propagules transported landward are able to survive and ultimately achieve reproductive success. As appears to be true for mangroves, studies of migration by terrestrial plants challenged by climate drivers have also reported examples of directional dispersal running counter to the predicted direction of a niche shift [Aglaia aff. flavida were preferentially deposited uphill by Casuarius bennetti while, in contrast, most undispersed seeds moved downhill. Thus spatial shifts of both this montane plant and black mangrove appear to depend upon a comparatively small subset of propagules that are transported to, and successfully establish in, suitable sites.Landward transport of mangrove propagules at the saltmarsh boundary occurred within days; yet a pattern demonstrating inland recruitment persisted for at least 6 weeks, after which time most propagules became established seedlings. Moreover, a proportional increase in seedling establishment and leaf production was recorded for propagules that dispersed landward relative to seaward. These observations are aligned with Rabinowitz  who docuhe shift , 15, 16.he shift , 14, 43 he shift . Directihe shift . Mack [4Previously unavailable information on the direction of mangrove propagule dispersal across saltmarsh boundaries and spatial patterns of seedling establishment in the context of landscape features emerged from our experiments. Building on these findings, conditions under which boundary permeability to tidally-dispersed mangrove propagules and subsequent recruitment patterns might be altered can be identified. For instance, the potential for mangroves to be transported landward and establish at comparatively higher tidal elevations should vary if dispersal vectors or saltmarsh community composition are modified because of associated impacts to boundary function , 36, 39.Climate change is expected to increase the frequency/intensity of storms , which mAdditionally, propagule dispersal may be altered if the ecotone between saltmarsh succulents and grasses itself responds dynamically to climate drivers by shifting landward . As struFurthermore, complex biotic interactions between mangroves and saltmarsh taxa may operate not only during mangrove dispersal and recruitment, as shown here, but also during later life stages . In thisIn summary, our results suggest that interplay between tidal transport and physical attributes of saltmarsh vegetation assumes a critical role in directing the initial phase of shifting mangrove distributions and thus the capacity of black mangroves to respond to rising sea-level. These combined findings imply that any modification of tidal conditions or changes in plant composition of intertidal/supratidal landscapes through which propagules must disperse should impact the rate of successful mangrove migration as a consequence of altered mangrove dispersal and boundary permeability. The next challenge is to evaluate the capacity of mangroves to migrate inland as the coastal landscape is rearranged not only by rising sea-level but also other climate drivers.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.


The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. However, manual delineation is time-consuming and there is considerable inter-observer variability. This is pertinent as function-sparing and adaptive IMRT have increased the number and frequency of delineation of OARs. We evaluated accuracy and potential time-saving of Smart Probabilistic Image Contouring Engine (SPICE) automatic segmentation to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.Five clinicians recorded the time to delineate five organs at risk  for each of 10 CT scans. SPICE was then used to define these structures. The acceptability of SPICE contours was initially determined by visual inspection and the total time to modify them recorded per scan. The Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm created a reference standard from all clinician contours. Clinician, SPICE and modified contours were compared against STAPLE by the Dice similarity coefficient (DSC) and mean/maximum distance to agreement (DTA).For all investigated structures, SPICE contours were less accurate than manual contours. However, for parotid/submandibular glands they were acceptable . Modified SPICE contours were also less accurate than manual contours. The utilisation of SPICE did not result in time-saving/improve efficiency.Improvements in accuracy of automatic segmentation for head and neck OARs would be worthwhile and are required before its routine clinical implementation. The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. HoweverFollowing head and neck radiotherapy, adverse late effects are highly prevalent and these impact on both organ function and more general domains of well-being, such as physical, mental and social health. RadiatiSwallowing dysfunction is seen in up to half of patients treated with definitive synchronous chemo-radiotherapy and is the most common late grade ≥3 toxicity; the incidence has increased with intensification of treatment including addition of chemotherapy or altered fractionation-16. ThisPermanent and predominantly high frequency sensori-neural hearing loss may occur in 40-60% of patients who receive radiotherapy to areas such as the nasopharynx, para-nasal sinuses and parotid bed-31. ThisSignificant anatomic changes and alteration in dose to target volumes and OARs may occur during a course of head and neck radiotherapy-37. A stSmart Probabilistic Image Contouring Engine (SPICE) is an automated commercially available algorithm, which combines an atlas-based and model-based approach to segmentation of head and neck lymph node levels and OARs. The atlThis study aims to evaluate accuracy and time-saving of SPICE to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.utilisation of SPICE in clinical practice (clinician review and modification). These also demonstrate introduction of bias by automatic segmentation .Ten radiotherapy planning CT scans were selected where the OARs of interest were not distorted by tumour or artefact . Five clinicians (four Consultants/Attending Physicians and one Fellow) recorded for each scan the time to manually delineate the parotid and submandibular glands, larynx (supraglottic and glottic larynx defined as one structure), pharyngeal constrictor muscles  and cochleae according to a locally agreed protocol based on published guidelines ,48,49. SThe Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm employs a probability map to create a ‘best fit’ from a collection of contours Figure 50]. Th. Th50]. t-test (to determine efficiency in the utilisation of SPICE). Significance was assessed at the p < 0.05 level.Statistical comparisons using multiple linear regression analysis  were made between mean values of all matrices for: SPICE against STAPLE versus manual against STAPLE (to determine the accuracy of SPICE); and modified SPICE against STAPLE versus manual against STAPLE . As a further measure of accuracy, SPICE was compared with the most discordant clinician contours (determined against STAPLE and by ranking of clinicians) for each structure measured by DSC and DTA, using the Wilcoxon signed rank test. The total times to manual versus modify SPICE contours for all structures and clinicians were compared using Student’s paired SPICE submandibular gland ‘1’ and parotid gland ‘2’ contours demonstrated best concordance with STAPLE Table  and4. SThe total proportions of SPICE contours determined by visual inspection not to require alteration were: parotid glands 17%), submandibular glands (41%), larynx (8%), pharyngeal constrictor muscles (4%), and cochleae (28%). The mean DSCs were significantly reduced for modified SPICE contours compared with manual for all structures Figure . However%, submanThe respective per scan overall mean times for manual and modified SPICE contours were 14.0 and 16.2 minutes  Figure . Only onThis study showed that for head and neck OARs: (i) SPICE contours were less accurate than manual contours, but acceptable for the definition of parotid and submandibular glands; (ii) modified SPICE contours remained inferior to manual contours; and (iii) the utilisation of SPICE compared with manual delineation did not result in time-saving/improve efficiency.et al compared for two CT scans and eight clinicians, manual and automatic modified contours for delineation of the clinical target volume as well as parotid glands, spinal cord, brainstem and (for one scan) the optic apparatus[ISOgray atlas-based auto-segmentation algorithm was evaluated for definition of the brainstem, parotid glands and mandible[Automatic segmentation to define selected head and neck OARs may reduce inter-observer variability,55. Chaopparatus. For theBrainlab automated segmentation algorithm, which employs atlas-based and deformable registration, was assessed for accuracy of definition of neck nodal regions and selected head and neck OARs[The updated eck OARs. In 10 ‘Clinical validation of a multiple-subject atlas-based autosegmentation tool was performed by measuring the DSC and mean DTA for manual contours (outlined by one of 10 clinicians and agreed by an expert panel) and modified contours (outlined by one of two clinicians) for neck levels, parotid and submandibular glands in 12 patients. For manWe found that SPICE automatic contours were less accurate/inferior to manual contours for all investigated structures, but acceptable for the parotid and submandibular glands. For the parotid and submandibular glands, the DSCs were satisfactory;,52 for pWhether differences between manual, automatic or modified contours result in clinically relevant alterations in measured doses to OARs is uncertain. This will partly depend on proximity of normal structures to the treatment volume and the dose gradient. In this study, the target volumes were not defined. This may have influenced the low percentage of OARs determined by visual inspection not to require alteration i.e., clinicians only considered the conformity of automatic contours to normal structures rather than clinical relevance or requirement for this.This study represents an independent clinical evaluation of automatic segmentation using SPICE and its utilisation for head and neck OARs. It determined the accuracy of SPICE by comparison against a reference standard created using STAPLE, for five head and neck OARs important in function-sparing IMRT. Future work should evaluate automatic segmentation in the presence of distortion by tumour or artefact e.g., dental amalgam; and determine the variation in measured dose to OARs between manual, automatic and modified contours.For the investigated head and neck OARs, SPICE automatic segmentations were less accurate than manual contours. However, these were acceptable for the definition of parotid and submandibular glands. The modification of SPICE contours improved accuracy, but these remained inferior to manual contours and the process did not result in time-saving. Improvements in automatic segmentation of head and neck OARs would be worthwhile and are required before routine clinical implementation.OARs: Organs at risk; IMRT: Intensity-modulated radiotherapy; SPICE: Smart Probabilistic Image Contouring Engine; STAPLE: Simultaneous Truth and Performance Level Estimation; DSC: Dice Similarity Coefficient; DTA: Distance to agreement; PARSPORT: Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer; Gy: Gray; kV: kilovoltage; CT: Computed tomography.The authors declare that they have no competing interests.DT designed and coordinated the study, participated in contouring, analysed part of the data, interpreted data, drafted the manuscript. CB performed STAPLE and volume overlap measurements. TL analysed the data. AA provided the DTA algorithm and helped with volume overlap measurements. LL, BY, AJS, NJS participated in contouring. CR/NJS conceived the study, participated in its design and coordination and helped draft the manuscript. All authors read and approved the final manuscript.


To assess medical and nursing students’ intentions to migrate abroad or practice in rural areas.We surveyed 3199 first- and final-year medical and nursing students at 16 premier government institutions in Bangladesh, Ethiopia, India, Kenya, Malawi, Nepal, the United Republic of Tanzania and Zambia. The survey contained questions to identify factors that could predict students’ intentions to migrate. Primary outcomes were the likelihoods of migrating to work abroad or working in rural areas in the country of training within five years post-training. We assessed predictors of migration intentions using multivariable proportional odds models.Among respondents, 28% (870/3156) expected to migrate abroad, while only 18% (575/3158) anticipated a rural career. More nursing than medical students desired professions abroad . Career desires before matriculation correlated with current intentions for international  and rural  careers. Time spent in rural areas before matriculation predicted the preference for a rural career  and against work abroad .A significant proportion of students surveyed still intend to work abroad or in cities after training. These intentions could be identified even before matriculation. Admissions standards that account for years spent in rural areas could promote greater graduate retention in the country of training and in rural areas. We know very little regarding the characteristics of students inclined to work in rural areas or remain in the country in which they train.–http://biostat.mc.vanderbilt.edu/StudentMigration).Previous studies on health worker retention are mainly from high-income countries,–We considered countries in sub-Saharan Africa and south-east Asia that were classified by WHO as having a critical shortage of health service providers .,To enhance similarity between study institution governance structure and founding principles, we excluded countries without both a government medical and nursing school, or in which either school was established after 1993. This date corresponds to a period of increased attention to health sector reform in developing countries that may have affected guiding missions of health training institutions established thereafter.The 16 study sites selected are listed in We conducted the study from September 2011 to April 2012. Students eligible for our study were first- or final-year students enrolled in medical  or nursing (Bachelor of Science) degree programmes. At each institution, a self-administered questionnaire was given to all eligible students attending a mandatory class lecture. Written informed consent was obtained before survey administration. Survey items assessed student background characteristics such as socioeconomic status and place of origin, attitudes towards rural and international careers and student career intentions (Appendix). Questions, derived from literature review (Appendix), consisted largely of multiple-choice items and five-point Likert scales. Surveys were in English. To minimize potential bias from variable English proficiency, official language translations were provided as an aide alongside the English questions in five countries  where English is not an official language. Translations were validated using independent back-translation. Field testing was performed in each country and country-specific modifications were made to ensure relevant terminology. The two primary outcomes were self-reported likelihood of choosing to work outside the country or in a rural setting inside the country within five years post-training.Questionnaire results were entered electronically and data entry audited by randomly selecting 22 electronic questionnaires from each country for comparison with hard copies. Audit sample size was calculated to ensure an estimated data entry error rate less than 5% with 95% confidence interval (CI). Questionnaires with more than 25% of responses missing were excluded from analysis.http://www.r-project.org) for data analyses.For each country, we used summary statistics to describe respondent characteristics and multivariable proportional odds models to estimate the independent relationship between 14 selected characteristics  and the likelihood to work internationally or in rural areas. The number of characteristics selected was computed using the smallest country sample size.At the 16 institutions studied, 3822 students were enrolled in first- or final-year medical or nursing degree classes . Of thesTen schools in sub-Saharan Africa comprised 66% (2118/3199) of the study population, while six South Asian schools encompassed 34% (1081/3199) . MedicalOf all students, 28% (870/3156) reported being very likely to choose work abroad within five years of completing training . InternaMultivariable analysis showed that nursing students were more likely than medical students to intend careers abroad . Final-year students were less likely to plan international careers than first-year counterparts  of all students reported high likelihood of choosing a rural career within five years of training, including 16% (360/2257) of medical and 24% (215/901) of nursing students . In sub-As with international migration intentions, individuals who upon school entry had desired a rural career were now nearly five times more likely to plan one . Our aggregate class response rate is high (84%). Our study is systematic, employing rigid yet relevant selection criteria to identify study sites. All participating nations face significant health worker shortages and ongoing emigration, but possess stable environments where retention policies are not superseded by larger systemic sociopolitical motivators of migration. We independently analysed 14 student characteristics to identify predictors for a career in the country or in rural areas. Our results have implications for education and health-care policy-makers in LMIC and donor nations.Our sample cannot be generalized to areas where internal conflict or political turmoil may drive migration regardless of student characteristics, nor can it be extrapolated to non-Anglophone countries. Sub-Saharan African countries have comparable physician emigration rates regardless of national language,,,,,Our data suggest that students’ career desires before matriculating may persist into the last year of training. Although our study design cannot exclude recall bias, the direction of recall error is unclear and should be further investigated through longitudinal assessment. Similarly, under-reporting of true migration intentions due to perceived values of the school professionals might create a social bias. However, if such bias is present it would strengthen our results, since the true number of students intending to migrate may be higher and those planning to work in rural areas even lower than we report. Social bias was mitigated by survey anonymity and is unlikely to have affected class years differently. Our cross-sectional questionnaire of students’ intentions is not validated for predicting actual migration behaviour. Nonetheless, the similarity of our results to existing migration statistics suggests that students’ intentions may resemble such behaviour.,Further research is needed to understand the migration intentions of students. Our study focused on students at premier public schools, where institutional missions focus on producing practitioners for domestic service and health-care leadership, and where public funds offset educational expenses. Migration ambitions may differ at private or newly-established public institutions with varying school resources, values and admissions standards. Also, longitudinal analysis is needed to discern whether differences in career plans between first- and final-year classes represent an evolution of students’ preferences during the schooling period or a change in class composition resulting from recent enrolment expansions at many institutions studied. Finally, additional migration routes of health professionals in LMIC remain to be studied: from public to private sector and from clinical to administrative sector. This is important research since health professionals’ movements from clinical public-sector work threaten already fragile public-health systems.–,,,Increased demand for health professionals in developed countries is projected to attract even more LMIC graduates,With nearly 64% of people in sub-Saharan Africa and 69% in South Asia residing in rural areas,


Addiction services organizations have been slow to adopt and implement evidence-based practices (EBPs) for substance abuse and dependence. This is due in part to poor worker morale and organizational climates that are not conducive to successful learning and integration of these practices . Person-Direct service providers (N = 120) from four addiction services organizations in a large Midwestern city responded to a survey assessing provider morale, organizational learning climate, agency expectations for EBP use, agency resources for EBP use, and provider attitudes towards EBP use. Difference scores between provider- and agency-level factors were computed to model provider-agency fit. Linear regression models were accounted for in all analyses, but were determined to be insufficiently sensitive in modeling the curvilinear (inverted U-shaped) relationships expected in this study. Therefore, quadratic regression analyses were conducted to more adequately model the level of the dependent variables across the entire “fit continuum.”Misfit between agency expectations and provider attitudes and between agency resources and provider attitudes were associated with poorer provider morale and weaker organizational learning climate. For all hypotheses, the curvilinear model of provider-agency misfit significantly predicted provider morale and organizational learning climate Figures  and 2. MThis research benefits from a strong theoretical framework, consistent findings, and significant practical implications for substance abuse treatment agencies. Provider morale and organizational learning climate are important indicators of successful EBP implementation. Comprehensive attempts to strengthen these outcomes must consider both provider- and agency-level characteristics regarding EBP use. Managers and supervisors should consider conducting periodical self-assessments of their agency’s cultural predispositions toward EBP implementation  and addiction service providers’ openness, abilities, and general attitudes towards using EBPs. Organizational efforts to more closely align provider attitudes and agency priorities will likely constitute a key strategy in fostering the implementation of EBPs in addiction services organizations.


In MOF the competition for the amino acid arginine between the microcirculation and the inflammatory response is important. The endothelial nitric-oxide synthase (eNOS) uses arginine to produce nitric oxide (NO), which results in microcirculatory vasodilatation, whereas arginase and the inflammatory nitric-oxide synthase (iNOS) use arginine in the inflammatory response to produce acute phase proteins and to stimulate the host response. Enhanced arginine consumption combined with decreased arginine To investigate the role of the NOS enzymes during endotoxemia and the effect of citrulline supplementation on the arginine-NO synthesis and microcirculation.-/-; n= 39), deficient eNOS mice  and double knock-out (KO) mice  received a continuous LPS  infusion for 18 hrs alone or combined with citrulline (37.5mg) for the last 6 hrs. SDF-imaging was used to evaluate the microcirculation in jejunal villi and the NO production in jejunal tissue was determined by in vivo NO spin trapping and quantified by electron spin-resonance spectrometry. After the microcirculatory measurements or in vivo NO spin trapping, mice were sacrificed, blood and tissues were sampled. Amino-acid concentrations in blood and tissue were measured by High Performance Liquid Chromotography.Wildtype (n= 39), deficient iNOS mice, (iNOS-/- or eNOS-/- mice this was not accompanied by a decreased intracellular arginine availability. Jejunal NO production was significantly decreased in all mouse strains during endotoxemia, except for eNOS-/- mice. LPS infusion resulted in a significantly decrease in jejunal microcirculation in wildtype and iNOS-/- mice. However, mice lacking a functional eNOS enzyme, as present in eNOS-/- and double KO mice, perfusion in jejunal tissue did not decrease during LPS infusion. Also the beneficial effects of citrulline supplementation during LPS infusion on the microcirculation were not present in eNOS-/- or double KO mice, although citrulline significantly enhanced the plasma arginine availability in all mouse strains. In addition, tissue arginine availability did not increase in citrulline supplemented NOS deficient mice.LPS infusion significantly decreased plasma arginine availability in all mouse strains. However, in the jejunal tissue of iNOSde novo synthesis during sepsis, however to enhance the microcirculation during sepsis, citrulline requires a functional eNOS enzyme. Therefore, future research needs to focus both on improvement of the arginine de novo synthesis and maintenance of a functional eNOS enzyme during sepsis.Citrulline improves the arginine


There is increasing integration of qualitative research within randomised controlled trials (RCTs). However, how these methods are applied at the pre-trial stage to inform trial design and conduct is less well explored. Here we describe how qualitative methods were used in a feasibility study to inform the design of a pilot RCT.Semi-structured interviews with purposely sampled clinicians (n=61) and patients (n=32) explored current clinical practice and views about the proposed trial interventions and protocol. Analysis used constant comparative approaches. Emerging findings were disseminated through focused reports/presentations to the study management group and steering committee as research progressed.Qualitative findings informed changes to fundamental aspects of trial design and proposed outcome measures. Clinicians' interpretations of the original interventions were variable, and descriptions of current practice/terminology consistently differed with assumptions made in the grant proposal and commissioned call for research. New outcomes were recognised, prompted by clinicians'/patients' priorities. Measuring and reporting these outcomes was deemed crucial for a full trial's potential to impact future practice. Interviews with clinicians also prompted new ‘in trial’ data collection requirements, as clinicians anticipated potential changes to their clinical practice to accommodate the trial interventions. These changes had potential to impact the primary outcomes, prompting recommendations to measure/record these practices during trial conduct.Qualitative research at the pre-trial stage can transform fundamental aspects of trial design/delivery. Presenting emergent findings as the research progresses is one approach to enhancing impact, facilitated by participation of qualitative researchers as core members of investigator teams.


In contrast, remarkable advances in its basic genomics have not been sufficiently translated into the molecular epidemiology of diphtheria. A recent report by Zasada . More recently, a multilocus sequence typing (MLST) scheme for C. diphtheriae was developed . The second approach is locus oriented and makes use of the repetitive DNA sequences, namely, variable number tandem repeats (VNTR) and clustered, regularly interspaced short palindromic repeats (CRISPR) loci.Two in silico–inspired approaches have recently been pursued toward more precise molecular genetics and epidemiology of diphtheria. The first approach is based on whole-genome sequencing (WGS). After years of stagnation, the number of complete C. diphtheriae   analysis might offer a broader range of possible general solutions from global tracing of large clonal clusters (current threshold) toward fine-tuned strain discrimination. At the same time, a multicenter evaluation of recently developed inexpensive and discriminatory VNTR and CRISPR methods is warranted to see if and how they could complement regional surveillance.


The brainstem is the major site of trigeminal pain processing and modulation and plays a key role in the pathophysiology of various headache disorders. However, comprehensive human imaging studies on function and activity of brainstem areas following trigeminal nociceptive stimulation are scarce.To develope a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation.21 healthy participants  were scanned on a 3T scanner with a standardized trigeminal nociceptive stimulation protocol for event-related fMRI using a specifically designed sequence for high resolution brainstem echo planar imaging as well as a brainstem specific noise correction technique and brainstem template.We observed significant BOLD responses in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, SII, insular cortex and cerebellum as well as in a pain modulating network including the dorsal raphe nuclei (DRN), periaqueductal grey area (PAG), hypothalamus (HT) and nucleus cuneiformis (CN) . Using PPI analyses, we found enhanced connectivity of the sTN with the HT and the CN.Our results are in line with previous animal and human imaging studies on brainstem processing of nociceptive stimuli. However, using the proposed high resolution imaging technique, we achieved a more detailed insight into brainstem pain processing as compared to whole brain fMRI. High resolution brainstem fMRI of trigeminal nociceptive stimulation offers a unique opportunity to better understand headache pathophysiology.No conflict of interest.


The mechanism by which this activity regime is generated is well-known [While the physics of local field potential (LFP) generation are well-established, the complexity of neural network dynamics means that interpreting LFP measurements in terms of the underlying neural activity is very difficult . Recent ll-known , and manWe describe three key results from our simulations. Firstly, we found that perisomatic synaptic currents on pyramidal neurons resulting from basket interneuron firing dominate the LFP during gamma oscillations, in agreement with recent experimental results ,4. We pr