ADG) of growing animals. The objective of this study was to identify commercial single nucleotide polymorphism (SNP) panels that could improve the predictability of days on feed (DOF) to reach a target United States Department of Agriculture (USDA) grade given animal, diet, and environmental information under feedyard conditions. The data for this study was comprised of crossbred heifers (n = 681) and steers (n = 836) from commercial feedyards. Eleven molecular breeding value (MBV) scores derived from SNP panels of candidate gene polymorphisms and two-leptin gene SNP (UASMS2 and E2FB) were evaluated. The empty body fat (EBF) and the shrunk body weight (SBW) at 28% EBF (AFSBW) were computed by the Cattle Value Discovery System (CVDS) model using hip height (EBFHH and AFSBWHH) or carcass traits (EBFCT and AFSBWCT) of the animals. The DOFHH was calculated when AFSBWHH and ADGHH were used and DOFCT was calculated when AFSBWCT and ADGCT were used. The CVDS estimates dry matter required (DMR) by individuals fed in groups when observed ADG and AFSBW are provided. The AFSBWCT was assumed more accurate than the AFSBWHH because it was computed using carcass traits. The difference between AFSBWCT and AFSBWHH, DOFCT and DOFHH, and DMR and dry matter intake (DMI) were regressed on the MBV scores and leptin gene SNP to explain the variation. Our results indicate quite a large range of correlations among MBV scores and model input and output variables, but MBV ribeye area was the most strongly correlated with the differences in DOF, AFSBW, and DMI by explaining 8, 13.2 and 6.5%, respectively, of the variation. This suggests that specific MBV scores might explain additional variation of input and output variables used by nutritional models in predicting individual animal performance.Cattle body composition is difficult to model because several factors affect the composition of the average daily gain ( USDA) Choice or Canadian AAA graded meat versus lower quality grade meat  CT was asAn analysis  indicateIn conclusion, our analysis indicates that it is possible (and desirable) to incorporate genomic information into mathematical nutrition models to enhance their predictability by accounting for individual makeup  differences. This incorporation, however, may require profound modifications of nutrition models to accommodate new concepts, such as genome wide associated studies , 55, to S1 File(ZIP)Click here for additional data file.


In 2008 the Paediatric Rheumathology European Society (PReS) promoted an International Project for the study of Autoinflammatory Diseases (AID) named Eurofever whose main purpose is to create a web-based registry for the collection of clinical, laboratory and response to treatment information in patients with AID.To implement the Registry with the new recently described AID and genes and modify the web-system to make it suitable for the collection of longitudinal data.With the technical help of Paediatric Rheumatology INternational Trial Organization (PRINTO) web-masters, we were able to revise the electronic case report forms bringing 2 main novelties: i) inclusion of the more recently described AID  and the relative clinical manifestation ii) modification of drug layout. In this process information on safety and efficacy has been included. Very soon Centres will be asked to update on a yearly base the information regarding each patient with particular focus on modification of the clinical picture, onset of complication/sequelae, treatment, adverse events if present, laboratory and instrumental findings.At present baseline demographic information from 3089 (M:F=1513:1576) patients from 101 centers in 38 countries are available. In 77% complete clinical information from disease onset to diagnosis and response to treatment is also available. For each disease the number of enrolled patients is: FMF 894 pts ; TRAPS 268 pts (226 complete); CAPS 284 pts (208 complete); MKD 189 pts (165 complete); Blau's disease 71 pts (22 complete); PAPA 27 pts (22 complete); NLRP-12 mediated periodic fever 14 pts (9 complete); DIRA 3 pts ; CANDLE 2 pts (1 complete), Schnitzler 1 pt and Majeed 2 pts (both complete). Among multifactorial autoinflammatory diseases: PFAPA 612 pts (380 complete); CRMO 417 pts (394 complete); pediatric Bechet disease 92 pts (72 complete) and 217 patients with undefined periodic fever (182 complete). Longitudinal electronic data capture is now ready and online for authorized PRINTO members.A common registry for collection of patients with AID is available and the enrollment is ongoing. This project represents the first attempt of a common registry for different autoinflammatory syndromes. The longitudinal collection and analysis of data coming from the Registry will improve our knowledge in the field of autoinflammation both on the natural history of the single disease and the efficacy and safety of the treatment commonly used in the clinical practice with particular regards to biologics.


Pompe disease (OMIM 232300) is an AR glycogenosis due to deficiency of the lysosomal enzyme alpha-glucosidase (GAA). As a result, glycogen storage occurs in muscles and patients present a wide clinical spectrum ranging from early onset severe cardiomyopathy (EOPD) to adult onset forms (LOPD). Severe loss of GAA activity correlates with early onset and severe phenotypes. Residual enzyme activity warrants later onset and a slowly progressive course, although a strict correlation is not always observed. Patients with Classic infantile Pompe disease show hypotonia, macroglossia, respiratory insufficiency and early death for cardiorespiratory failure.The availability of enzyme replacement therapy (ERT) with alglucosidase alfa ( human recombinant GAA) has changed the natural history of the disease allowing most children with EOPD a longer survival and a longer preserved muscle performance with increased quality of life in LOPD.The experience of the Regional referral Center for Metabolic Diseases, University of Catania, concerns 11 patients ( 9 months to 65 years at the time of the diagnosis). Their clinical and laboratory follow-up included eye tracking and Muscle MRI.EOPD, with a severe clinical picture since the first weeks of life and cardiomyopathy was observed in a newborn who died at age 4 months, despite early started and high dosage ERT. Another girl with EOPD is on ERT since the age of 9 months and, today, after 7 years of treatment shows only mild signs of muscle weakness and no cardiac involvement.Five more LOPD patients on ERT had a significant improvement of blood parameters including transaminases, LDH and CPK. No progression of muscle impairment was seen after 5 to 8 years of treatment, except for one 35 years old man, who was already severely compromised and did not show any benefit in terms of respiratory ventilation.In a recently performed Italian survey of classical Pompe disease treated with ERT, a substantial improvement in cardiac parameters and gross motor function was observed, even if residual muscle weakness still exist and gross motor function remain below age-appropriate levels.The different response to ERT depends on several factors mainly on timing of treatment (worse outcome if started later than 5 months of age) and cross reactive immune material (CRIM-negative status associated with less good response to ERT).Although some residual mild weakness is present in treated patients, ERT has demonstrated its effects on respiration, lowering nocturnal apneas and allowing patients a better quality of life.


Road traffic injury (RTI) has assumed major public health importance world-wide and the burden is heavier on the health-care infrastructure of countries in Sub-Saharan Africa. In Nigeria, RTI is the leading cause of trauma related morbidity and mortality. While there are some published epidemiological reports on RTI in the region, studies on the mechanism of causation of road traffic crashes (RTC) are not available.Over a 9-month period, we prospectively captured the 571 victims of RTC presenting to a single tertiary health care center in Nigeria. Data collected include demographic data, Mechanism of causation of RTC, Injuries sustained and outcomes.Over three-quarters of the victims are young people and half were either traders (27.5%) or students (20%). Pedestrians, motorcycle riders and open truck occupants (people sitting at the rear loading compartment of trucks) often had fatal injuries. Analysis of collision patterns showed that lone crashes were the most frequent though car-to-motorcycle crashes caused a quarter of the deaths. Host factors  were responsible for four-fifths of the crashes while vehicular and environmental factors accounted for the remaining. On binary regression analysis, head injured victims had higher odds of dying than the non-head injured (Odds ratio = 6.5).This paper elucidates the mechanisms of causation of and types of injuries sustained following RTC in Nigeria and thus provide opportunities for prevention and control of this unacceptable situation. Worldwide, Road Traffic Injury (RTI) has assumed major public health concern as it is responsible for an increasing number of morbidity and mortality. The World Health Organization (WHO) has attributed this increase to rapid urbanization and motorization and has aptly identified RTI as the price humanity must pay for modernization . The cosAll RTI victims who presented to University of Ilorin Teaching Hospital between October 2006 and June 2007 were prospectively captured. Biodata of victims, details of how the RTI occurred (mechanism of causation), the location of the victim during the incident (host status), the types of injuries sustained and eventual outcome was documented. Age categorization: The age of the victims were categorized into three groups  for statistical analysis. Host status: The host status was also categorized as riders of motorcycles (two wheeler vehicles); drivers of cars, buses or trucks (four wheeler vehicles); passengers of motorcycles; passengers of four wheeler vehicles; pedestrians and open truck occupants . Crash mThere were 571 patients over the nine month period consisting of 427 males and 144 females (M:F ratio = 3:1). There was no statistical significant difference in outcome between the sexes (p = 0.439). Median age was 30 years (range 6 months to 84 years). Over three-quarters of victims were young people, with another one-fifth being middle-aged and only 0.5% were elderly. There was however no significant statistical difference in outcomes between the age categories (p = 0.168). Majority of victims were either engaged in business or trading (27.5%) or were students (20%). The least involved group was the professional (2%). There were a total of 388 crashes consisting of 310 single patient and 78 mass (>1 victim) involvements (single: mass crash ratio = 4:1). Two crashes which involved 15 and 11 casualties constituted the highest mass crash casualty.Pedestrians, motorcycle riders and open truck occupants  represenOf the various collision patterns, lone crashes (Solitary crash involving only one vehicle with no collision with another vehicle or pedestrian) were the most frequent on our roads accounting for about 29% of 388 crashes and were responsible for the highest casualty of 199 patients (35%) . Car-to-Soft tissue injuries constituted the largest (35%) injuries . Head inThe African region has been identified to carry the highest road traffic death rate of all continents , 4. SoutAbout 43% of victims in this study were passengers of 4 wheeled vehicles, 28.4% were on motorcycles (rider and passengers), and 14.5% were pedestrians. These three groups of road users are particularly prone to RTI in the developing countries . The motEighty percent of crashes were due to host factors and accounted for 74% of morbidity and about 84% of mortality. Over-speeding/inappropriate speed constituted the major host problem (80%). Odero's presentation also identified human error as leading cause with over-speeding topping the list in Kenya, Uganda, South Africa, Ghana, Zimbabwe, Ethiopia and Tanzania . AlcoholThe following recommendations are suggested to policy makers to reduce the occurrence of and injuries from RTI: 1) Enforcement of helmet use by motorcyclists, seat belts by drivers and passengers of 4 wheeled vehicles and a law against travelling on the back of trucks and Lorries. 2) Strict regulation and enforcement of speed limit. The Federal Road Safety Corps should be equipped with speed detectors in their patrol cars and our roads must have speed detectors at strategic points with camera facilities. 3) Appropriate road engineering with road signs and conspicuously displayed speed limits to guide road users. Provision of road shoulders and service lanes will prevent broken down vehicles from being impediments to traffic. 4) Construction of new roads to open new network of roads so as to decongest the major roads. 5) Regular road maintenance to eliminate potholes. 6) House to house waste collection coordinated by the local government authority should be introduced to replace the current practice of refuse tanks dumped on major roads. 7) Use of “Tokunbo” tires must be banned urgently.This paper has elucidated the mechanisms involved in causation of RTIs, the injury spectrum seen in involved victims and the relationships of these variables to outcome of clinical management of the victims. Several opportunities for control are also put forward based on the findings in the study.


Nature Communications7: Article number: 10578 10.1038/ncomms10578 (2016); Published 02232016; Updated 03212016The original version of this article contained an error in the spelling of the author Eugen Buehler, which was incorrectly given as Eugen Beuhler. This has now been corrected in both the PDF and HTML versions of the article.


Active JIA of the knee can lead to bony overgrowth and leg length discrepancies in children with JIA. Fixed flexion deformities of the knee result in loss of inner range quadriceps strength, abnormal gait and reduced independent function and participation in sports and activities.Our objective was to review the use of stretch and cast procedures alongside Intra-articular steroid injections (IAI) for active JIA of the knee resulting in fixed flexion deformities (FFD) of greater than 15 degrees.A retrospective review was undertaken of all patients presenting to Great Ormond Street Hospital NHS Foundation Trust between 2005-2013 with active JIA of the knee resulting in FFD and loss of knee extension range of movement (ROM) greater than -15 degrees extension and underwent a stretch and cast procedure alongside IAI for treatment of their disease. ROM was assessed pre and post procedure. Patients received their IAI under general anaesthetic, and then the physiotherapists carried out a stretch and cast procedure.The stretch and cast procedure included patella mobilisations, gentle and prolonged knee extension passive stretching, and casting with a fibre-glass cast for 72 hours. All patients then received 2 weeks of intensive physiotherapy strengthening. ROM and inner range quadriceps strength were measured at the end of these 2 weeks post procedure.30 patients  had a FFD of between -15 and -90 degrees (mean -30) extension at the affected knee(s). A total of 35 joints were injected and underwent the stretch and cast procedure plus physiotherapy strengthening. Post intensive rehab the patients all had improved or normal ROM (mean -7 degrees) and improved muscle strength  in order to maintain this improvement. This was maintained at 4-6 month follow up in 94% of patients. The 2 patients who did not maintain range of movement had poor compliance to their physiotherapy home exercise programme.ROM improved following procedure in all patients, indicating that stretch and cast treatment is an effective intervention for the management of fixed flexion deformities secondary to active JIA. Ongoing strengthening of inner range quadriceps is vital to maintain this improved range of movement and restoration of function and normal gait.None declared.


Rare diseases; clinical practice guidelines; recommendationshttp://www.rarebestpractices.eu) is a 4-year project (2013-2016) funded by the EC FP7. The project aims at improving clinical management of patients with rare diseases (RD) and at narrowing the existing gap in quality of healthcare among countries.RARE-Bestpractices (http://www.rarebestpractices.eu) involves 9 EU countries, including 15 partners from academic institutions, governmental bodies, patient organizations and networks, which will exploit the added value of integrating different contributions and viewpoints.RARE-Bestpractices  and systematic reviews.http://rarejournal.org)Project expected outputs include: 1) identification of challenges to be considered in deriving high quality standards for CPG on RD; 2) transparent procedures and criteria for the evaluation of CPG and their collection in a publicly searchable database; 3) identification of notation criteria to improve user understandability and implementation of CPG; 4) production of mechanisms to assess RD clinical research needs; 5) development of training activities targeted to key stakeholders to disseminate process and tools for developing and evaluating CPG; 6) the publication of a new scientific journal  for RD; in fact, one main criterion for ERNs should be the competence to produce CPG and actively disseminate them among Centers of Expertise.


Asthma is the most prevalent of all childhood diseases and accounts for the majority of hospitalizations and school absences in children . Current1262 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study with complete skin prick test and wheeze data at one year were grouped into four clinically relevant phenotypes: atopy + wheeze, atopy only, wheeze only, and control. Bacterial 16S rDNA from 3-month and 1-year stool samples of 319 children in these four phenotypes was extracted, amplified, and subjected to high throughput Illumina sequencing. Quantitative polymerase chain reaction (qPCR) and short chain fatty acid (SCFA) analysis were also conducted on 44 children in the two extreme phenotypes (atopy + wheeze vs. control).16S sequence analysis of our sample cohort (319 subjects) identified bacterial populations that differed in abundance in the atopy + wheeze group at 3-months of age but not at 1-year of age. Additionally, significant changes in the abundance of certain bacterial genera were found in the atopy + wheeze group when compared to controls by qPCR at 3-months of age only. Changes in stool short chain fatty acid production between the atopy + wheeze group and the control group were also observed at 3-months of age only.Shifts in the relative abundance of certain gut bacterial populations and differences in the levels of stool SCFAs before 3-months of age are associated with atopy and wheeze at one year of age.


Suppressor of cytokine signaling (SOCS) proteins are the negative regulators in cellular signal transduction system. SOCS family proteins consisting of 8 proteins (CIS and SOCS1-7) inhibit JAK/STAT protein activity to maintain proper cytokine functions. Initially identified for the negative feed-back function of cytokine signal transduction, suppressors of cytokine signaling (SOCS) have emerged as multi-functional protein involved in the regulation of development, apoptosis and oncogenesis. Recent reports showed that SOCS can be also affected by cytokine and other cell signaling factors to regulate cancer development and progression as well as cell death. The present study was aimed to investigate various effects of SOCS1 protein on the tumor suppressive function. We have found that SOCS1 promotes radiation-induced apoptosis of colon cancer cells through cell cycle arrest at G1 involving activation of p53 and p21 induction. SOCS1 also exhibits radiosensitization effects on the growth of implanted colon tumor cells in nude mice. As a mechanism of anti-tumor action of SOCS, we now present the data on the suppressive effects of SOCS1 on tumor cell migration and invasion. Notably SOCS1 over-expression and knock-out inversely regulates the expression of EMT markers such as E-cadherin and vimentin along with modest morphological change of cells from epithelial to fibroblast shape, representing EMT process. Data on the invasion and EMT signaling pathways suggest that SOCS1 potentially regulates tumor cell invasion and metastasis in vitro and in vivo in colon cancer models. SOCS1 may be not only a useful predictive factor for radiation response but also a possible drugable target for human colon cancer.


Evaluation of segmental instability in DLS is essential for spinal surgery to make the decision "fusion or not fusion." Some previous studies have shown radiographic data regarding segmental instability in DLS. However, little is known about segmental motion of wedging segments in DLS. To evaluate the segmental instability of wedging segments using dynamic films and the impact of osteophyte formation on segmental motion in degenerative lumbar scoliosis (DLS).A total of 101 patients complaining of neurogenic claudication owing to lumbar spinal canal stenosis (LCS) were enrolled and divided into 2 groups based on their coronal spinal deformity; Cobb angle of >10 degree (DLS group) or <10 degree (LCS group). The following parameters were measured on anteroposterior films: lateral translation, degree of osteophyte formation, and range of motion (ROM) in lateral bending films. The facet joint space discrepancy was measured on computed tomography images. The radiographic parameters were compared between 85 wedging segments (>5 degrees) in DLS group and 150 nonwedging segments in LCS group.Mean lateral translation was significantly greater in the DLS group (P<0.01 for each level). Average joint space discrepancy was significantly greater in the DLS group . ROM was significantly greater in the DLS group with the same degree osteophyte formation. Degree of osteophyte formation was inversely correlated with ROM in the DLS group (R(2)=0.5696).The present study indicated that wedging segments in DLS had greater motion than nonwedging segments in LCS. However, the osteophyte formation provided restabilization for the wedging segments in DLS, suggesting that evaluation of osteophyte formation is an important factor in surgical decision making for DLS.


The new tendency in rehabilitation involves non-invasive tools that, if applied early after stroke, promote neurorecovery. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may correct the disruption of cortical excitability and effectively contribute to the restoration of movement and speech. The present paper analyses the results of non-invasive brain stimulation (NIBS) trials, highlighting different aspects related to the repetitive transcranial magnetic stimulation frequency, transcranial direct current stimulation polarity, the period and stimulation places in acute and subacute ischemic strokes. The risk of adverse events, the association with motor or language recovery specific training, and the cumulative positive effect evaluation are also discussed.Abbreviations: AAT = Aachen Aphasia Test, BDNF = brain-derived neurotrophic factor, IFG = inferior frontal gyrus, M1 = primary motor cortex, MRI = magnetic resonance imaging, NIBS = non-invasive brain stimulation, PET = positron emission tomography, rTMS = repetitive transcranial magnetic stimulation, SLT = speech and language therapy, STG = superior temporal gyrus, tDCS = transcranial direct current stimulation, NIHSS = National Institutes of Health Stroke Scale After an injury, there are changes in motor and sensitive cortical somatotopies, both in the damaged region and the remote areas from ipsi- and contralateral hemisphere. An increased activation in contralesional primary motor cortex (M1), bilateral ventral premotor cortex and supplementary motor area are commonly found in stroke patients [3]. While the healthy subjects show greater activity in the contralateral hemisphere to the moving hand, stroke patients assume a bilateral pattern in general [4]. Due to its intrinsic plasticity, the brain has the capacity to restructure its neural networks and to reconfigure its activity after an ischemic or haemorrhagic stroke. The metabolic and functional cerebral alteration can be observed by functional imaging studies (positron emission tomography (PET) scan and functional magnetic resonance imaging (fMRI), and also by transcranial magnetic stimulation mapping of the motor area [5]. These mechanisms are activated differently depending on stroke size and location. Small ischemic or haemorrhagic lesions may be compensated by the recruitment of residual language areas and the increase in perilesional activity. By contrast, the larger lesions in the language regions are followed by the recruitment of homotopic non-dominant areas [6]. In the recovery of aphasia, three models of neuroplasticity were framed by prior research: (1) activation of perilesional language areas in the dominant hemisphere, (2) recruitment of homologue area in the non-dominant hemisphere, and (3) improper recruitment of different regions in the non-dominant hemisphere  [5]. Secondary to the decrease of transcallosal inhibition, some right hemispheric areas may deploy an inhibitory effect over the residual perilesional areas in the left hemisphere, interfering with the language recovery. Based on these data, a new model for the recovery of aphasia was proposed based on the suppression of non-dominant hemisphere activity and the stimulation of the perilesional areas in dominant hemisphere [5]. However, the role of right language homologues in the early recovery after stroke seems to be transient, to an extent perilesional neuronal recruitment occurs [4]. Transcranial direct current stimulation (tDCS) of the brain is an electrophysiological method which may be used to modulate the neocortical excitability. A direct current generator is connected to two patch electrodes (an active and a reference one) positioned over the scalp, to stimulate the subjacent tissue with low amplitudes currents (0.5 - 2.0 mA) and to modify the threshold for discharge of cortical neurons. The modulation of cortical excitability is polarity-dependent: “anodal stimulation” (increased in network excitability) – when the active electrode generates a positive potential compared to the reference electrode; “cathodal stimulation” (decreased in network excitability) – when the active electrode generates a negative potential . Repetitive transcranial magnetic stimulation (rTMS) is another therapeutic tool that can contribute to the modulation and reconfiguration of different cortical areas. In contrast to tDCS, rTMS results in the induction of action potentials and depolarization of the neuronal membrane. The principle of transcranial magnetic stimulation is to produce a perpendicular magnetic field, by a stimulating coil, which induces an electric field, which, in contact with the cerebral tissue, is transmitted as an electric current, parallel to the generating coil. The depth of the stimulation depends on the type of coil and the intensity of the stimulation. The excitatory or inhibitory effect is correlated with the frequency of rTMS: high frequencies (≥ 5 Hz) are excitatory, while low frequencies (≤ 1 Hz) are inhibitory . By modulating cortical excitability with respect to neural plasticity, these two non-invasive brain stimulation (NIBS) techniques represent potential therapeutic tools in recovery after stroke [10-14]. This model suggests that the balance between the left and the right hemisphere of stroke patients is altered by an increased interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere. Accordingly, a therapeutic effect may be obtained either by increasing the excitability of the affected hemisphere, or by decreasing the excitability of the unaffected hemisphere [10]. The mechanism of excitability enhancement in the motor cortex underlies the motor learning and the use-dependent plasticity, which are impaired in the affected hemisphere. Other positive effects of the NIBS are the enhancement of neural coupling between the primary and secondary motor areas in the affected hemisphere, the reduction of the hyperactivity in the primary and secondary motor areas in the unaffected hemisphere, and the excitability modulation in both hemispheres [10].There are two main directions of NIBS treatment in neurorehabilitation: the motor deficit and the speech disorders. The improvement of motor and language performances is based on interhemispheric competition theory [15]. The major disadvantage is the deterioration of bimanual movement due to the reduction of transcallosal inhibition that controls that kind of movement. This possible consequence may be prevented by applying a low frequency rTMS concomitant with anodal tDCS over the affected hemisphere [16]. The neural modulation induced by NIBS and the improvement of motor and speech deficits can be sustained by subsequent motor training and speech therapies .The advantages of inhibitory NIBS over the intact hemisphere are the uniform response and the lower risk of potential epileptic seizures, which are more probably to appear after rTMS in the infarcted area . The genetic polymorphism can be involved and may explain the different response of stroke patients to this therapy. BDNF is one of the factors strongly involved in synaptic plasticity of the human motor cortex [9]. The consequence of BDNF val66met, a common single nucleotide polymorphism, is the reduced secretion of BDNF [19]. This is clinically expressed by a poorer retention in short-term motor learning and slower cognitive and motor recovery . Therewith, the individual variation in response to rTMS may be explained by the difference in BDNF concentration [20]. Although it was demonstrated that the early rehabilitation facilitates motor recovery after stroke, the application of NIBS in acute stages is controversial [21]. In this respect, a recent Cochrane meta-analysis evaluated the efficacy and safety of rTMS in recovery after stroke regardless of the duration of illness [22]. Nineteen randomized controlled trials (RCTs) with a total of 588 patients were included. Even if the rTMS treatment was not associated with a significant improvement in activities of daily living, or a significant improvement of motor function, a positive trend was noted, larger and homogeneous RCTs being needed in order to confirm the results [22]. The majority of the clinical studies evaluating the role of rTMS in rehabilitation were performed in subacute and chronic stroke patients, few data being available for acute stroke [22]. Also, epileptiform discharge on EEG and seizures, can be noted especially after high-frequency rTMS (10 Hz) [11].The most encountered adverse events reported in clinical trials evaluating rTMS are transient or mild headache (2.4%), anxiety (0.3%), neurocardiogenic syncope after initial exposure to rTMS (0.6%), exacerbation of pre-existing insomnia (0.3%) and local discomfort at the site of the stimulation [23]. In 2005, Khedr and colab. applied 3 Hz, in 10 daily stimulation sessions on the affected side in 26 patients with acute cortical stroke and in 26 patients with acute subcortical stroke (recruited between the fifth and tenth day post-stroke). The evaluation of motor recovery showed an improved function in the paretic hand in both groups [24]. Liepert and colab. showed that one session of 1 Hz rTMS therapy  on the contralesional hemisphere in 12 patients with acute subcortical stroke (mean 7 days), disclosed an enhancement in the hand functioning at Nine Hole Peg Test (a transient improved dexterity of the affected hand), but no change in the grip strength [25]. In 2010 Khedr and colab. published another study on 48 acute stroke patients  which supported 3 Hz, 130% resting motor threshold intensity, or 10 Hz, 100% resting motor threshold intensity, in 5 daily stimulation sessions on the ipsilateral hemisphere. The improved hand function persisted for 12 months after rTMS treatment [26]. Participants  were divided in two groups – the study group (5 patients) – stimulated in the right pars triangularis, and the control group (5 patients) – stimulated in vertex (sham stimulation). The results pointed out an improvement of Aachen Aphasia Test (AAT) scores in patients from the study group, but not in those with sham stimulation. Compared with baseline, a larger activation index was observed on PET scan in the right hemisphere in the control group compared with the study group, 2 weeks after rTMS, suggesting that inhibitory magnetic stimulation of the right-hemispheric Broca homologue followed by SLT might be a feasible and effective complementary therapy for post stroke aphasia [26]. Weiduschat studied the effect of 1 Hz rTMS stimulation together with subsequent speech and language therapy (SLT) in 10 right-handed patients at 16 weeks after stroke [27]. The patients were included between 2-12 weeks after the onset. This group was compared with a sham stimulation group . The assessment included Computerized Picture Naming Test, Boston Diagnostic Aphasia Examination and Aphasia Severity Rating Scale. After a follow-up period of 15 weeks, no differences in naming accuracy between the two groups were noted, but reaction time was slightly faster in real rTMS group [27].Waldowski and collab. studied the effects of 1 Hz rTMS  over pars triangularis and pars opercularis from the right inferior frontal gyrus (IFG), followed by 45 min/ day SLT, in 13 right-handed patients with aphasia [18]. Forty patients received 3 weeks of motor training on the paretic upper limb (45 minutes daily) preceded by 30 minutes of 1 Hz rTMS (stimulated group) or by 30 minutes of sham rTMS over the contralesional M1 (control group). The functional assessment of the paretic hand (by Wolf Motor Function Test and NIHSS) performed before, immediately after and at the 3 months follow-up revealed no statistically significant differences between the two groups [18]. In a randomized, sham-controlled, double-blind study, Seniów and colab. evaluated the association of low-frequency rTMS of the contralesional M1 area with physiotherapy [13]. In 2013, Heiss et al. analyzed for the first time the consequences of the inhibitory NIBS over the contralesional IFG in left-handed aphasic patients. They reported the results of a randomized controlled trial comparing the effect of combined rTMS/ SLT in 29 right-handed patients with left hemisphere infarcts and 2 left-handed patients with right hemisphere infarcts. The start of treatment was between 25 and 93 days after stroke onset. Fifteen right-handed patients  received 10 sessions of inhibitory 1 Hz rTMS over the triangular part of the right IFG (20 min each) followed by 10 sessions of SLT, while 14 right-handers with heterogeneous aphasia forms  received 10 sessions of 20 min rTMS over the midline at the vertex (sham stimulation). Two left-handers  were treated according to the same protocol with real rTMS over the left hemisphere. The speech performance was evaluated by AAT, and the language activation patterns were assessed with PET scan prior to and after the treatment. The results showed better recovery of language function in right-handed patients after real rTMS than in sham-treated right-handers. Furthermore, a shift of network activity towards the left, ipsilesional hemisphere was observed in treated right-handers, while the sham group maintained the activation in the contralesional hemisphere. Both left-handed volunteers also improved, the PET scan showing a very small interhemispheric shift (less than in rTMS-treated right-handers) and a consolidation of active networks in both hemispheres [12]. In both groups, the inhibitory NIBS was followed by SLT 45 min/ day. The global AAT and naming subtests disclosed better scores, which correlated with a PET activation in the left hemisphere in rTMS group post-treatment compared to the sham group [12]. Another RCT compared the effect of 1 Hz real rTMS versus sham stimulation  over the right pars triangularis, in 24 patients suffering of subacute stroke [28]. The tDCS was initiated 4 to 8 weeks after stroke onset. Each of the 6 daily stimulation sessions was followed by a robot-assisted arm training. Motor arm function was assessed with the Fugl-Meyer motor score and language impairment with the AAT. The motor function improved in all patients (in a significant manner in 3 cases), and aphasia improved in 4 patients [28]. Hesse and colab. evaluated the role of anodal tDCS on the ipsilesional side in the recovery after stroke in 10 patients [29]. In all patients, the reference electrode was placed on the contralateral supraorbital region, the sessions of stimulation lasted 30 min/ day for 10 days and were completed by online SLT. The application of Korean-Western Aphasia Battery evidenced a significant improvement in auditory verbal comprehension after right cathodal tDCS compared to sham and left anodal tDCS, with an overall improvement in Aphasia Quontient and spontaneous speech across groups [29]. In 2011, You and collab. evaluated the role of tDCS in 21 aphasic patients with subacute stroke divided in 3 equal groups: the patients in the first group received anodal tDCS on the left Wernicke’s area , the subjects from the second group received cathodal tDCS on the right Wernicke’s area and the other 7 participants were sham stimulated [NIBS could be a useful therapeutic tool in the early rehabilitation after stroke. Both methods may enhance the neuroplasticity in the injured area and reestablish the balance between different regions of the brain. The association with specific motor tasks and SLT reinforces the effect of NIBS and partially restores the damaged neural networks.Larger RCTs are needed in order to confirm the effectiveness of NIBS, but the small clinical studies published so far showed encouraging results in motor and speech recovery.


Previous studies reported that patients in end-of-life (EOL) care may still receive aggressive treatment in the Intensive Care Unit (ICU). Despite To characterize factors associated with death in the ICU in patients accompanied by a palliative care team (PCT) in a tertiary private hospital in Brazil.Retrospective analysis of prospectively collected data based on a standardized questionnaire of PCT. All 628 questionnaires from June 2008 to December 2013 were included. Two groups were compared: patients that eventually died in the ICU versus patients that died outside the ICU.Out of 443  patients who died; 76 12.1%) died in ICU and 367 (58.4%) outside the ICU setting. a comparison between groups is shown in Table 2.1% diedNon-cancer patients died more frequently in the ICU (p = 0.03). We observed the presence of conflicts among patients who died in ICU: conflicts between family members (family-family conflicts) and between family and the attending physician (family-physician conflicts) were equally common, but there were a significant number of conflicts originating between family and nurse staff Figure .Figure 1Explicit directives of EOL care were more commonly explicitly written in non-ICU patients . As expected, we also observed that a remarkable percentage of ICU patients received advanced life support until death (42%). There were no association between death in the ICU and age, late PCT consultation (less than 3 days before death) and prolonged hospitalization .Circumstances associated with death in the ICU of patients assisted by PCT included a non-cancer diagnosis, conflicts as reason to referral, being in the ICU or receiving life support at the time of the initiation of PCT consultation, and the lack of written advanced directives of EOL care. Further studies are needed to evaluate whether modifying these circumstances may be related to a different EOL care.


World leaders remain committed to globally-coordinated oral poliovirus vaccine (OPV) cessation following successful eradication of wild polioviruses, but the best timing and strategy for implementation depend on existing and emerging conditions.Using an existing integrated global poliovirus risk management model, we explore alternatives to the current timing plan of coordinated cessation of each OPV serotype . We assume the current timing plan involves OPV2 cessation in 2016 followed by OPV1 and OPV3 cessation in 2019 and we compare this to alternative timing options, including cessation of all three serotypes in 2018 or 2019, and cessation of both OPV2 and OPV3 in 2017 followed by OPV1 in 2019.If Supplemtal Immunization Activity frequency remains sufficiently high through cessation of the last OPV serotype, then all OPV cessation timing options prevent circulating vaccine-derived poliovirus (cVDPV) outbreaks after OPV cessation of any serotype. The various OPV cessation timing options result in relatively modest differences in expected vaccine-associated paralytic poliomyelitis cases and expected total of approximately 10–13 billion polio vaccine doses used. However, the expected amounts of vaccine of different OPV formulations needed changes dramatically with each OPV cessation timing option. Overall health economic impacts remain limited for timing options that only change the OPV formulation but preserve the currently planned year for cessation of the last OPV serotype and the global introduction of inactivated poliovirus vaccine (IPV) introduction. Earlier cessation of the last OPV serotype or later global IPV introduction yield approximately $1 billion in incremental net benefits due to saved vaccination costs, although the logistics of implementation of OPV cessation remain uncertain and challenging.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype to manage cVDPV risks. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options. The Global Polio Eradication Initiative (GPEI) continues to make progress toward the primary goal of interrupting all global transmission of the three wild poliovirus (WPV) serotypes . After aOPV comes in different formulations. Trivalent OPV (tOPV) protects against all three serotypes and represents the current vaccine of choice for OPV RI and the vaccine used for SIAs up until 2004. In 2005, the GPEI began using serotype 1 monovalent OPV (mOPV1) and later some serotype 3 (mOPV3) for some SIAs, because of their higher seroconversion  for the mOPV serotype than achieved by the same serotype component of tOPV, particularly for the first dose , 16. In The inactivated poliovirus vaccine (IPV) currently represents the only vaccine alternative to OPV. While the killed, injectable IPV provides very good individual protection from paralytic poliomyelitis and boosts intestinal immunity in individuals with immunity from a prior live poliovirus infection , it does not protect as well against asymptomatic participation in poliovirus transmission as OPV, particularly in settings with more intense fecal-oral transmission, and it does not spread beyond the vaccine recipient –28. ConsRecognizing the risks associated with OPV2 cessation, the GPEI established 6 prerequisites for OPV2 cessation, including the need to validate the elimination of persistent cVDPV2s , which rWe use an integrated global model of long-term poliovirus risk management options  described in detail elsewhere . Brieflystatus quo of OPV use in most countries to characterize incremental cost-effectiveness ratios (ICERs) and incremental net benefits (INBs) using 2013 United States dollars ($). The global model estimates financial costs associated with RI and SIAs, including any outbreak response SIAs (oSIAs) before and after OPV cessation [The global model  estimateessation . The gloessation  and the essation , includiessation  and emphTo model the global population and poliovirus transmission, the global model  assumes Table status quo) option assumes OPV2 cessation on April 1, 2016, consistent with the current target date [All options assume tOPV intensification from January 1, 2015 characterized by an increased proportion of planned, preventive SIAs  using tOPV instead of bOPV , 39. Theget date , and OPVget date . For theget date , 39 untiget date , 39, whiget date  and the Due to the assumed sufficiently high frequency of SIAs leading up to OPV cessation of any serotype for all OPV cessation options, none of the options lead to any subsequent cVDPV cases. With only a small number of paralytic cases from WPV1 remaining in the model during the first year of the time horizon , VAPP cases represent the main source of paralytic poliomyelitis in the model for 2015–2019. Table With respect to vaccine dose estimates, our results include the entire world , assume relatively high effective wastage, and assume sustained high SIA frequency up until cessation of the last OPV serotype . Most scTable The INBs represent a more informative metric for this analysis. OPV23 cessation in 2017, OPV123 cessation in 2019, and OPV123 cessation in 2019 with tOPV-only from 2017 all result in the same expected financial costs for vaccination as the current timing plan because they involve different OPV formulations without affecting the overall duration of OPV or IPV use in any of the income levels. Thus, for these alternative OPV cessation timing options the incremental costs reflect only treatment costs (or savings) associated with additional incurred (or prevented) paralytic cases. Given the relatively small number of paralytic cases involved in any of these options, their INBs remain close to 0. The INB estimate of approximately -$4.5 million for OPV123 cessation in 2019 (with or without tOPV-only from 2017) suggests that if the excluded logistical costs of coordinating OPV cessation once instead of twice amount to more than $4 million , then some economic justification exists for this original path of coordinated OPV cessation of all three OPV serotypes. OPV123 cessation in 2019 with tOPV-only from 2017 yields almost the same INBs as OPV123 cessation in 2019, which involves some continued bOPV SIAs , because the cases would occur for all OPV cessation timing options. However, longer transmission of WPV1 and/or cVDPV2 will affect the feasibility of some of the options and expected SIA frequency and costs. Some reduction in SIA frequency may remain sufficient to keep population immunity high enough to avoid cVDPVs after OPV cessation, although too much reduction or inconsistency in SIA quality would result in cVDPVs , and insOur analysis leads to the realization that flexibility in national vaccine licensing for the transition period may prove helpful. While under the current plan the GPEI continues to encourage countries to pursue licenses of bOPV for RI use after OPV2 cessation, our analysis suggests potential value in simultaneously pursuing national licenses for RI use of bOPV or mOPV1, and potentially also securing licenses now to use any mOPV serotype for outbreak response if ever needed. In addition, given uncertainty about the status of population immunity for serotype 2, our results underscore the importance of developing contingencies with manufacturers to continue tOPV production past the current planned OPV2 cessation target of April 2016.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options.


The fat signal can lead to misinterpretation and poor visualization of epicardial enhancement. In previous work fat was suppressed by using two appropriately timed fat-selective RF pulses which re-invert and invert fat signal  but this technique was sensitive to off-resonance and heart rate variations. The goal of the present work is to make two improvements to fat-saturated LGE: (1) increase robustness against B0 and B1 variations by using asymmetric adiabatic RF pulses, and (2) increase robustness against heart rate variations through dynamic timing of fat-selective RF pulses.Late Gadolinium Enhancement (LGE) allows imaging of infarction and cardiomyopathies by measuring the accumulation of contrast agent within the myocardium. The shortened T1 (10μT) and pulse duration (40 ms). Mz magnetization depends on the repetition time of the IR pulse and therefore in cardiac gated sequences depends on the patient heart rate. Heart rate variation leads to a shifting of the inversion time (TIfat) at which the fat signal is nulled. Therefore a heart rate independent nulling of fat signal was developed by measuring the length of each R-R interval during the examination and time-shifting the fat-selective inversion pulse accordingly  and 3.0T (300 ms). With appropriate TI selection the technique led to nulling of signal from healthy myocardium and from fat. The cases without contrast injection had poor blood-myocardium contrast due to the lack of Gd  but fatBenefits of fat-saturated LGE imaging include avoiding image wrapping of subcutaneous fat and therefore reduced possible misdiagnosis Figure ), and in


It was more effective following vaccination with live than killed vaccines. In conclusion, application of synbiotic Biomin Imbo, as a feed-additive adjuvant promotes acquired humoral immune responses of broiler chickens. Increased susceptibility of birds to avian pathogens in intensive husbandry system has emphasized on necessity of improvement of innate and specific immune responses of birds by the fast establishment of a beneficial microflora and immune stimulator factors to guarantee healthy and low-price products. During this study, 192 one-day-old broiler chicks (Ross-380) in four groups with three replicates per group were used to investigate effectiveness of synbiotic Biomin Imbo on immune responses of the chickens following routine vaccination against Newcastle disease (ND), avian influenza (AI), infectious bronchitis (IB) and infectious bursal disease (IBD). The results of this study indicated that supplementation of Biomin Imbo in diet enhanced humoral immune responses significantly in the case of ND, IB, IBD ( Finding novel antigens as well as adjuvants is the most beneficial methods to induce an optimal protective immunity against human1 and poultry diseases including avian infectious bronchitis (IB), infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) which cause significant economic losses in poultry industry worldwide.2,3 Interest in the dietary use of prebiotics and probiotics blossomed in the late 1800s/ early 1900 and the growing enthusiasm on the beneficial effects of pre-, pro- and synbiotics was motivated near the turn of the 20th century.4 Ban of antibiotic growth promoters (AGPs) due to increased bacterial resistance and drug residues in poultry production together with consumer's demand for "natural" products have encouraged findings of alternatives for AGP. In order to preserve gut microbiota and to promote host innate defenses, administration of synbiotic  as alternative approach for promoting of performance and immune responses in modern poultry husbandry widely accepted.5,6 Probiotics affect the intestinal microbial balance and subsequently improve performance and reduce mortality in broiler chickens.7,8 Probiotics also protect chickens against avian pathogens,9,10 activate immunocytes and stimulate systemic immune responses11 including promoting the endogenous host defense mechanisms12 and enhancement of production natural antibodies13 as well as specific antibodies.14 On the other hand, prebiotics may control or manipulate microbial composition and/or activity, therefore combination of probiotics and prebiotics improve the survival rate of probiotics in digestive tract contributing to the stabilisation and/or enhancement of the probiotic effects.15,16 Under the present circumstances, improvement of post-vaccination immune responses against the most economically important poultry diseases, in particular IB, IBD, ND and AI is topic for research. Ideologically, synbiotics would have more beneficial effects than these elements alone.17-20 Therefore, the present project was undertaken to study the immuno-modulatory effects of the synbiotic Biomin Imbo on antibody responses during a routine vaccination of broiler chickens against IB, IBD, ND and AI as well as to compare its immunomodulatory effectiveness in vaccination with live and killed vaccines.In the 21Chickens and experimental design. One hundred and ninety-two one-day-old broiler  chicks (Ross-308 strain) were randomly allocated into four groups: (A) vaccinated + diet containing Biomin Imbo, (B) vaccinated + diet not-containing Biomin Imbo, (C) environmental control (unvaccinated + diet without Biomin Imbo), and (D) Biomin control (unvaccinated + diet containing Biomin Imbo). Three replicates were considered for each group (16 chicks per replicate). After leg labeling, the chicks of each replicate were housed in separated boxes and nutritional requirements , ambient temperature, lighting, ventilation as well as other environmental conditions fully met the requirements laid down in the technical instructions of Ross-308 broiler management.21 Vaccinated groups (A and B) and unvaccinated groups (C and D) were kept in separated houses.Enterococcus facium IMB 52; 5 × 1011 CFU per kg), cell wall fragments of useful micro-organisms, prebiotic (fructo-oligosaccharides) and phycophytics  was used as recommended by manufacturer . Synbiotic Biomin Imbo containing of probiotic  level (below log2-3), chickens of the groups A and B were vaccinated  and  on 11-days and second vaccination (only live vaccine) was carried out on 21-days of age using clone 30 strain of ND virus by eye-drop route as a recommended route inducing higher antibody titer with the closest-rang.22 In the case of AI, one vaccination is carried out on 11-days-old using killed (H9N2) vaccine by subcutaneous injection as a routine vaccination for broilers in the region. In the case of IBD, optimal time for first vaccination was estimated3 and D78 vaccine was used on day 16 and repeated on day 24 of age (based on MDA of the chicks). In the case of IB, as protection significantly (p < 0.05) correlated with levels of local respiratory antibody and not with serum antibody23 therefore, regardless to the potential negative effects of MDA against IB virus, Ma5 vaccine was used via eye-drop for vaccination of one-day-old chicks against IB on day 1 and is repeated on day 18 of age using the same vaccine.2,24Sampling. As level of MDA titer is very important for determination of the best timing of vaccination against IBD as well as ND. On day 1 (one-day-old chicks), blood samples were collected from half the chicks of each replicate as previously described.25,26 On day 7 and then at weekly intervals  until 42 days of age, blood samples were collected from jugular veins and brachial vein, respectively as previously described.27,Serum antibody titers assessment. Antibody level was determined using weekly serum samples of each bird separately in each replicate and treatment. Hemagglutination inhibition test (HI) was used for evaluation of antibody titers against ND and AI, as it has been reported that HI test is an excellent indicator of the immune status and disease resistance of a flock especially to assess protective response following vaccination,27,28 while the indirect enzyme-linked immunosorbent assay  was used for evaluation of antibody titers as recommended for IB29 and IBD.3,29,30Statistical analysis. SPSS software  was used for analyzing of the results under completely randomized design employing one-way ANOVA analysis of variance and the means of different treatments were compared with Bonferroni, Duncan multiple range and repeated measure tests. Significance differences were taken at p < 0.05 level. Newcastle disease antibody titer. Antibody titers against ND of the chickens of different groups are shown in Avian influenza antibody titer. Antibody titers of the chickens against AI are shown in p = 0.160).Infectious bronchitis antibody titer. Status of MDA and acquired antibody titer against avian infectious bronchitis are shown in nd vaccination and peaked around 42 day of age. In comparison to groups A and B (vaccinated groups), antibody titers of chickens treated with Biomin Imbo (group A) differed significantly (p = 0.020) from those of group B during day 28 to end of experiment  antibody titer than those of vaccinated but not treated with Biomin Imbo diet. 31,32 but also leads to immuno-modulation of humoral immune responses as well as cellular immune responses,33 however debates on their potential side effects (cytotoxic and moderate genotoxic effects) is open.34 Comparison of a growth promoters, prebiotics, probiotics as well as synbiotics on their preventive effects in colonization of salmonella in poultry revealed that antimicrobial agents allowed higher colonization as compared to prebiotics and probiotics,9 but Biomin controls the intestinal colonization of Salmonella enteritidis in chickens.35In general, dietary supplementation of synbiotic Biomin Imbo not only ameliorate performance of poultryEnterococcus faecium) of Biomin Imbo enhances humoral immune responses against sheep red blood cells (SRBC).36 Biomin Imbo also increases most parameters of blood profile including total protein37 and higher protein promotes induction of specific antibody titer against avian pathogens. Dietary inclusion of synbiotic Biomin Imbo increased growth performance and improved intestinal morphology, nutrient absorption38 and resistance of birds to pathogens or diseases.37 Comparison of the synbiotic with another probiotic indicated that the synbiotic had much more beneficial effects than probiotic alone5 as well as prebiotics alone39 or AGP alone.40 Enhanced effects of Biomin Imbo on antibody titers of the chickens against ND, AI, IB and IBD were observed during this study and is in agreement with previous reports that the serum antibody responses to oral and systemic administration of antigens were significantly enhanced by probiotics supplementation.41 Due to the immunomuadulatory effects of vitamin E, future synbiotics may include vitamin E as well.42With regards to immunomodulatory effects of Biomin Imbo, there are some reports that probiotic (nd vaccination). Analyzing of the results, as shown in p = 0.100) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.010); c) Comparison between antibody titers of chickens of group A (vaccinated and treated with Biomin Imbo) and those of chickens of group B (vaccinated but not treated with Biomin Imbo) was significant on the day 35 (p = 0.049) and on the day 42 (p = 0.048) of age. Continuously reduction of ND antibody titer of chickens of unvaccinated groups (C and D) and its remaining at undetectable level during experimental period confirmed that neither environmental nor cross contamination had occurred. Antibody titers of vaccinated chickens (groups A and B) increased following first vaccination (live + killed) and reached the highest level on day 35 of age  is the highest available titer that could be induced by vaccinations (two live + one killed vaccines) as mean titers 4 to 6 log2 for single live and at least log2-8 for live plus killed vaccine was reported by OIE.43 Higher ND titers of chickens treated by Biomin Imbo is observed in our study is also in agreement with those of log2-7.2 and mean titer of log2-7.5 was reported for mentofin treated chickens.44 The beneficial effects of Biomin Imbo could be more evident in undesirable circumstances due to intensive husbandry systems. However, the enhancement effects of Biomin Imbo on humoral immune responses against ND observed during this study is also been reported for an another probiotics14 as well as other synbiotics.The results obtained during this study  is in agp = 0.150) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was not significant (p = 0.160). Regarding lack of significant increasing effects of Biomin in the case of AI, it may be attributed to the mechanism of this product on providing a better condition for multiplication of live vaccines whereas a killed vaccine was used in the case of AI. High antibody titers observed during this study (-5.6) of chicken group A could be attributed to enhancement effects of Biomin Imbo on antibody titers of the chickens as it has been reported that optimal nutritional status may enhance immune function indicated by increased vaccine response following vaccination against influenza.37,45As shown in is study  for chic24 As shown in p < 0.05).33 As maternal IBV antibodies are in low concentrations in the tear secretions than in sera, therefore, the interference between MDA and virus of vaccine may happen in a very low level. However, in the eye-drop or spray routes, invasion of the gland by virus of vaccine without the involvement of blood borne circulation after infection by the conjunctival and intranasal routes, would explain why the high levels of MDA of one-day-old chicks did not impair immunization.46 Lack of rising of antibody titers of unvaccinated chickens (groups C and D) during experimental period indicated that there was neither environmental nor cross contamination. Late rising of antibody titer (28 days post-1st vaccination and 10 days post-2nd vaccination) of the vaccinated chickens (groups A and B) and reaching the highest level at six weeks age were observed during this study is in agreement with the studies reporting that antibody peaked around 45 day of age following vaccination on day 1 and on day 25. Our observation on enhancement effects of Biomin Imbo on humoral response against IB is in agreement with the results reported for an another synbiotic.33 Recent studies indicate that supplementation of vitamin E may also enhances higher immune responses against IB.42Humoral immunity has a key role in protection of chickens against IB.3 Maternally-derived antibody transferring rate (up to 73.00%) from breeders to yolk/chicks not only varied among different chickens' line but also MDA varied among one-day-old chicks even from same broiler breeder flock47 and depending on the range of MDA, finding optimal timing of primary vaccination would be too difficult. Although there are several methods for predicting the timing of initial vaccination,30,48 in routine vaccination program for intensive poultry husbandry system, primary vaccination against IBD may equalized MDA of the chicks and good immune response may be obtained following booster dose. Generally, infectious bursal disease with clinical signs occurs around three to six weeks of age3 and the birds are most susceptible at 30 to 35 days old. Therefore, an ideal vaccination program must induce protective antibody titer at this age as occurred during this study  Differences among the groups  were not significant (p = 0.100) until day 28 of age; b) From day 28 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was significant (p = 0.036) only on day 42 of age. Humoral antibody plays a key role in protection against IBD.is study  and IBD In conclusion, Application of synbiotic Biomin Imbo enhances antibody responses following vaccination against ND, AI, IB and IBD but it is more effective in live than killed vaccines and could be used as a feed-additive adjuvant for improving innate and acquired immune responses in chickens.


We also update the information about the inhibition properties of single pgip gene products against microbial PGs and the results, including field tests, showing the capacity of PGIP to protect crop plants against fungal, oomycetes and bacterial pathogens.Polygalacturonase inhibiting proteins (PGIPs) are cell wall proteins that inhibit the pectin-depolymerizing activity of polygalacturonases secreted by microbial pathogens and insects. These ubiquitous inhibitors have a leucine-rich repeat structure that is strongly conserved in monocot and dicot plants. Previous reviews have summarized the importance of PGIP in plant defense and the structural basis of PG-PGIP interaction; here we update the current knowledge about PGIPs with the recent findings on the composition and evolution of  To this end, pathogens produce a wide array of plant cell wall degrading enzymes (CWDEs), among which endo-polygalacturonases  are secreted at very early stages of the infection process . Most of these genes have been identified as pgip genes on the basis of sequence identity but only a few of them have been shown to encode proteins with PG-inhibitory activity.Early characterization of a polygalacturonase-inhibiting activity was reported in 1970s . These proteins do not interact in vitro, although VvPGIP1 reduces symptoms caused by BcPG2 upon co-infiltration in leaves. The number and sources of PGs tested is also limited; only a few studies have been carried out against PGs of bacteria and insects  possessing non functional pgip genes . Recently, a wheat gene with some sequence similarity to pgip genes has been reported and was shown to be involved in the defense response against Fusarium graminearum  forms with PG from A. niger (AnPGII), F. phyllophilum (FpPG) and C. lupini (ClPG). Site-directed mutagenesis has shown that the residues involved in the interaction are located in the concave surface of the inhibitor  suggesting that the protein is highly versatile in recognizing different epitopes of various PGs  Bnpgip1 or Bnpgip2. Arabidopsis plants overexpressing Atpgip1 or Atpgip2 showed a significant reduction of disease symptoms caused by B. cinerea  PGIP (PcPGIP) capable of inhibiting the PGs secreted by B. cinerea, showed a reduction of disease lesions caused by this fungus both on ripening fruit (15% reduction) and leaves (about 25% reduction). The initial establishment of infection was not affected in the transgenic plants but the later colonization of the host tissue was significantly reduced , Vvpgip1 (from V. vinifera), Capgip1 [from pepper (Capsicum annum)] and Brpgip2 (from B. rapa) have been obtained in transgenic tobacco. Plants expressing PvPGIP2 showed about 35% reduction of symptoms caused by B. cinerea  that are highly resistant to blue mold disease. These transgenic plants expressing PvPGIP2 represented the first example of PGIP-expressing plants subjected to field trails. Recently, transgenic rice expressing OsPGIP1 showed also improved resistance against Rhizoctonia solani in field experiments  caused by Solanum tuberosum) plants expressing the gene StPGIP1 from S. torvum showed a 50% reduction of wilt disease symptoms caused by Verticillium dahliae and a normal plant growth  plants constitutively expressing the pear PcPGIP gene represent an interesting example of the potential of PGIP for protection against pathogens other than fungi and oomycetes. These plants show a delayed development of the Pierce's disease (PD) caused by bacterial pathogen Xylella fastidiosa  of the symptoms as compared to wild-type plants  plants overexpressing BrPGIP2 showed higher resistance against P. carotovorum and produced normal looking pods-like structures with no viable seeds. Combination of crossing with non-transgenic plants did not restore fertility of the transgenic plants, suggesting that mechanisms such as ploidy changes occurring during the tissue culture stage or changes in cell-wall architecture of sexual organs are responsible for the abnormality , transformed with Ripgip from raspberry (Rubus idaeus L.)  and apple  transformed with pear PcPGIP  transformed with bean Pvpgip2  transformed with bean Pvpgip1  to transform both durum and bread wheat by particle bombardment. PvPGIP2 was correctly targeted to the apoplast and the transgenic plants did not show any major morphological and growth defects. Transgenic wheat showed a significant reduction (46–50%) of foliar spot blotch symptoms caused by the hemibiotrophic fungal pathogen Bipolaris sorokiniana and improved resistance (25–30%) against the hemibiotrophic fungal pathogen F. graminearum  E3 ligase that is involved in several stress responses, including Pi starvation, and flowering (Sato and Miura, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Different reports of shared manifestations for malignancy and rheumatic diseases in children since 1970s indicate the presentation of malignancies, particularly ALL, with musculoskeletal (MS) symptoms.To evaluate the rate and the characteristics of hematological malignancies in Iranian children with joint manifestations based on two different scopes of data collection since 1981.In this retrospective review, we considered two different aspects of evaluation within two pediatric tertiary centers in Iran: 1- Children's Hematology/Oncology Research Center, 2- Pediatric Rheumatology Center.Here we report the results of 3 studies  conducted through 1981-2006, followed by current (IV) study performed since 2006. Findings of four different studies are mentioned in detail, in Table The relative increase in the rate of malignancy in this review (period of 1981-2012) could be an alarm to perform BM aspiration in children with joint manifestations harboring the following as "Red Flags": (i) Boys at the age of 5-7, (ii) Large joint involvement  and (iii) Arthralgia at presentation. According to recent recommendations by ACR for early aggressive treatments in JIA patients, this precautionary measure may minimize the potential dangers and consequences of misdiagnosis prior to initiation of any treatment.None declared.


Glycine max) because of ruptured cell walls. Using RNA-Seq, we examined the seed coat transcriptome from three stages of immature seed development in two pairs of isolines with normal or defective seed coat phenotypes due to the net pattern. The genome-wide comparative study of the transcript profiles of these isolines revealed 364 differentially expressed genes in common between the two varieties that were further divided into different broad functional categories. Genes related to cell wall processes accounted for 19% of the differentially expressed genes in the middle developmental stage of 100–200 mg seed weight. Within this class, the cell wall proline-rich and glycine-rich protein genes were highly differentially expressed in both genetic backgrounds. Other genes that showed significant expression changes in each of the isoline pairs at the 100–200 mg seed weight stage were xylem serine proteinase, fasciclin-related genes, auxin and stress response related genes, TRANSPARENT TESTA 1 (TT1) and other transcription factors. The mutant appears to shift the timing of either the increase or decrease in the levels of some of the transcripts. The analysis of these data sets reveals the physiological changes that the seed coat undergoes during the formation of the breaks in the cell wall.The plant cell wall performs a number of essential functions including providing shape to many different cell types and serving as a defense against potential pathogens. The net pattern mutation creates breaks in the seed coat of soybean ( Plant cells are surrounded by cell walls which provide tensile strength, mechanical support, protection from insects and pathogens, prevention of water loss, and that participate in cell to cell communication Glycine max) has been well characterized, and contains features in common with the majority of the legumes: an epidermal layer of palisade cells, or macrosclereids, a sub-epidermal layer of hourglass cells, or osteosclereids, a few layers of parenchyma, and an aleurone layer The seed coat, or testa, of the mature soybean  of the cell wall leading to higher levels of this transcript in the defective seed coats at the middle weight range of 100–200 mg seed weight The effect on PRP1 transcript levels was assumed to be a downstream effect of the net pattern mutation. In this report, we present the global gene expression analysis of the net pattern cell wall mutant in soybean using transcriptome analyses of three different stages of seed development at 50–100 mg, 100–200 mg, and 400–500 mg. By comparing RNA-Seq data from the two lines containing the defective seed coat trait compared to their standard counterpart isolines using Bowtie alignments The isolines in the background of cultivar Clark are referred to as Clark standard (CS) which exhibits an intact seed coat and Clark defective (CD) that contains the defective seed coat mutation that had been backcrossed into the Clark standard line. Likewise, Harosoy standard (HS) is compared to the Harosoy defective (HD) isoline that contains the defective seed coat mutation. The genotypes and phenotypes of these two isoline pairs is presented in Next-generation high throughput sequencing of the transcriptome (RNA-Seq) was used and the cDNA libraries were constructed from seed coats from 50–100 mg, 100–200 mg and 400–500 mg seed weight stages in standard and mutant isolines of Clark and Harosoy cultivars. Each library was sequenced on the Illumina GAII or HiSeq 2000 platforms. The number of raw sequence reads obtained from all four isolines, at different seed weight stages are presented in As presented in As shown in A selection of 29 of the 364 differentially expressed genes at the 100–200 mg seed weight stage are shown in As presented in The expression levels of PRP1 and PRP2 at different seed weight stages were previously demonstrated by The graphical representations of the expression levels of the other differentially expressed genes shown in It is clear from the 68 graphs of the gene expression patterns shown in There were 21 hormone regulated genes that were differentially expressed in the seed coat of wild type and defective isolines of both Clark and Harosoy background  includinThe expression pattern of two other hormone regulated genes in ie., if expression of a particular gene was higher in the standard isoline of Clark, then it was lower in the standard isoline of Harosoy)  .Two zinc finger domain (C2H2 type) containing protein genes that had TT1 (TRANSPARENT TESTA1) annotations were approximately 6-fold and 15-fold more highly expressed in the defective seed coats of the Clark and Harosoy lines, respectively, at the 100–200 mg seed weight stage  & 4. TheAlong with the two TT1 gene models, there were 14 total transcription factor genes that showed differential expression in seed coats of standard and defective isolines in both of the Clark and Harosoy backgrounds at the 100–200 mg stage . The mosWe provide an overview of the genes that are affected by the “net pattern” mutation which affects the structural integrity of the soybean seed coat. As shown in Allergens, thaumatin-like proteins, and cysteine-rich domain containing proteins have also been reported to play important roles in various functions related to the cell wall While we have concentrated on the 51 cell wall related genes that were significantly differentially expressed in both varieties, we note that there are 920 additional cell wall related genes that did not show differential expression in the seed coats of either of the two isoline pairs. Thus, there are many processes related to the cell wall that are not affected at the transcript level by the net-pattern mutation.Auxin is a plant growth regulator that is required for cell expansion, division and differentiation. Auxin pathway related genes have been reported to regulate several cell wall related genes in Arabidopsis Glycine maxThe proline-rich proteins are composed of small tandem repeats such as PPVYK or PPVEK, where the second proline is often hydroxyproline I alleles), as compared to black Clark isolines   . LikewisOur RNA-Seq data  show excet al., WRKY transcription factors are involved in regulation of downstream genes encoding the NAM, ATAF1/2, and CUC2 (NAC) and CCCH type (C3H) zinc finger TFs that activate secondary wall synthesis Arabidopsis thaliana, these were expressed in specific cell types of roots, stems and seeds that undergo suberization Transcription factors are important players for controlling the flow of genetic information from DNA to RNA and ultimately affecting the growth and physiology of the plant. In this study, there were approximately 240 differentially expressed transcription factor genes at different seed weight stages –S4. ThesIt is likely that the defective seed coat mutation in soybean sets in motion changes in many pathways related to the cell wall. Some of the differential expression may be a temporal shift in developmental appearances of transcripts. Notably, in the case of the TT1 homolog, it appears that the decline in its transcript levels was delayed in the defective seed coats relative to the standard seed coats , thus leGlycine max. There were approximately 1300 significantly differentially expressed genes affected by this mutation in each isoline pair with 364 in common between the two isolines of different genetic backgrounds. The cell wall structural protein genes including proline-rich proteins (PRP1 and PRP2) and glycine-rich proteins were among the transcripts affected by the mutation as well as a number of transcription factors. Some of the transcript patterns indicate that a developmental shift in timing of gene expression underpins the differential gene expression changes at mid-maturation as shown by graphical presentation of expression patterns for 82 out of 364 genes that were significantly differentially expressed in both the Clark and Harosoy backgrounds. In summary, the mutation appears to set in motion a complex series of events, many manifested at the transcript level, that lead to changes in physiology and ultimately structure of the cell wall. The information on potential candidate genes for this mutation and the regulated genes will not only be helpful in understanding cell wall physiology in soybean, but could also provide a platform for improvement in bioenergy crops like sorghum, maize and Miscanthus.We present an overview of genes whose expression was affected by the “net pattern” mutation in soybean. Two isolines of different genetic backgrounds were used to understand physiology related to this mutation that causes defective cracks in the seed coats. Twelve samples representing three stages of seed coat development from each of the four lines were subjected to the power of next-generation sequencing to obtain millions of transcript reads that were mapped to all 78,773 high and low confidence gene models of Glycine max used in this study were a black seeded Clark line, Clark defective seed coat, Harosoy standard and Harosoy defective seed coat. The defective seed coat mutation was originally found in two PI (plant introduction) lines, PI 339.994 and PI423.730B and these lines were backcrossed to the black seeded Clark line (UC9) to create an isoline UC412 containing this mutation. The same mutation was also backcrossed into the Harosoy line to create an isoline UC508. The L or PI numbers represent the official USDA isoline or plant introduction numbers, respectively. The UC number is an internal number used by our laboratory. Detailed information on these lines is presented in The isolines of For RNA extraction, immature seeds were harvested over the course of several weeks. The individual seeds were pooled and sorted by weight. Following this, each seed was dissected, separating the cotyledon and embryo from the seed coat, and placed in separate 15-ml polypropylene centrifuge tubes . All tissue was then frozen in liquid nitrogen and placed in storage at −80°C until it could be lyophilized. RNA of seed coats of seeds from the 50–100 mg, 100–200 mg and 400–500 mg seed weight stages of each isoline was extracted separately using the RNA for 5 ml volumes from ∼30 mg (50–100 mg and 100–200 mg seed weight stage) and ∼70 mg (400–500 mg seed weight stage) dry weight. The modified protocol used here is based on the protocols of McCarty The 75 bp and 100bp reads were mapped to the 78,773 Glyma cDNA gene models (JGI/Phytozome) using Bowtie et al. Coding region gene models were collected from the masked soybean genome from Phytozome version 6.0 and the soybean genome version 1.0 GFF file of the soybean genome DESeq (available via Bioconductor) is an R package to analyze count data from high-throughput sequencing data such as RNA-Seq and test for differential expression 32P]dATP by random primer reaction method Total RNA was extracted from the frozen tissue including 4–5 day old soybean hypocotyls minus their cotyledons and seed coats of 100–200 mg seeds from four lines using a standard phenol chloroform method with lithium chloride precipitation The data have been entered into Gene Expression Omnibus at that National Center for Biotechnology Information as Accession Series GSE54903.Figure S1The Distribution of Expression Levels in RPKMs of Differentially Expressed Genes in the Clark Isoline Pair at Three Different Seed Weight Stages. (A) 50–100 mg in Clark Standard (B) 50–100 mg in Clark Defective (C) 100–200 mg in Clark Standard (D) 100–200 mg in Clark Defective (E) 400–500 mg Clark Standard (F) 400–500 mg Clark Defective.(TIFF)Click here for additional data file.Figure S2The Distribution of Expression Levels of Differentially Expressed Genes in the Harosoy Isoline Pair at Three Different Seed Weight Stages. (A) 50–100 mg in Harosy Standard (B) 50–100 mg in Harosoy Defective (C) 100–200 mg in Harosoy Standard (D) 100–200 mg in Harosoy Defective (E) 400–500 mg Harosoy Standard (F) 400–500 mg Harosoy Defective.(TIFF)Click here for additional data file.Figure S3Williams (Phytozome) and Wayne (NCBI) cultivars showed 100% sequence homology.The Nucleotide and Amino Acid Sequence Alignment for PRP1. (A) Alignment of PRP1 nucleotide sequence from NCBI (J02746) and PRP1 sequence (Glyma09g12200.1) from Phytozome database (B) Alignment of PRP1 amino acid sequence from NCBI with PRP1 amino acid sequence from Phytozome database. The nucleotide and amino acid sequence from (TIFF)Click here for additional data file.Figure S4The Nucleotide and Amino Acid Sequence Alignment of the PRP2 Gene. (A) Alignment of PRP2 nucleotide sequence from NCBI (J05208) and PRP2 sequence from Phytozome database (Glyma09g12260.1) (B) Alignment of PRP2 amino acid sequence from NCBI with PRP2 amino acid sequence from Phytozome database. There is difference of one tandem repeat in the amino acid sequence. The PRP2 protein is shorter in Williams (Phytozome) as compared to Wayne (NCBI) cultivar.(TIFF)Click here for additional data file.Figure S5The Genome Organization of PRP1 and PRP2. As in the Phytozome database, PRP1 and PRP2 are on chromosome 9 and the distance between these genes is ∼146 kb.(TIFF)Click here for additional data file.Figure S6The Expression Pattern of 13 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Backgrounds. The genes over expressed in the defective isolines . CS: Cla(TIF)Click here for additional data file.Figure S7The Expression Pattern of 16 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. The genes overexpressed in the Standard isolines . CS: Cla(TIF)Click here for additional data file.Figure S8The Expression Pattern of 11 Fasciclin-like Arabinogalactan Gene in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. These genes showed higher expression in defective isoline as compare to wildtype isoline . CS: Cla(TIF)Click here for additional data file.Figure S9The Expression Pattern of Cell Wall Genes Overexpressed in the Seed Coats of Defective Isolines in Both Clark and Harosoy Background. These graphs present data for 25 additional cell wall related genes not previously shown in (TIF)Click here for additional data file.Figure S10The Expression Pattern of Cell Wall Genes Overexpressed in the Standard Seed Coats of Both Clark and Harosoy Background. These graphs present data for 3 additional cell wall related genes not previously shown in (TIFF)Click here for additional data file.Figure S11The Distribution of Differentially Expressed Genes in the Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 50–100 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 720 genes in Clark isolines and (B) 48 genes in Harosoy isolines. In both backgrounds, there were major categories related to the cell wall.(TIFF)Click here for additional data file.Figure S12The Distribution of Differentially Expressed Genes in Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 100–200 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 173 genes in Clark isolines and (B) 156 genes in Harosoy isolines at 100–200 mg seed weight stage. In both backgrounds, one of the major categories was related to the cell wall.(TIFF)Click here for additional data file.Figure S13The Distribution of Differentially Expressed Genes in Seed Coats of (A) Clark or (B) Harosoy Backgrounds at the 400–500 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 417 genes in Clark isolines and (B) 1068 genes in Harosoy isolines. In both backgrounds, the cell wall related genes occupied 5% of the chart area.(TIFF)Click here for additional data file.Figure S14The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Defective Isolines in Both Clark and Harosoy Background. Overexpressed in defective isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S15The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Standard Isolines in Both Clark and Harosoy Background. Overexpressed in standard isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S16The Distribution of Differentially Expressed Transcription Factor Genes into Different Classes in Clark at the 50–100 mg Seed Weight Stage. The 59 differentially expressed transcription factor genes  were divided into 12 classes based on functional annotations.(TIFF)Click here for additional data file.Figure S17The Distribution of Differentially Expressed Transcription Factor Genes in (A) Clark or (B) Harosoy Backgrounds at the 100–200 mg Seed Weight Stage. (A) The 16 differentially expressed transcription factor genes  were divided into 9 different classes (B) The 12 differentially expressed transcription factor genes  were divided into 10 different classes based on functional annotation.(TIFF)Click here for additional data file.Figure S18The Distribution of Differentially Expressed Transcription Factor Genes in Different Classes in (A) Clark and (B) Harosoy Backgrounds at the 400–500 mg Seed Weight Stage. (A) The 43 differentially expressed transcription factor genes  were divided into 10 different classes (B) The 111 differentially expressed transcription factor genes  were divided into 15 different classes based on functional annotation.(TIFF)Click here for additional data file.Table S1The Total Number of Expressed Genes in Seed Coats of the Different Isolines. The total number of expressed genes at ≥10 RPKM or ≥1 RPKM in different backgrounds at different seed weight stages are presented in this table. CS: Clark standard, CD: Clark defective, HS: Harosoy Standard and HD: Harosoy defective.(DOCX)Click here for additional data file.Table S2Significantly Differentially Expressed Genes Found in the Seed Coats of Either Clark or Harosoy Backgrounds at the Indicated Stages of Seed Development.(XLSX)Click here for additional data file.Table S3The 364 Significantly Differentially Expressed Genes Found in Common in Both Clark and Harosoy Backgrounds as Defined in (XLSX)Click here for additional data file.Table S4The 109 Significantly Differentially Expressed Genes Common in Both Background But with Expression in Opposite Directions as Described in (XLSX)Click here for additional data file.


Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sjia) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) or sjia-associated MAS has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sjia-associated MAS in patients with sjia who developed MAS.The study sample included 362 children with sjia who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially "confusable" conditions, including active sjia without MAS (n = 404) and a systemic febrile infection requiring hospitalization (n = 345). Diagnostic guidelines for HLH and sjia-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. Sjia-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sjia-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS.None declared.


Quantification of interstitial (diffuse) myocardial fibrosis by T1 mapping may prove useful in a range of conditions. Both native T1 maps and extracellular volume fraction (ECV) are being increasingly used clinically and have been shown to be sensitive to a wide range of conditions and associate with worse prognosis. However, quality control by T1 phantoms is essential  and thei2-agarose gel phantoms [NiClphantoms  were prephantoms . PhantomBoth high resolution and low resolution sequences had similar T1 means, standard deviation and coefficient of variation (CoV) for blood and myocardium native and post-gadolinium  may require further investigation.There was significant stability of the NiClNIHR Cardiovascular Biomedical Research Unit of Royal Brompton & Harefield NHS Foundation Trust and Imperial College London.


To the Editor: Feline morbillivirus (FeMV) was first reported in Hong Kong and mainland China in 2012  of the L gene of the US strains (We generated amplicons from 10 (3%) of 327 samples; 3 samples were from cats with CKD and 7 from cats without CKD. Sequencing results confirmed that these 493 bp amplicons correspond to unique strains of FeMV . Approximately 15 months later, we obtained a follow-up urine sample from the still healthy cat, performed reverse transcription PCR (RT-PCR), and generated amplicons  by using RT-PCR and rapid amplification of cDNA ends. The major morbillivirus surface antigen is the HA glycoprotein, and we used pan-FeMV HA gene primer sets to detect additional viruses  , and antibodies to FeMVUS5 were detected in nonpermeabilized cells    Figure 2US1 is closely related to viruses from Asia, highlighting the global distribution of FeMV  clustered phylogenetically in a basal sister relationship with all other viruses from Asia and the United States (We used complete genome and H gene sequences in a comprehensive phylogenetic analysis. FeMV of FeMV , panel Ad States , panel BEcologic surveys continue to identify novel viruses that are homologous to known paramyxoviruses in many wildlife species, including bats and rodents (The detection of FeMV sequences in a clinically healthy animal after 15 months is a novel and surprising observation but is consistent with the known propensity for morbilliviruses to persist in vivo (Technical Appendix. Methods for the molecular and serologic detection of feline morbillivirus in clinical samples.


Ribavirin (RBV) is a synthetic nucleoside analogue  used for the treatment of a number of viral diseases. RBV inhibits inosine 5′-phosphate dehydrogenase (IMPDH), the enzyme required for synthesis of guanosine monophosphate (GMS) as well as DNA and RNA synthesis. Based on this mechanism of action, RBV is also used in the treatment of solid tumors, lymphoproliferative disease and some inflammatory diseases such as Crohn's disease. A number of nucleoside analogs including RBV diffuse across cell membranes through a membrane transporter protein called equilibrative nucleoside transporter-1 (ENT1). Our recent publication demonstrated that an autophagy response induced by hepatitis C virus (HCV) in a cell culture reduces RBV uptake and antiviral activity by diminishing the surface expression of ENT1 [Human ENTs are the nucleoside transporter proteins expressed on the cell membrane that occur as four isoforms ENT1-ENT4). These proteins play important roles in transporting nucleosides- and nucleotides-based small molecule drugs. The expression of ENT1 is critical for salvage of natural nucleotides and nucleosides for nucleic acid synthesis, neurotransmission, and regulation of cardiovascular activity . The exp. These pTaking into consideration the previously mentioned autophagy related mechanism that regulates the expression of ENT1, it is reasonable to speculate that cellular autophagy status could regulate the uptake and response to nucleoside based treatment of viral infection or cancer. RBV has been used for the treatment of a number of viral infections with modest antiviral activity. The decreased antiviral activity of RBV against virus disease could be related to the degree of cellular autophagy response and expression of ENT1. Based on our results, we propose that inhibiting cellular autophagy response should improve the RBV uptake and antiviral activity against other viruses. One report showed that RBV has a potent antitumor activity against metastatic breast cancer . The celThe responses to gemcitabine treatment of pancreatic cancer have been shown to be correlate with reduced expression of ENT1 transporter. Over expression of ENT1 enhances the gemcitabine response in human pancreatic cancer, tumor cells lacking ENT1 expression are highly resistant to gemcitabine . This is


There is an emerging evidence that critical illnes induces an alteration in the immune response of patients that makes them more susceptible to the development of nosocomial infections and influences its clinical response.The aim of this study is to characterize the immunocompetence status of critically ill patients undergoing mechanical ventilation and to determine impaired immune patterns associated with an increased risk of developing ventilator-associated pneumonia (VAP) and a poorer clinical evolution.All immunocompetent patients over 18 years old admitted to the Intensive Care Unit of the Hospital Universitario and Politecnico la Fe , undergoing mechanical ventilation for more than 48 hours were included. Patients with clinical suspicion of ventilator-associated respiratory infection were considered as cases and compared with a selection of controls matched by age, comorbidities, severity scales and days of mechanical ventilation. At the moment of intubation and each 72 hours until the moment of extubation, clinical surveillance was performed and respiratory samples  were taken to evaluate clinical and microbiological response. Samples of plasma and mini-BAL were also taken for immunoglobulins IgG1 - IgG4, IgM, IgA and IgE determination. Comparison of numerical and categorical variables was performed with the Mann-Whitney U test. Results were expressed as medians with interquartile (25% to 75%) ranges (IR) in brackets.16 cases and 14 controls were considered for analysis. Response to antibiotic treatment was evaluated in cases and patients were classified in responders (7 cases) and non-responders (8 cases). Initial empirical antibiotic treatment was more accurate in responders patients . At the moment of orotracheal intubation and beginning of mechanical ventilation, VAP patients showed lower serum IgA levels  (figure A), lower serum IgG1 and IgM and lower respiratory levels of IgG1, IgG2 and IgA, without statistical signification. At the moment of VAP diagnosis, responders patients showed higher levels of IgG2  (figure B), lower serum IgG1 and IgM  and higher levels of IgA  (figure C).Our findings show the protective role of IgA and IgG2 against the inflammatory aggression of mechanical ventilation and in the response against ventilator-associated pneumonia.This study was supported by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 129/2011).