Genome-Wide Association Study of Growth and Feeding Traits in Pekin Ducks.
Growth rate and feeding efficiency are the most important economic traits for meat animals. Pekin duck is one of the major global breeds of meat-type duck. This study aims to identify QTL for duck growth and feeding efficiency traits in order to assist artificial selection. In this study, the growth and feeding related phenotypes of 639 Pekin ducks were recorded, and each individual genotype was evaluated using a genotyping-by-sequencing (GBS) protocol. The genetic parameters for growth and feeding efficiency related traits were estimated. Genome-wide association analysis (GWAS) was then performed for these traits. In total, 15 non-overlapping QTLs for the measured traits and 12 significant SNPs for feed efficiency traits were discovered using a mixed linear model. The most significant loci of feed intake (FI) is located in a 182Mb region on Chr1, which is downstream of gene RNF17, and can explain 2.3% of the phenotypic variation. This locus is also significantly associated with residual feed intake (RFI), and can explain 3% of this phenotypic variation. Among 12 SNPs associated with the feed conversion ratio (FCR), the most significant SNP (P-value = 1.65E-06), which was located in the region between the 3rd and 4th exon of the SORCS1 gene on Chr6, explained 3% of the phenotypic variance. Using gene-set analysis, a total of two significant genes were detected be associated with RFI on Chr1. This study is the first GWAS for growth and feeding efficiency related traits in ducks. Our results provide a list of candidate genes for marker assisted selection for growth and feeding efficiency, and also help to better understand the genetic mechanisms of feed efficiency and growth in ducks.


Computerized mechanical validation of custom-made stems.
The new community laws regarding medical devices require that custom-made devices be prescribed by the surgeon, who assumes responsibility for the device along with the manufacturer. It is the purpose of this study to indicate a method that allows use to check whether custom-made prostheses in particular conform to the requirements established by European laws; these are prostheses produced in a single model and that have rather short development and realization times. The pre-clinical method of validation proposed, based on a calculation with finite elements, was first verified by in vitro measurements and then used to evaluate 15 cases selected among the most critical ones in terms of size and/or geometrical irregularity from a group of 100 stems that had already been implanted. The method proposed was confirmed to be accurate and reliable; in 3 out of 15 stems analyzed we found values for mechanical resistance that were less than minimum values required by law.


[Follow-up study after dynamic and static stabilisation of the lumbar spine].
The clinical indication for graf's ligamentoplasty and dorsoventral fusion may be described as the "lumbar instability syndrome". A follow-up comparison between Graf's ligamentoplasty and instrumental dorsoventral fusion in a consecutive series of 52 patients was performed. 52 patients operated on for low back pain were recalled for a clinical and radiological review (at mean 79 months postoperatively). 26 patients underwent Graf' ligamentoplasty and 26 patients underwent dorsoventral fusion. We evaluated the surgical results and measured an objective outcome using the Oswestry Score, Low Back Outcome Score (LBOS) and Visual Analogue Scale (VAS). For radiological evaluation the Mimura and the Pathria Scores were used. There was no statistically significant difference between the two groups, when measured by the Oswestry Score, LBOS and VAS at the latest follow-up. The difference between the preoperative and actual VAS in each group was statistically significant (p < 0.001). Furthermore, there was no provable preoperative parameter in favour of either one of these therapies. Both methods for stabilisation methods of the lumbar spine had a comparable clinical outcome.


Neonatal diabetes caused by activating mutations in the sulphonylurea receptor.
Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.


Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site. A retrospective study.
Abdominal computed tomography (CT) and other studies were evaluated retrospectively in 46 patients with metastatic adenocarcinoma or undifferentiated carcinoma in whom the primary tumor site was not evident from the history, physical examination, or chest radiograph. The primary site was ultimately located in 21 patients (45.7%). CT of the abdomen in particular detected it in 16 patients (34.8%) and demonstrated additional and often unsuspected metastatic disease in 65%. CT proved superior to sonography in both diagnosis and assessment of the extent of disease and had a significantly higher diagnostic yield than contrast studies of the urinary and gastrointestinal tracts. abdominal CT is recommended as the initial modality in patients with metastatic adenocarcinoma of unknown primary origin. If the abdominal scan is negative, it should be followed by pelvic sonography or CT, particularly in women. Contrast studies should be limited to patients with specific organic dysfunction.


Reduced stress perfusion in myocardial infarction with nonobstructive coronary arteries.
Myocardial infarction with nonobstructive coronary arteries (MINOCA) has several possible underlying causes, including coronary microvascular dysfunction (CMD). Early cardiovascular magnetic resonance imaging (CMR) is recommended, however cannot provide a diagnosis in 25% of cases. Quantitative stress CMR perfusion mapping can identify CMD, however it is unknown if CMD is present during long-term follow-up of MINOCA patients. Therefore, this study aimed to evaluate presence of CMD during long-term follow-up in MINOCA patients with an initial normal CMR scan. MINOCA patients from the second Stockholm myocardial infarction with normal coronaries study (SMINC-2), with a normal CMR scan at median 3 days after hospitalization were investigated with comprehensive CMR including stress perfusion mapping a median of 5 years after the index event, together with age- and sex-matched volunteers without symptomatic ischemic heart disease. Cardiovascular risk factors, medication and symptoms of myocardial ischemia measured by the Seattle Angina Questionnaire 7 (SAQ-7), were registered. In total, 15 patients with MINOCA and an initial normal CMR scan (59 ± 7 years old, 60% female), and 15 age- and sex-matched volunteers, underwent CMR. Patients with MINOCA and an initial normal CMR scan had lower global stress perfusion compared to volunteers (2.83 ± 1.8 vs 3.53 ± 0.7 ml/min/g, p = 0.02). There were no differences in other CMR parameters, hemodynamic parameters, or cardiovascular risk factors, except for more frequent use of statins in the MINOCA patient group compared to volunteers. In conclusion, global stress perfusion is lower in MINOCA patients during follow-up, compared to age- and sex-matched volunteers, suggesting that CMD may be a possible pathophysiological mechanism in MINOCA.Clinical Trial Registration: Clinicaltrials.gov identifier NCT02318498. Registered 2014-12-17.


Management of early cancer of the breast. Report on an international multicentre trial supported by the Cancer Research Campaign.
In the largest controlled clinical study so far undertaken on the management of early cancer of the breast in women the results of a radical regimen (simple mastectomy and radiotherapy) were compared with those of a conservative policy (simple mastectomy alone). The study included enough patients (2268) to ensure that small but significant differences between the two treatments would emerge. With a five-year follow-up there was no evidence that routine postoperative radiotherapy was harmful or that it conferred further benefit as regards survival or distant recurrence. Radiotherapy did, however, reduce the incidence of local recurrence. Neither form of treatment can counter occult disease far from the breast that is present at the time of initial treatment, which probably accounts for the high death rate from breast cancer, but the results of the study would support the view that conservative primary treatment and subsequent adjuvant chemotherapy may be the treatment of choice in future.


A Delphi developed syllabus for the medical specialty of sport and exercise medicine.
Training in the medical specialty of sport and exercise medicine is now available in many, but not all countries. Lack of resources may be a barrier to the development of this important specialty field and the International Syllabus in Sport and Exercise Medicine Group was convened to reduce one potential barrier, the need to develop a syllabus. The group is composed of 17 sport and exercise medicine specialists residing in 12 countries (Australia, Canada, India, Ireland, Malaysia, the Netherlands, Qatar, South Africa, Sweden, Switzerland, the UK and USA). This paper presents the first phase of this project covering the domains and general learning areas of a specialist training syllabus in sport and exercise medicine.


Motor neurons contain agrin-like molecules.
Molecules antigenically similar to agrin, a protein extracted from the electric organ of Torpedo californica, are highly concentrated in the synaptic basal lamina of neuromuscular junctions in vertebrate skeletal muscle. On the basis of several lines of evidence it has been proposed that agrin-like molecules mediate the nerve-induced formation of acetylcholine receptor (AChR) and acetylcholinesterase (AChE) aggregates on the surface of muscle fibers at developing and regenerating neuromuscular junctions and that they help maintain these postsynaptic specializations in the adult. Here we show that anti-agrin monoclonal antibodies selectively stain the cell bodies of motor neurons in embryos and adults, and that the stain is concentrated in the Golgi apparatus. We also present evidence that motor neurons in both embryos and adults contain molecules that cause the formation of AChR and AChE aggregates on cultured myotubes and that these AChR/AChE-aggregating molecules are antigenically similar to agrin. These findings are consistent with the hypothesis that agrin-like molecules are synthesized by motor neurons, and are released from their axon terminals to become incorporated into the synaptic basal lamina where they direct the formation of synapses during development and regeneration.


Substance Use Disorders Among Veterans in a Nationally Representative Sample: Prevalence and Associated Functioning and Treatment Utilization.
Several epidemiological studies have reported that veterans and nonveterans have comparable substance use disorder (SUD) prevalence and SUD treatment rates for SUD and treatments of several types. No studies have compared functioning among veterans with SUD to veterans without SUD or to nonveterans. We investigated the prevalence of past-year and lifetime SUD (based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), overall and by substance, and estimated the association with physical and mental health functioning and treatment utilization and need among veterans and nonveterans in a nationally representative sample. Predicted prevalence of any past-year SUD, with and without tobacco use disorder (TUD), among veterans was 32.9% and 17.1%, and prevalence of any lifetime SUD, with and without TUD, was 52.5 and 38.7%, respectively. Veterans had higher prevalence of past-year and lifetime SUD for some substances (e.g., tobacco, alcohol) but not others (e.g., cannabis, opioid). Lower physical and mental health functioning was found among veterans, relative to nonveterans, and participants with SUD, relative to those without SUD, and veterans with SUD reported the lowest functioning across all domains. More veterans than nonveterans received any SUD treatment and SUD treatment in specific domains (e.g., self-help). About 70% of veterans with past-year SUD did not receive treatment, but only 5.4% reported needing and not receiving treatment. Relative to nonveterans, veterans have higher prevalence of past-year TUD and lifetime alcohol use disorder or TUD and lower physical or mental health functioning. A minority of veterans receive SUD treatment, and few report unmet need for treatment.


Home blood pressure normalcy in non-European adolescents.
Evidence on normal range of home blood pressure (BP) in adolescents relies on only one European study. This study aims to investigate the normal range of home BP in a healthy non-European population of adolescents. Cross-sectional study with a representative sample of secondary school students (12-17 years) from a Brazilian state capital. Adolescents' heights were classified in percentiles according to age and sex. Height percentiles were divided in 50th or less or more than 50th percentile. The home BP protocol included two day-time and two evening-time measurements over 6 days. Exams were considered valid with at least 12 measurements. A total of 1024 adolescents were included, mean age 15.21 ± 1.61 years, mostly women (52.4%), from public schools (68.4%) and nonwhite (51.3%). The 50th (midpoint of distribution) and the 95th percentile (upper normal limit) for home SBP and DBP in adolescents are provided by sex, age and height percentiles. There was a marked increase in the estimated 95th percentile for home SBP with increasing age in men for both height percentiles examined (16 mmHg for ≤50th percentile and 14.5 mmHg for >50th percentile) and less so for home DBP (1 and 5 mmHg, respectively). In women, the 95th percentile increase with age was less significant for SBP and similar for DBP when compared with men in the two height percentiles evaluated (6/2 mmHg for ≤50th percentile and 4/4 mmHg for >50th percentile). Reference values for home BP by height percentiles for age and sex in a non-European population of adolescents are provided.


Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes.
Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor cohorts within which they are frequently mutated. For many genes, neither the transcriptomic effects of these variants nor their relationship to one another in cancer processes have been well-characterized. We sought to identify the downstream expression effects of these mutations and to determine whether this heterogeneity at the genomic level is reflected in a corresponding heterogeneity at the transcriptomic level. By applying a novel hierarchical framework for organizing the mutations present in a cohort along with machine learning pipelines trained on samples' expression profiles we systematically interrogated the signatures associated with combinations of mutations recurrent in cancer. This allowed us to catalogue the mutations with discernible downstream expression effects across a number of tumor cohorts as well as to uncover and characterize over a hundred cases where subsets of a gene's mutations are clearly divergent in their function from the remaining mutations of the gene. These findings successfully replicated across a number of disease contexts and were found to have clear implications for the delineation of cancer processes and for clinical decisions. The results of cataloguing the downstream effects of mutation subgroupings across cancer cohorts underline the importance of incorporating the diversity present within oncogenes in models designed to capture the downstream effects of their mutations.


[Diagnosis and treatment of intravenous leiomyomatosis].
Intravenous leiomyomatosis is a rare tumor that is histologically benign but biologically invasive. It originates from the smooth muscle of the uterine or the uterine vein. It can grow through the uterus and extend into the pelvic cavity, or grow along the veins without invading the wall of the venous vessel itself. The tumors are estrogen-dependent and can metastasize through the bloodstream. Thus, in addition to continuous growth, some tumors exhibit isolated growths in the venous system and heart chambers or show disseminated growth in the lungs, although distant metastasis to other regions usually do not occur. Currently, there is limited research on this disease, the majority of which are case reports, surgical experience summaries, and differentiation from ordinary gynecological myomas in terms of pathogenesis and radiological diagnostic experience. There are two main theories on the origin of the disease: uterine smooth muscle and smooth muscle of the uterine veins. Some studies have verified the role of estrogen, progesterone receptor-related pathways, and angiogenesis in the development of the disease. The clinical symptoms of this disease are varied, depending on the affected area. In the early stages, when the tumor only affects the pelvic cavity, patients show mild symptoms resulting from pelvic organ compression. When it progresses to the inferior vena cava and heart, patients show more complex symptoms resulting from venous return obstruction, cardiac obstruction, and hemodynamics appearing. Different institutions have proposed different disease staging and classification strategies for different clinical purposes. Some are based on the affected area of the lesion; others are based on the size of the tumor. Although surgery remains the main treatment for this disease, the specific surgical approach, adjuvant drug therapy, and prognosis still need further exploration.


Association of ambient air quality with pulmonary function of youngster footballers.
Air pollution has remained a major health concern in Kolkata. The present study was carried out to analyze the association between the levels of air pollutants and pulmonary function of youngster footballers living in two different air pollutant zones of Kolkata, West Bengal. Air pollution data of the two ambient air quality-monitoring stations located at Rabindrabharati and Victoria Memorial was collected for the period from January 2012 to March 2012. Study was conducted on two hundred and twenty boys of the age range 14-16 years living within 3km radius of the two monitoring stations. Sample consisted of 60 footballers (30 from Rabindrabharati and 30 from Victoria Memorial) and 160 sedentary boys (80 from Rabindrabharati and 80 from Victoria Memorial). They were investigated for their spirometric lung functions by the method and technique recommended by American Thoracic Society. Results were expressed as mean ± SD and independent samples T test was conducted to compare between two groups. Results revealed that particulate matter (PM10), oxides of sulfur (SO2) concentrations were significantly higher in Rabindrabharati zone, whereas no significant differences were noted in oxides of nitrogen (NO2) and carbon monoxide (CO) concentrations though values were higher at Rabindrabharati than Victoria Memorial. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced mid expiratory flow (FEF25-75%), maximum voluntary ventilation (MVV) were significantly lower both in footballers (P<0.05) and sedentary boys (P<0.01) of Rabindrabharati zone. Exposure to high air pollutant concentration might be associated with reduced pulmonary function in both sedentary and trained boys in spite of the fact that regular participation in training program may improve pulmonary function.


Using charcoal as base material reduces mosquito coil emissions of toxins.
Mosquito coils are used to prevent mosquito exposures indoors by approximately 2 billion people worldwide. However, the smoldering of organic matters used as base materials of mosquito coils emits particulate and gaseous toxic compounds. A previous study indicates that emission rates of toxic compounds depend on types of base materials and can be high enough to generate room concentrations markedly higher than health based standards or references. The objective of this study is to evaluate a new type of mosquito coil that uses charcoal powder as base material and to compare its emission rates with those of several current-market brands and several brands tested in the previous study. Results show that the charcoal-based coil had emission rates of PM(2.5) mass, total particle number, polycyclic aromatic hydrocarbons (PAH), and aldehydes, substantially (up to 10 times) lower than other tested conventional mosquito coils. Results also show that particles freshly generated from burning mosquito coils were all fine and mostly ultrafine in size. This study presents emission rates for PM(2.5) mass, total particle number, gas-phase and particle-phase PAHs, 14 aldehydes and acetone, and 10 volatile hydrocarbons. These data, along with emission rates presented in the previous study are useful for estimating indoor concentrations of toxic compounds generated from mosquito coil uses. Practical Implications Mosquito coils are widely used indoors to prevent mosquitoes from entering indoor environments. This is achieved through the release of insecticides impregnated in biomass base materials of mosquito coils during coil combustion. A previous study reported that burning one mosquito coil releases the same amount of fine particles as burning 75-135 cigarettes, largely depending on what biomass (saw dust or coconut husk) is used as base material. This 'follow-up' study measured several current-market brands of mosquito coils, including a new charcoal-based coil labeled as smokeless coil by the China Environmental Labeling, for their emissions of particulate and gaseous pollutants. Results show that using charcoal powder as base material reduces fine particle emissions by a factor of 5-10 and also reduces emissions of pollutants such as formaldehyde and PAHs substantially.


Effects of rebamipide in a model of experimental diabetes and on the synthesis of transforming growth factor-beta and fibronectin, and lipid peroxidation induced by high glucose in cultured mesangial cells.
Oxidative stress has been proposed as the basis for the pathogenesis of diabetic nephropathy. Rebamipide is a novel antiulcer drug that has, in addition, oxygen radical scavenging activity. Our study examines whether rebamipide could ameliorate the pathophysiology associated with experimental diabetes in vivo, such as microalbuminuria, and to reverse the increased production of transforming growth factor-beta1 and fibronectin in SV-40 transformed murine mesangial cells in culture that were stimulated with high glucose. Chronic administration of rebamipide (100 mg/kg/day, p.o., for 3 wk) to rats, in which diabetes was previously induced by the i.v. injection of streptozotocin 50 mg/kg, reversed hyperglycemia, which would contribute to prevent the increases in urinary excretion rates of albumin and lipid peroxides observed in this experimental model. Rebamipide, at this dose level, did not cause any discernible effect on age-matched control rats. Rebamipide 2 mM was as effective as 20 mM of dimethylthiourea, a known hydroxyl radical scavenger, in inhibiting the increase in lipid peroxides, transforming growth factor-beta1, fibronectin mRNAs and proteins induced by incubation of cultured mesangial cells with high glucose. Our data suggest that rebamipide attenuates high glucose-induced nephropathy, which is attributable, in part, to its antioxidative property and, in part, to its effect on reversing hyperglycemia.


Optimized anion exchange membranes for vanadium redox flow batteries.
In order to understand the properties of low vanadium permeability anion exchange membranes for vanadium redox flow batteries (VRFBs), quaternary ammonium functionalized Radel (QA-Radel) membranes with three ion exchange capacities (IECs) from 1.7 to 2.4 mequiv g(-1) were synthesized and 55-60 μm thick membrane samples were evaluated for their transport properties and in-cell battery performance. The ionic conductivity and vanadium permeability of the membranes were investigated and correlated to the battery performance through measurements of Coulombic efficiency, voltage efficiency and energy efficiency in single cell tests, and capacity fade during cycling. Increasing the IEC of the QA-Radel membranes increased both the ionic conductivity and VO(2+) permeability. The 1.7 mequiv g(-1) IEC QA-Radel had the highest Coulombic efficiency and best cycling capacity maintenance in the VRFB, while the cell's voltage efficiency was limited by the membrane's low ionic conductivity. Increasing the IEC resulted in higher voltage efficiency for the 2.0 and 2.4 mequiv g(-1) samples, but the cells with these membranes displayed reduced Coulombic efficiency and faster capacity fade. The QA-Radel with an IEC of 2.0 mequiv g(-1) had the best balance of ionic conductivity and VO(2+) permeability, achieving a maximum power density of 218 mW cm(-2) which was higher than the maximum power density of a VRFB assembled with a Nafion N212 membrane in our system. While anion exchange membranes are under study for a variety of VRFB applications, this work demonstrates that the material parameters must be optimized to obtain the maximum cell performance.


Natural orifice transgastric endoscopic wedge hepatic resection in an experimental model using an intuitively controlled master and slave transluminal endoscopic robot (MASTER).
The lack of triangulation of standard endoscopic devices limits the degree of freedom for surgical maneuvers during natural orifice transluminal endoscopic surgery (NOTES). This study explored the feasibility of adapting an intuitively controlled master and slave transluminal endoscopic robot (MASTER) the authors developed to facilitate wedge hepatic resection in NOTES. The MASTER consists of a master controller, a telesurgical workstation, and a slave manipulator that holds two end-effectors: a grasper, and a monopolar electrocautery hook. The master controller is attached to the wrist and fingers of the operator and connected to the manipulator by electrical and wire cables. Movements of the operator are detected and converted into control signals driving the slave manipulator via a tendon-sheath power transmission mechanism allowing nine degrees of freedom. Using this system, wedge hepatic resection was performed through the transgastric route on two female pigs under general anesthesia. Entry into the peritoneal cavity was via a 10-mm incision made on the anterior wall of the stomach by the electrocautery hook. Wedge hepatic resection was performed using the robotic grasper and hook. Hemostasis was achieved with the electrocautery hook. After the procedure, the resected liver tissue was retrieved through the mouth using the grasper. Using the MASTER, transgastric wedge hepatic resection was successfully performed on two pigs with no laparoscopic assistance. The entire procedure took 9.4 min (range, 8.5-10.2 min), with 7.1 min (range, 6-8.2 min) spent on excision of the liver tissue. The robotics-controlled device was able to grasp, retract, and excise the liver specimen successfully in the desired plane. This study demonstrated for the first time that the MASTER could effectively mitigate the technical constraints normally encountered in NOTES procedures. With it, the triangulation of surgical tools and the manipulation of tissue became easy, and wedge hepatic resection could be accomplished successfully without the need for assistance using laparoscopic instruments.


Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases.
Ellis-van Creveld (EVC) syndrome is a rare genetic abnormality that has been linked to a mutation in the EVC or EVC2 genes. Common atrium (CA) is an uncommon cardiac malformation, and yet it is commonly found in patients with EVC. We performed a retrospective review of the cases submitted to the Pediatric Cardiac Care Consortium (PCCC) between 1982 and 2007. A review of the English-language literature for previously published cases, as well as current genetic research findings, was also performed. Thirty-two pediatric patients with congenital heart disease (CHD) and EVC syndrome were identified in the PCCC database. Twenty-eight (88%) had an endocardial cushion defect, with 15 of these having primary failure of atrial septation resulting in CA. Persistent left superior vena cava (LSVC) and pulmonary venous connection abnormalities were common. The incidence of persistent LSVC and pulmonary venous abnormalities were greater than previously reported for patients with EVC. Our study reviews the reported literature and adds 32 additional cases from the PCCC database. Review of the cardiac phenotype in patients with EVC syndrome reveals a characteristic pattern of atrioventricular canal defects with systemic and pulmonary venous abnormalities. The frequent association of these abnormalities is strongly reminiscent of the cardiac phenotype found in patients with heterotaxy syndromes. Emerging molecular and developmental studies suggest that EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. It is speculated that coordinate function between the EVC proteins is required for a cilia-dependent cardiac morphogenesis.


Variability and Predictors of Response to Continuous Theta Burst Stimulation: A TMS-EEG Study.
Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG.


meta-Substituted benzenesulfonamide: a potent scaffold for the development of metallo-β-lactamase ImiS inhibitors.
Metallo-β-lactamase (MβL) ImiS contributes to the emergence of carbapenem resistance. A potent scaffold, meta-substituted benzenesulfonamide, was constructed and assayed against MβLs. The twenty-one obtained molecules specifically inhibited ImiS (IC50 = 0.11-9.3 μM); 2g was found to be the best inhibitor (IC50 = 0.11 μM), and 1g and 2g exhibited partially mixed inhibition with K i of 8.0 and 0.55 μM. The analysis of the structure-activity relationship revealed that the meta-substitutes improved the inhibitory activity of the inhibitors. Isothermal titration calorimetry (ITC) assays showed that 2g reversibly inhibited ImiS. The benzenesulfonamides exhibited synergistic antibacterial effects against E. coli BL21 (DE3) cells with ImiS, resulting in a 2-4-fold reduction in the MIC of imipenem and meropenem. Also, mouse experiments showed that 2g had synergistic efficacy with meropenem and significantly reduced the bacterial load in the spleen and liver after a single intraperitoneal dose. Tracing the ImiS in living E. coli cells by RS at a super-resolution level (3D-SIM) showed that the target was initially associated on the surface of the cells, then there was a high density of uniform localization distributed in the cytosol of cells, and it finally accumulated in the formation of inclusion bodies at the cell poles. Docking studies suggested that the sulfonamide group acted as a zinc-binding group to coordinate with Zn(ii) and the residual amino acid within the CphA active center, tightly anchoring the inhibitor at the active site. This study provides a highly promising scaffold for the development of inhibitors of ImiS, even the B2 subclasses of MβLs.


Direct in vivo evidence of activated macrophages in human osteoarthritis.
Through binding to folate receptor-β (FR-β), the new (99m)Tc-EC20 (Etarfolatide) imaging technique detects activated but not resting macrophages in vivo. The goal of this study was to investigate macrophage-related inflammation in osteoarthritis (OA). Twenty-five individuals (50 knees) with symptomatic OA of at least one knee underwent SPECT-CT imaging of both knees and planar imaging of the whole body after injection of Etarfolatide. Scans and knee radiographs were scored blinded to clinical information including knee and other joint site pain severity. Measures of association controlled for age, gender, body mass index (BMI) and employed repeated measures to adjust for correlation between knees. Activated macrophages were present in the majority (76%) of knees. The quantity of knee-related macrophages was significantly associated with knee pain severity (R = 0.60, P < 0.0001) and radiographic knee OA severity including joint space narrowing (R = 0.68, P = 0.007), and osteophyte (R = 0.66, P = 0.001). Macrophages were also localized to joints commonly affected by OA including hand finger joints (12%), thumb bases (28%), shoulders (26%), great toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists, ankles and great toes was significantly positively associated with presence of activated macrophages at these sites (P < 0.0001-0.04). This study provides the first direct in vivo evidence for macrophage involvement in OA in a substantial proportion of human knees. The association of quantity of activated macrophages with radiographic knee OA severity and joint symptoms suggests that drugs targeting macrophages and macrophage-associated inflammatory pathways may have the potential to be both symptom and structure modifying.


[Risk factors in cerebrovascular disease and their prognostic importance].
The prevalence of cerebrovascular disease risk factors and their immediate mortality prognostic value together with the initial analytical parameters are evaluated. 250 cases of cerebral infarction (CI), 150 cases of intracerebral hemorrhage (ICH) and 60 cases of transitory ischemic events (TIE) were studied and compared to a control group. A higher prevalence of arterial hypertension, cardiopathy, previous cerebrovascular disease and elevated hematocrit was found in the CI group. In the TIE group there was an increased prevalence of cardiopathy, previous cerebrovascular disease and high hematocrit. In the ICH group an increased prevalence of hypertension and left ventricular hypertrophy was found. We have to point out the importance of a global approach of the risk factors. The intrahospital mortality due to CI was associated with old age, low hematocrit, leukocytosis and high blood sugar at admission. ICH was associated with a higher systolic arterial pressure leukocytosis and elevated blood glucose at admission.


Wisconsin's BadgerCare Plus reform: impact on low-income families' enrollment and retention in public coverage.
To examine the impact of a Wisconsin health care reform enacted in early 2008 on public insurance enrollment and retention. Administrative data covering the period January 2007 to November 2009. We calculate unadjusted enrollment trends and exit rates stratified by age, income group, and enrollment mode. Kaplan-Meier curves and Cox proportional hazards models are estimated to assess the impact of the reform on program exits. Overall enrollment increased by approximately one-third and exit rates decreased by approximately one-fifth. The majority of new enrollment came from the previously income eligible. Wisconsin's enactment of eligibility expansions coupled with administrative simplification and targeted marketing and outreach efforts were successful in enrolling and retaining low-income children and families in public coverage.


A computer assisted method for nuclear cataract grading from slit-lamp images using ranking.
In clinical diagnosis, a grade indicating the severity of nuclear cataract is often manually assigned by a trained ophthalmologist to a patient after comparing the lens' opacity severity in his/her slit-lamp images with a set of standard photos. This grading scheme is often subjective and time-consuming. In this paper, a novel computer-aided diagnosis method via ranking is proposed to facilitate nuclear cataract grading following conventional clinical decision-making process. The grade of nuclear cataract in a slit-lamp image is predicted using its neighboring labeled images in a ranked image list, which is achieved using a learned ranking function. This ranking function is learned via direct optimization on a newly proposed approximation to a ranking evaluation measure. Our proposed method has been evaluated by a large dataset composed of 1000 different cases, which are collected from an ongoing clinical population-based study. Both experimental results and comparison with several existing methods demonstrate the benefit of grading via ranking by our proposed method.


Pearls from an inpatient headache unit.
Much can be learned from treating over 15,000 headache hospitalized patients over the course of 30 years. By the very need to be admitted, these individuals are complicated, both physiologically and often psychologically. Founded in 1978, the Michigan Head Pain and Neurological Institute and its hospital unit developed a set of criteria for admission and a growing staff of professionals to serve this complex population of patients. Experience has taught us many lessons; several are considered in this review. Among the important topics discussed are: admission criteria to the hospital unit; treatment protocols and other hospital-based strategies; integration of behavioral therapy and therapists into the treatment system; diagnostic testing of patients with intractable headache; identifying the "problem patient" and "medication misuse" early in the course of therapy; approaching the headache patient with cluster B personality disorder; and the use of interventional and anesthesiological treatment for intractable headache. Outcome data and a review of recent publications are presented.


Confined NaAlH4 nanoparticles inside CeO2 hollow nanotubes towards enhanced hydrogen storage.
NaAlH4 has been widely regarded as a potential hydrogen storage material due to its favorable thermodynamics and high energy density. The high activation energy barrier and high dehydrogenation temperature, however, significantly hinder its practical application. In this paper, CeO2 hollow nanotubes (HNTs) prepared by a simple electrospinning technique are adopted as functional scaffolds to support NaAlH4 nanoparticles (NPs) towards advanced hydrogen storage performance. The nanoconfined NaAlH4 inside CeO2 HNTs, synthesized via the infiltration of molten NaAlH4 into the CeO2 HNTs under high hydrogen pressure, exhibited significantly improved dehydrogenation properties compared with both bulk and ball-milled CeO2 HNTs-catalyzed NaAlH4. The onset dehydrogenation temperature of the NaAlH4@CeO2 composite was reduced to below 100 °C, with only one main dehydrogenation peak appearing at 130 °C, which is 120 °C and 50 °C lower than for its bulk counterpart and for the ball-milled CeO2 HNTs-catalyzed NaAlH4, respectively. Moreover, ∼5.09 wt% hydrogen could be released within 30 min at 180 °C, while only 1.6 wt% hydrogen was desorbed from the ball-milled NaAlH4 under the same conditions. This significant improvement is mainly attributed to the synergistic effects contributed by the CeO2 HNTs, which could act as not only a structural scaffold to fabricate and confine the NaAlH4 NPs, but also as an effective catalyst to enhance the hydrogen storage performance of NaAlH4.


The effect of centrophenoxine at the skeletal neuromuscular junction.
Centrophenoxine exhibited some interesting actions at the neuromuscular junction. The drug was ineffective in rat or chick preparations, but blocked neuromuscular transmission in frog preparations. The blockade was reversed by adrenaline, potassium, choline and physostigmine. The drug had no effect on muscle contractility or endplate cholinoceptor. Hemicholinium 3 induced a neuromuscular blockade in rat (in vivo) which was reversed by choline but not by centrophenoxine. Neither of these two drugs could reverse the blocking effect of hemicholinium in frog preparations. It is concluded that centrophenoxine acts only in frog and the blockade involves a presynaptic mechanism. The work further suggests that choline uptake systems in the rat and the frog may not be identical, since choline competed with hemicholinium for the uptake system in rat and with centrophenoxine (but not with hemicholinium) in the frog.


Optimization of submerged fermentation conditions for lovastatin production by the culinary-medicinal oyster mushroom, Pleurotus ostreatus (Higher Basidiomycetes).
Statistical experimental designs were used to optimize lovastatin production by culinary-medicinal oyster mushroom Pleurotus ostreatus OBCC 1031 under submerged fermentation. The Plackett-Burman design was used to determine effective culture parameters, glucose, lactose, maltose, glycerol, peptone, yeast extract, NH4SO2, NaCl, thiamine, and agitation speed. Statistical analyses of data from the Plackett-Burman design show that glucose, yeast extract, and agitation speed are significant parameters. The interactive effects of these culture parameters on lovastatin production by P. ostreatus OBCC 1031 were further studied by a Box-Behnken design. Maximum lovastatin production (114.82 mg/L) was reached after 6 days of fermentation in optimized culture conditions (30 g/L glucose, 10 g/L yeast extract, 200 rpm, 28°C, and pH 6). This amount was found to be 50 times higher than that produced under unoptimized conditions in submerged fermentation by P. ostreatus.


[Structure of the lipopolysaccharide/human plasma low density lipoprotein complex. 31P-NMR and fluorescence spectroscopy studies].
Complexes of Salmonella typhimurium lipopolysaccharide toxin (LPS) with low density lipoproteins (LDL) containing various amounts of LPS were prepared in vitro. The 31P-NMR spectra showed that in the LDL-LPS complexes as well as in native LDL all phosphate groups of phospholipids are accessible to the paramagnetic shift reagent, Pr3+. Besides, the low frequency mobility of phospholipid phosphates in the complex is diminished. It was supposed that the phospholipid molecules in the LDL/LPS complex as in native LDL form a monolayer structure on the surface of LDL. The intrinsic fluorescence spectra of tryptophan residues of the apoprotein (apo B-100) revealed that the incorporation of LPS molecules into LDL particles is accompanied by minor changes in the conformation and orientation of the apo B molecule. As a result of these changes, certain fragments become exposed to a more hydrophilic environment and become more accessible to fluorescence quenchers. The use of charged (I-, Cs+) and uncharged (acrylamide) quenchers permitted to identify in the apo B molecule different tryptophan residues, some of which are localized in the vicinity of negatively charged groups, whereas others are neighbouring positively charged groups. It is suggested that the LPS molecules incorporated into LDL particle do not screen the apo B molecule to such an extent that it would hinder the LDL/LPS complex binding to apo B/E cellular receptors.


Strain engineering effects on electrical properties of lead-free piezoelectric thin films on Si wafers.
Using radio frequency - magnetron sputtering, calcium-doped barium zirconate titanate ((Ba(0.85)Ca(0.15))(Zr(0.1)Ti(0.9))O(3), BCZT) thin films were deposited on Si wafers with different bottom electrodes. The obtained BCZT thin film on a lanthanum nickel oxide (LNO) electrode had a highly c-axis preferred orientation, while the BCZT thin film on a Pt bottom electrode had (111) preferred orientation. Furthermore, the out-of-plane lattice constant of the BCZT on LNO/Si was 3.4% larger than that of the reported bulk material because of the compressive thermal stress from LNO with a large thermal expansion coefficient. This compressive thermal stress engenders an increase of the Curie temperature. The local piezoelectric response of the BCZT thin film on a LNO/Si structure was measured by piezoresponse force microscope.


Relaxation of non-equilibrium entanglement networks in thin polymer films.
It is known that polymer films, prepared by spin coating, inherit non-equilibrium configurations which can affect macroscopic film properties. Here we present the results of crazing experiments that support this claim; our measurements indicate that the as-cast chain configurations are strongly stretched as compared to equilibrium Gaussian configurations. The results of our experiments also demonstrate that the entanglement network equilibrates on a time scale comparable to one reptation time. Having established that films can be prepared with an equilibrium entanglement network, we proceed by confining polymers to films in which the thickness is comparable to the molecular size. By stacking two such films, a bilayer is created with a buried entropic interface. Such an interface has no enthalpic cost, only an entropic penalty associated with the restricted configurations of molecules that cannot cross the mid-plane of the bilayer. In the melt, the entropic interface heals as chains from the two layers mix and entangle with one another; crazing measurements allow us to probe the dynamics of two films becoming one. Healing of the entropic interface is found to take less than one bulk reptation time.


Effects of ouabain and furosemide on transepithelial electrical parameters of the isolated shark ciliary epithelium.
Sections of the ciliary epithelium of adult sharks (Squalus acanthias) were mounted in Ussing-type chambers (area 0.2 cm2) for measurements of transepithelial potential difference (PD), short circuit current (SCC) and calculation of transepithelial resistance (R). In 15 preparations PD was aqueous side negative (-0.51 +/- 0.12 mV; SCC 18.3 +/- 2.5 microA cm-2; R 30.7 +/- 3.1 Ohm cm2). However, in 15 other preparations incubated in identical Ringer's solution PD was aqueous side positive (0.53 +/- 0.09 mV; SCC -19.6 +/- 2.3 microA cm-2; R 27.9 +/- 2.8 Ohm cm2). 10(-5) M ouabain or 10(-4) M furosemide were applied either to the aqueous or blood side of the isolated ciliary epithelium at transepithelial negative or positive PD. When the transepithelial PD was positive on the aqueous side ouabain decreased PD and SCC within 15 to 45 min. When the spontaneous PD was negative both PD and SCC decreased when ouabain was applied to the blood side. When the drug was given to the aqueous side a biphasic response (first stimulation, then inhibition) of PD and SCC was observed. Furosemide when given to the blood side (with aqueous side PD positive) or to the aqueous side (with aqueous side PD negative) decreased PD and SCC. However, a transient stimulation of both electrical parameters was observed when furosemide was applied to either the blood side (with aqueous side PD negative) or to the aqueous side (with aqueous side PD positive). The polarity and magnitude of PD and SCC probably depend on the relative activity of sodium and chloride pumps across the cell membranes of the non-pigmented and/or pigmented cell layer. However, additional transport mechanisms cannot be excluded.


Risk factors associated with the onset and progression of posttransplantation diabetes in renal allograft recipients.
The aim of this study was to assess the incidence of posttransplantation diabetes mellitus (PTDM) in renal allograft recipients and to investigate factors contributing to the onset and progression of PTDM and its underlying pathogenic mechanism(s). A total of 77 patients with normal glucose tolerance (NGT) were enrolled in this study. An oral glucose tolerance test was performed 1 week before transplantation and repeated at 1 and 7 years after transplantation. The overall incidence of PTDM was 39% at 1 year and 35.1% at 7 years posttransplantation. The incidence for each category of PTDM was as follows: persistent PTDM (P-PTDM) (patients who developed diabetes mellitus within 1 year of transplantation and remained diabetic during 7 years), 23.4%; transient PTDM (T-PTDM) (patients who developed diabetes mellitus during the 1st year after transplantation but eventually recovered to have NGT), 15.6%; late PTDM (L-PTDM) (patients who developed diabetes mellitus later than 1 year after transplantation), 11.7%; and non-PTDM during 7 years (N-PTDM7) (patients who did not develop diabetes mellitus during 7 years), 49.3%. Older age (> or = 40 years) at transplantation was a higher risk factor for P-PTDM, whereas a high BMI (> or = 25 kg/m2) and impaired fasting glucose (IFG) at 1 year posttransplantation were higher risk factors for L-PTDM. Impaired insulin secretion rather than insulin resistance was significantly associated with the development of P- and L-PTDM. Impaired insulin secretion may be the main mechanism for the development of PTDM. Older age at transplantation seems to be associated with P-PTDM, whereas a high BMI and IFG at 1 year after transplantation were associated with L-PTDM.


Crystal structure at 1.8 A resolution and identification of active site residues of Sulfolobus solfataricus peptidyl-tRNA hydrolase.
The 3-D structure of the peptidyl-tRNA hydrolase from the archaea Sulfolobus solfataricus has been solved at 1.8 A resolution. Homologues of this enzyme are found in archaea and eucarya. Bacteria display a different type of peptidyl-tRNA hydrolase that is also encountered in eucarya. In solution, the S. solfataricus hydrolase behaves as a dimer. In agreement, the crystalline structure of this enzyme indicates the formation of a dimer. Each protomer is made of a mixed five-stranded beta-sheet surrounded by two groups of two alpha-helices. The dimer interface is mainly formed by van der Waals interactions between hydrophobic residues belonging to the two N-terminal alpha1 helices contributed by two protomers. Site-directed mutagenesis experiments were designed for probing the basis of specificity of the archaeal hydrolase. Among the strictly conserved residues within the archaeal/eucaryal peptidyl-tRNA hydrolase family, three residues, K18, D86, and T90, appear of utmost importance for activity. They are located in the N-part of alpha1 and in the beta3-beta4 loop. K18 and D86, which form a salt bridge, might play a role in the catalysis thanks to their acid and basic functions, whereas the OH group of T90 could act as a nucleophile. These observations clearly distinguish the active site of the archaeal/eucaryal hydrolases from that of the bacterial/eucaryal ones, where a histidine is believed to serve as the catalytic base.


Effects of (-)-epicatechin on hepatic triglyceride metabolism.
(-)-Epicatechin (EC) consumption is associated with an improvement of hyperlipemia and other metabolic changes linked to obesity and western-style diets. This work investigated the effects of EC on triglyceride (TG) metabolism both in vivo, where mice were supplemented with EC (2 and 20 mg EC per kg body weight), and in vitro, when human HepG2 hepatocytes were incubated in the presence of EC and the main EC metabolites found in human plasma. Increased hepatic TG levels were only observed after 24 weeks supplementation with EC (20 mg per kg body weight), with a preserved liver structure and absence of inflammation or oxidative stress. EC caused increased expression of diacylglycerol acyltransferases (DGAT2), key enzymes in TG synthesis, and the upregulation of PPARα, which promotes free fatty acid (FFA) oxidation. On the other hand, incubation of HepG2 cells in the presence of high concentrations of EC (1-10 μM) did not affect TG deposition nor DGAT2 expression. In summary, in mouse liver, EC upregulated mechanisms that can neutralize the potential toxicity of FFA, i.e. TG synthesis and FFA β-oxidation. Results in mouse liver and HepG2 cells stress the safety of EC in terms of TG metabolism and development of hepatopathies in doses within the limits given by a rational time and dose for human consumption.


Long-term outcome of hepatitis C infection after bone marrow transplantation.
Chronic hepatitis C is often asymptomatic, at least during the first decade following hematopoietic stem cell transplantation. Progression to advanced liver disease or cirrhosis in patients surviving more than 10 years is currently thought to be rare. Among 1078 patients who underwent an allogeneic transplantation between January 1973 and January 1995, 96 patients infected by hepatitis C virus (HCV) during the transplantation period were studied. Cumulative incidence and analysis of risk factors for cirrhosis were analyzed, and the rate and risk of cirrhosis in transplant recipients were compared with those of 158 HCV-infected controls who did not receive transplants. At a median follow-up of 15.7 years, 15 patients developed biopsy-proven cirrhosis, leading to a cumulative incidence of cirrhosis of 11% and 24% at 15 and 20 years, respectively. By multivariate analysis, extrahepatic HCV manifestations and HCV genotype 3 were associated with risk of cirrhosis. The median time to cirrhosis in transplant recipients was 18 years as compared with 40 years in the control population. The risk of cirrhosis in transplant recipients relative to controls was significantly higher by multivariate analysis (P =.0008). Roughly a quarter of long-term HCV-infected survivors with transplants progressed to cirrhosis that is much more rapid than in patients without transplants. Systematic detection of HCV infection, liver biopsy, and therapeutic intervention are therefore warranted in long-term marrow transplant recipients.


Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.
We investigated the expression of the proinflammatory cytokine interleukin (IL)-17 in cardiac fibroblasts and its induction by high glucose (HG). Our results show that primary mouse cardiac fibroblasts (mCFs) secrete low basal levels of IL-17 and that HG (25 mM D-glucose) as opposed to low glucose (5 mM D-glucose + 20 mM mannitol) significantly enhances its secretion. HG induces IL-17 mRNA expression by both transcriptional and posttranscriptional mechanisms. HG induces phosphoinositide 3- kinase [PI3K; inhibited by adenoviral (Ad).dominant negative (dn)PI3Kp85], Akt (inhibited by Ad.dnAkt1), and ERK (inhibited by PD-98059) activation and induces IL-17 expression via PI3K-->Akt-->ERK-dependent signaling. Moreover, mCFs express both IL-17 receptors A and C, and although IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stimulates net collagen production by mCFs. Pretreatment with the phytoalexin resveratrol blocks HG-induced PI3K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that 1) cardiac fibroblasts express IL-17 and its receptors; 2) HG upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia; 3) IL-17 enhances net collagen production; and 4) resveratrol can inhibit these HG-induced changes. Thus, in hyperglycemic conditions, IL-17 may potentiate myocardial inflammation, injury, and remodeling through autocrine and paracrine mechanisms, and resveratrol has therapeutic potential in ameliorating this effect.


Use of a sheathless 8-French balloon guide catheter (Walrus) through the radial artery for mechanical thrombectomy: technique and case series.
The effectiveness of transradial stroke thrombectomy has been limited by guide catheter size and lack of good balloon options. In this study we describe our technique for the use of a sheathless 8-French balloon guide catheter (Walrus) through radial access and present our initial clinical experience. This was a retrospective case series of consecutive patients who underwent mechanical thrombectomy for large vessel occlusion using the sheathless catheter over a period of 3 months. Clinical characteristics, procedural details, reperfusion success (modified Thrombolysis in Cerebral Infarction (mTICI) 2b-3 grade), first-pass effect (FPE; mTICI reperfusion grade 2c or 3 with a single pass), access site complications and clinical improvement at discharge were recorded. A descriptive analysis was performed. Among the 10 patients in the series, median age was 77 years (IQR 75-79) and three were women. All patients had a baseline modified Rankin Scale score ≤2. Median admission National Institutes of Health Stroke Scale (NIHSS) score was 12.5 (IQR 9-16). Four patients received intravenous alteplase before mechanical thrombectomy. Eight patients had M1 occlusion and two had proximal M2 occlusion. The median radial artery diameter was 2.5 mm (IQR 2.5-2.7). Successful reperfusion was achieved in all patients. FPE was achieved in six patients. No access site-related complications or post-procedural intracranial hemorrhages occurred. All patients had improvement in NIHSS score at discharge. The use of this sheathless catheter for transradial access was safe and feasible. The technique can potentially improve the outcomes of transradial access for stroke intervention.


Effector discovery in the fungal wheat pathogen Zymoseptoria tritici.
Fungal plant pathogens, such as Zymoseptoria tritici (formerly known as Mycosphaerella graminicola), secrete repertoires of effectors to facilitate infection or trigger host defence mechanisms. The discovery and functional characterization of effectors provides valuable knowledge that can contribute to the design of new and effective disease management strategies. Here, we combined bioinformatics approaches with expression profiling during pathogenesis to identify candidate effectors of Z. tritici. In addition, a genetic approach was conducted to map quantitative trait loci (QTLs) carrying putative effectors, enabling the validation of both complementary strategies for effector discovery. In planta expression profiling revealed that candidate effectors were up-regulated in successive waves corresponding to consecutive stages of pathogenesis, contrary to candidates identified by QTL mapping that were, overall, expressed at low levels. Functional analyses of two top candidate effectors (SSP15 and SSP18) showed their dispensability for Z. tritici pathogenesis. These analyses reveal that generally adopted criteria, such as protein size, cysteine residues and expression during pathogenesis, may preclude an unbiased effector discovery. Indeed, genetic mapping of genomic regions involved in specificity render alternative effector candidates that do not match the aforementioned criteria, but should nevertheless be considered as promising new leads for effectors that are crucial for the Z. tritici-wheat pathosystem.


Development of a novel COMPAssion focused online psyChoTherapy for bereaved informal caregivers: the COMPACT feasibility trial protocol.
An easy-to-access and effective psychotherapy for bereaved informal caregivers has not been established. People with higher self-compassion status tend to have lower bereavement related grief, psychotherapy focused on self-compassion can be promising for this population. This study aimed to examine the feasibility of online self-compassion focused psychotherapy for bereaved informal caregivers. A total of 60 study participants will undergo an intervention programme comprising online sessions of 2 hours per week for five consecutive weeks and undertake postsession work. The intervention personnel will comprise psychologists who have received more than 10 hours of structured training. The primary endpoint will be assessed on the intervention completion rate, with secondary endpoints consisting of the Complicated Grief Questionnaire, Patient Health Questionnaire-9, Generalised Anxiety Disorder-7, Brief Resilience Scale and Self-Compassion Scale. Evaluations will be conducted preintervention, immediately after intervention, and 4 and 12 weeks after intervention. This study has been reviewed and approved by the Ethics Committee of the Kyoto University Graduate School and Faculty of Medicine, Kyoto University Hospital, Japan (Approved ID: C1565). The results of this study will be disseminated through publication in a peer-reviewed journal and conference presentations. UMIN000048554.


Tissue characterization by quantitative optical imaging methods.
Optical methods have a long history in the field of medical diagnosis. The biomolecular specificity possible with optical methods has been particularly valuable in microscopy and histopathology while in vivo imaging of deep structures has traditionally been the domain of X-ray and MRI. The use of optical methods in deep tissue has been limited by multiple-scattering which blurs or distorts the optical signal. New stochastic methods which account for multiple scattering have been developed that are extending the usefulness of optical methods deep into tissue. In optical mammography, photons may travel through 10 cm of tissue before arriving at the detector. We have developed a method for quantifying parameters of anomalous sites in breast tissue that may be used for functional characterization of tumors. In other work presented here, we are developing fluorescence based methods to detect and monitor tumor status. The immune response to a tumor is a target for fluorescently labeled specific antibodies. We have developed a method to localize the tumor site using CW fluorescence. Additionally, we have developed a method which uses time-resolved data and capitalizes on probe lifetime sensitivity to metabolic parameters such as pH and temperature to obtain functional information from the tumor site.


Cystic fibrosis and beta-adrenergic response of airway epithelial cell cultures.
Confluent cell sheets were cultured from the tracheal epithelium of normal humans or from tracheal and nasal epithelia of patients with cystic fibrosis (CF). Changes in short-circuit current (Isc) or cyclic AMP (cAMP) levels in response to 10(-5) M isoproterenol were measured. In CF tracheal cells the response to isoproterenol was transient, and the maximal increase in Isc was one-tenth normal. In CF nasal cells, isoproterenol or epinephrine caused only small transient increases in Isc. However, in both CF nasal and tracheal cells, the Ca ionophore, A23187, caused relatively large increases in Isc that were inhibited by the Cl transport blocker, bumetanide, suggesting that Cl secretion can be induced by raising intracellular levels of Ca. In normal tracheal cell sheets, cAMP levels increased within 15 s of isoproterenol addition and continued to increase for up to 20 min. Resting levels of cAMP in CF tracheal cells were not statistically different from those of normal cells and showed linear increases for up to 4 min after addition of isoproterenol. Changes in cAMP in CF nasal cells were similar to the changes in CF tracheal cells. After 2 min, all three cell types showed cAMP levels elevated approximately equal to 10-fold. These results suggest that receptor-activated stimulation of adenylate cyclase is normal in CF. However, though raised cAMP levels stimulate Cl secretion in normal, they are unable to do so in CF airway epithelial cells.


Induction therapy for locally advanced distal esophageal adenocarcinoma: Is radiation Always necessary?
To compare outcomes between induction chemotherapy alone (ICA) and induction chemoradiation (ICR) in patients with locally advanced distal esophageal adenocarcinoma. Patients in the National Cancer Database treated with ICA or ICR followed by esophagectomy between 2006 and 2012 for cT1-3N1M0 or T3N0M0 adenocarcinoma of the distal esophagus were compared using logistic regression, Kaplan-Meier analysis, and Cox proportional hazards methods. The study group included 4763 patients, of whom 4323 patients (90.8%) received ICR and 440 patients (9.2%) received ICA. There were no differences in age, sex, race, Charlson Comorbidity Index, treatment facility type, clinical T or N status between the 2 groups. Tumor size ≥5 cm (odds ratio, 1.46; P = .006) was the only factor that predicted ICR use. Higher rates of T downstaging (39.7% vs 33.4%; P = .012), N downstaging (32.0% vs 23.4%; P < .001), and complete pathologic response (13.1% vs 5.9%; P < .001) occurred in ICR patients. Positive margins were seen more often in ICA patients (9.6% vs 5.5%; P = .001), but there was no difference in 5-year survival (ICR 35.9% vs ICA 37.2%; P = .33), and ICR was not associated with survival in multivariable analysis (hazard ratio = 1.04; P = .61). ICR for locally advanced distal esophageal adenocarcinoma is associated with a better local treatment effect, but not improved survival compared with ICA, which suggests that radiation can be used selectively in this clinical situation.


Genetic manipulation of polyphosphate metabolism affects cadmium tolerance in Escherichia coli.
The polyphosphate metabolic pathways in Escherichia coli were genetically manipulated to test the effect of polyphosphate on tolerance to cadmium. A polyphosphate kinase (ppk) and polyphosphatase (ppx) mutant strain produced no polyphosphate, whereas the same strain carrying multiple copies of ppk on a high-copy plasmid produced significant quantities. The doubling times of both strains increased with increasing cadmium concentrations. In contrast, the mutant strain carrying multiple copies of ppk and ppx produced 1/20 of the polyphosphate found in the strain carrying multiple copies of ppk only and showed no significant increase in doubling time over the same cadmium concentration range.


CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia.
Aplastic anemia (AA) is a disease characterized by T-cell-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells. Physiologically, T cells migrate to the BM in response to chemokines, such as SDF-1α, the ligand for CXCR4. However, how T cells traffic to the BM in AA is poorly understood. CXCR4 is aberrantly expressed in immune-mediated diseases and its regulation by nuclear factor-κB (NF-κB) in cancer models is well documented. In this study, we show that CXCR4 is highly expressed on BM-infiltrating CD4(+) and CD8(+) T cells in a mouse model of AA. Inhibiting CXCR4 in AA mice, using CXCR4(-/-) splenocytes or AMD3100, significantly reduced BM infiltration of T cells. We also report that NF-κB occupancy at the CXCR4 promoter is enhanced in BM-infiltrating CD8(+) T cells of AA mice. Moreover, inhibiting NF-κB signaling in AA mice using Bay11 or dehydroxymethylepoxyquinomicin, or transferring p50(-/-) splenocytes, decreased CXCR4 expression on CD8(+) T cells, significantly reduced BM infiltration of T cells, and strongly attenuated disease symptoms. Remarkably, therapeutic administration of Bay11 significantly extended survival of AA mice. Overall, we demonstrate that CXCR4 mediates migration of pathogenic T cells to the BM in AA mice, and inhibiting NF-κB signaling may represent a novel therapeutic approach to treating AA.


The gingipains from Porphyromonas gingivalis do not directly induce osteoclast differentiation in primary mouse bone marrow cultures.
Porphyromonas gingivalis is a major aetiological agent in the development of periodontitis, the major clinical hallmark of which is bone resorption. The cysteine proteases (gingipains) produced by P. gingivalis have a critical role in the pathogenesis of the disease, and previous studies on whole bacteria have implicated these enzymes in osteoclastogenesis, a process which serves to upregulate bone resorption. The effects of the gingipains from P. gingivalis on osteoclast differentiation were investigated here to determine whether the enzymes directly contribute to osteoclastogenesis and thus to bone resorption. The effects of the gingipains on osteoclast differentiation were investigated in primary mouse bone marrow cultures. The cultures harvested from C57BL6/J mice were incubated in the presence of parathyroid hormone, a known osteoclastogenic factor, or active/inactivated forms of three gingipains. Osteoclast differentiation was quantified by counting the number of multinucleated cells positive for tartrate-resistant acid phosphatase, an enzyme marker for these cells. After 10 days of culture, the gingipains, either active or inactive, failed to stimulate osteoclast differentiation in comparison to the parathyroid hormone. The data presented here demonstrate that the gingipains do not induce osteoclast differentiation in this system, indicating that the bacterium uses other mechanisms to induce bone loss.


"Virtual Surf Booth": Assessment of a Novel Tool and Data Collection Process to Measure the Impact of a 6-Week Surf Programme on Mental Wellbeing.
Surf therapy is increasingly used as a health intervention, but evidence of its mental health benefits remains unclear. This longitudinal mixed-method study assessed the usability and acceptability of a novel online data collection tool and process to measure the impact of a surf programme on acute and chronic mental wellbeing. Fifteen women attending a 6-week surf programme in the UK were asked to complete a tool consisting of video recordings, word association and the Short Warwick-Edinburgh Mental Well-Being scale (SWEMWBS). Usability and acceptability were assessed through focus groups and quantitative data. The data generated in the focus groups, video recordings and word association were analysed via reflexive thematic analysis, and SWEMWBS presented descriptively. Participants perceived the tool as easy to use due to the completion time and its functionalities, and useful for self-reflection. Facilitating conditions such as timing and location, areas for improvement such as increased privacy, accessibility, incentivisation, and factors impacting data generated were further identified. Data collected covered both acute and chronic mental wellbeing and showed a positive relationship between surf and mental wellbeing. Further research is needed to confirm these findings in diverse populations, identify potential moderators, and confirm the validity of this tool and process.


One decade of self exclusion: Missouri casino self-excluders four to ten years after enrollment.
For more than a decade, casinos around the world have offered self-exclusion programs (SEPs) to gamblers seeking help with their gambling behavior. Despite the proliferation of SEPs, little is known about the long-term outcomes for gamblers who utilize these programs. The current study assessed the experiences of a sample (N = 113) of Missouri self-excluders (SEs) for as long as 10 years after their initial enrollment in the Missouri Voluntary Exclusion Program (MVEP). Most SEs had positive experiences with MVEP and reduced their gambling and gambling problems after enrollment. However, 50% of SEs who attempted to trespass at Missouri casinos after enrollment were able to, indicating that the benefit of MVEP was attributable more to the act of enrollment than enforcement. SEs who engaged in complementary treatment or self-help groups had more positive outcomes than those who did not, suggesting that SEPs ought to encourage and provide information about additional support and treatment options to participants.


Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1β. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10-inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI.


Serodiagnosis of Porphyromonas gingivalis infection by immunoblot analysis with recombinant collagenase.
The Porphyromonas gingivalis collagenase-specific serum immunoglobulin A (IgA), IgM, and IgG responses from 20 patients with early-onset periodontitis (EOP), 20 patients with adult periodontitis, (AP), and 20 age- and sex-matched healthy controls were examined by immunoblot analysis. A recombinant collagenase antigen used for the immunoblot analysis was produced by using the plasmid pGEX-2T, which allows the fusion between the collagenase and glutathione S-transferase. There was no significant difference in collagenase-specific IgG antibody detection between samples from the EOP, AP, and control groups. In contrast, 85% of AP and EOP sera had collagenase-specific IgA antibodies, whereas only 20% of control sera showed collagenase-specific IgA reactivity. Plaque samples from all groups were assessed by PCR with primers complementary to the collagenase-encoding gene prtC. The results indicated that 90% of AP and EOP plaque samples and 10% of control samples were positive for P. gingivalis. All patients with collagenase-specific IgA antibodies were PCR positive. The results of the study indicate a nearly complete concordance (k = 0.856) between the presence of collagenase-specific IgA antibodies and PCR detection of P. gingivalis. By using PCR as the "gold standard," the sensitivity and specificity of the IgA immunoblot test were 94.7 and 90.9%, respectively. Therefore, the recombinant collagenase is a potential candidate for use in the serodiagnosis of periodontitis.


Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep.
Neurons in the ventrolateral preoptic nucleus (VLPO) in rats show c-fos activation after sleep and provide GABAergic innervation of the major monoamine arousal systems, suggesting that they may be a necessary part of the brain circuitry that produces sleep. We examined the effects on sleep behavior in rats of cell-specific damage to the VLPO by microinjection of ibotenic acid. Severe lesions of the central cell cluster of the VLPO ( approximately 80-90% cell loss bilaterally) caused a 60-70% decrease in delta power and a 50-60% decrease in nonrapid-eye-movement (NREM) sleep time (p < 0.001). The number of remaining Fos-immunoreactive neurons in the VLPO cell cluster was linearly related to NREM sleep time (r = 0.77; p < 0.001) and total electroencephalogram delta power (r = 0. 79; p < 0.001) but not to rapid-eye-movement (REM) sleep (r = 0.35; p > 0.10). Lesions in the region containing scattered VLPO neurons medial or dorsal to the cell cluster caused smaller changes in NREM sleep time (24.5 or 15%, respectively) but were more closely associated with loss of REM sleep (r = 0.74; p < 0.01). The insomnia caused by bilateral VLPO lesions persisted for at least 3 weeks. Lesions of the VLPO caused no change in mean body temperature or its circadian variation; after small lesions of the ventromedial preoptic nucleus, body temperature showed normal circadian variation but a wider temperature range, and sleep behavior was not affected. These experiments delineate distinct preoptic sites with primary effects on the regulation of NREM sleep, REM sleep, and body temperature.


Preclinical validation of the micropipette-guided drug administration (MDA) method in the maternal immune activation model of neurodevelopmental disorders.
Pharmacological treatments in laboratory rodents remain a cornerstone of preclinical psychopharmacological research and drug development. There are numerous ways in which acute or chronic pharmacological treatments can be implemented, with each method having certain advantages and drawbacks. Here, we describe and validate a novel treatment method in mice, which we refer to as the micropipette-guided drug administration (MDA) procedure. This administration method is based on a sweetened condensed milk solution as a vehicle for pharmacological substances, which motivates the animals to consume vehicle and/or drug solutions voluntarily in the presence of the experimenter. In a proof-of-concept study, we show that the pharmacokinetic profiles of the atypical antipsychotic drug, risperidone, were similar whether administered via the MDA procedure or via the conventional oral gavage method. Unlike the latter, however, MDA did not induce the stress hormone, corticosterone. Furthermore, we assessed the suitability and validity of the MDA method in a mouse model of maternal immune activation, which is frequently used as a model of immune-mediated neurodevelopmental disorders. Using this model, we found that chronic treatment (>4 weeks, once per day) with risperidone via MDA led to a dose-dependent mitigation of MIA-induced social interaction deficits and amphetamine hypersensitivity. Taken together, the MDA procedure described herein represents a novel pharmacological administration method for per os treatments in mice that is easy to implement, cost effective, non-invasive, and less stressful for the animals than conventional oral gavage methods.


Histopathological analysis of corticosteroid-antibiotic preparation and propolis paste formulation as intracanal medication after pulpectomy: an in vivo study.
Intracanal medication in pulpectomy therapy is used between appointments with the objective of reducing pain and inflammatory processes in pulp and periapical tissues. Propolis has been known as a natural antibiotic and has been subject of medical and dental research due to its therapeutic properties such as antibiotic, analgesic and anti-inflammatory effects. The aim was to carry out an in vivo evaluation of the periapical tissue response to propolis paste when used as an intracanal medication in the teeth of dogs after pulpectomy. 72 dog's incisors were selected for the experiment. After biomechanical preparation the root canal was filled with a corticosteroid-antibiotic preparation, experimental propolis paste, non-medicament (negative control) or non-pulpectomy at all (positive control). The medications were left inside the root canal for 7, 14 or 28 days. At the end of the experimental period histological sections were prepared and all laboratories processes for Harris hematoxylin and eosin staining was proceeded followed by the analysis using an optical microscope. Sections were classified according to a score representing the inflammatory events observed: the presence of polymorphonuclear neutrophils, polymorphonuclear eosinophils, lymphocytes and plasma cells, macrophages and/or giant cells, fibrous condensation and abscesses. There were statistically significant differences between the tissue reactions caused by the two substances being tested, after different experimental periods, with the periapical tissue that was in contact with propolis paste exhibiting fewer inflammatory reactions in comparison to corticosteroid-antibiotic preparation. The low tissue responses from propolis paste suggest that this material could be considered as an option for root canal medication after pulpectomy.


Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages.
TCR signaling plays a central role in directing developmental fates of thymocytes. Current models suggest TCR signal duration directs CD4 versus CD8 lineage development. To investigate the role of TCR signaling during positive selection directly, we switched signaling off in a cohort of selecting thymocytes and followed, in time, their subsequent fate. We did this using an inducible Zap70 transgenic mouse model that allowed Zap70-dependent signaling to be turned on and then off again. Surprisingly, loss of TCR signaling in CD4(+)CD8(lo) thymocytes did not prevent their development into committed CD4 single positives (SPs), nor their continued maturation to HSA(lo) SPs. However, numbers of CD4 SPs underwent a substantial decline following loss of Zap70 expression, suggesting an essential survival role for the kinase. Termination of TCR signaling is considered an essential step in CD8 lineage development. Loss of Zap70 expression, however, resulted in the rapid death of CD8 lineage precursor thymocytes and a failure to generate CD8 SPs. Significantly, extending the window of Zap70 expression was sufficient for generation and export of both CD4 and CD8 T cells. These data reveal a parallel requirement for TCR-mediated survival signaling, but an asymmetric requirement for TCR-mediated maturation signals.


Flexible Li[Li0.2Ni0.13Co0.13Mn0.54]O2/Carbon Nanotubes/Nanofibrillated Celluloses Composite Electrode for High-Performance Lithium-Ion Battery.
Rapidly-growing demand for wearable and flexible devices is boosting the development of flexible lithium ion batteries (LIBs). The exploitation of flexible electrodes with high mechanical properties and superior electrochemical performances has been a key challenge for the rapid practical application of flexible LIBs. Herein, a flexible composite electrode was prepared from the mixed solutions of Li[Li0.2Ni0.13Co0.13Mn0.54]O2 (LLOs), carbon nanotubes(CNTs), and nanofibrillated celluloses (NFCs) via a vacuum filtration method. The resulting LLOs/CNTs/NFCs electrode delivered an initial discharge capacity of 253 mAh g-1 at 0.1 C in the voltage range from 2.0 to 4.6 V, and retained a reversible capacity of 178 mAh g-1 with 83% capacity retention after 100 cycles at 1 C. The LLOs/CNTs/NFCs electrode exhibited excellent flexibility along with repeated bending in the bending test. The LLOs/CNTs/NFCs electrode after bending test remained a discharge capacity of 149 mAh g-1 after 100 cycles at 1 C, and the corresponding capacity retentions was 76%. The excellent electrochemical performance and high flexibility can be ascribed to the framework formed by CNTs with high conductivity and NFCs with good mechanical properties. The results imply that the as-fabricated electrode can be a promising candidate for the flexible LIBs.


[Cytokines in rheumatoid arthritis].
In this review we have examined the role of a variety cytokines in the pathogenesis of rheumatoid arthritis (RA) and their possible applications in the treatment of this disease. Cytokines are small protein molecules, released by activated cells which function as chemical messengers between cells of the immune, inflammatory and other systems. The studies using isolated cells from RA synovial membranes indicate that the vast majority of known cytokines are found in RA synovial tissue. These include IL-1, TNF alpha, IL-6, IL-8, TGF beta, GM-CSF and others. TNF alpha and IL-1 are important, "pivotal" molecules in the disease process. TNF alpha has been detected in the serum and synovial fluid of patients with RA, suggesting an important contribution of this cytokine to the development of arthritis. Clinically, TNF-alpha has been also associated with markers of rheumatoid disease activity. Rheumatoid synovial tissue synthesizes large amounts of both forms of IL-1 (IL-1 alpha and IL-1 beta) in vitro. IL-1 can exert a variety of systemic effects, including induction of fever and synthesis of acute phase proteins. It also induces local joint effects mediating production of fibroblast fibronectin and tissue collagenase. IL-6 is found in greater quantities in the synovial fluids from patients with RA compared to osteoarthritis. Synovial fluid IL-6 levels correlate with local IgM rheumatoid factor and systemic acute phase protein production. Chemokines, including IL-8, have potent chemotactic activity for cells of the immune system. IL-8 not only participates in the inflammatory phase of RA, but also participates in the vasculoproliferative phase of this disease. Recent data on the cytokine profile in RA implies that alternative treatment strategies should be considered. Potential approaches for modifying the cytokine network include inhibition of cytokine production or their action, inhibition of signal transduction and administration of suppressive cytokines.


Archaeal Sm proteins form heptameric and hexameric complexes: crystal structures of the Sm1 and Sm2 proteins from the hyperthermophile Archaeoglobus fulgidus.
Proteins of largely unknown function related to the Sm proteins present in the core domain of eukaryotic small nuclear ribonucleoprotein particles have recently been detected in Archaea. In contrast to eukaryotes, Archaea contain maximally two distinct Sm-related proteins belonging to different subfamilies, we refer to as Sm1 and Sm2. Here we report the crystal structures of the Sm1- and Sm2-type proteins from the hyperthermophilic euryarchaeon Archaeoglobus fulgidus (AF-Sm1 and AF-Sm2) at a resolution of 2.5 and 1.95 A, respectively. While the AF-Sm1 protein forms a heptameric ring structure similar to that found in other archaeal Sm1-type proteins, the AF-Sm2 protein unexpectedly forms a homo-hexamer in the crystals, and, as is evident from the mass spectrometric analysis, also in solution. Both proteins have essentially the same monomer fold and inter-subunit beta-sheet hydrogen bonding giving rise to a similar overall architecture of the doughnut-shaped six and seven-membered rings. In addition, a conserved uracil-binding pocket identified previously in an AF-Sm1/RNA complex, suggests a common RNA-binding mode for the AF-Sm1 and AF-Sm2 proteins, in line with solution studies showing preferential binding to U-rich oligonucleotides for both proteins. Clear differences are however seen in the charge distribution within the two structures. The rough faces of the rings, i.e. the faces not containing the base binding pockets, have opposite charges in the two structures, being predominantly positive in AF-Sm1 and negative in AF-Sm2. Differences in the ionic interactions between subunits provide an explanation for the distinctly different oligomerisation behaviour of the AF-Sm1 and AF-Sm2 proteins and of Sm1- and Sm2-type proteins in general, as well as the stability of their complexes. Implications for the functions of archaeal Sm proteins are being discussed.


What predicts outcome in non-operative treatments of chronic low back pain? A systematic review.
Systematic reviews have shown that as non-operative treatments exercise, behavioural and multimodal treatment programs are effective for chronic low back pain. There is, however, a lack of knowledge concerning the association between changes in treatment process variables and changes in outcome for the three treatment forms. The objective of this systematic review was to evaluate which changes in treatment process variables predict outcome of exercise, behavioural and multimodal treatment of chronic low back pain. Medline, Embase and PsychInfo were systematically searched. A descriptive analysis was used to summarize the results regarding the outcomes pain, disability and return to work (RTW). 13 studies were identified. The results showed that functional coping mechanisms and pain reduction were associated with a decrease in disability and increase in RTW, and physical performance factors were not. Related to pain reduction decreases in disability, functional coping mechanisms as well as physical performance factors were associated. Strong conclusions cannot be drawn from this review, because of the heterogeneity and the limited number of studies. The results of this review raise the question if changes in behavioural variables and reductions of disability which facilitate an improvement in function, may be more important than physical performance factors for successful treatment of chronic low back pain. This is relevant for the refinement of future treatment programs.


Evaluation of a new artificial tear formulation for the management of tear film stability and visual function in patients with dry eye.
Artificial tears are the first line of therapy for dry eye disease (DED) and are also the most frequently used treatment approach for this common condition. Despite this, there are few published studies that directly compare the effectiveness of different drop preparations, especially those formulated specifically for dry eye. In this study, we tested a new artificial tear product, Rohto® Dry-Aid™, for its ability to relieve the signs and symptoms of DED. The study used a second drop, Systane® Ultra, as a positive comparator. This was a prospective, single-center, open-label, parallel-group study comparing the effects of the two products when used continuously over ~30 days (Clinical Trials registration number NCT03183089). Subjects were randomly assigned to one of the two test groups and were monitored 2 and 4 weeks after enrollment. Efficacy endpoints included ocular staining, visual function, and ocular discomfort. Treatment groups had similar ocular staining and ocular comfort scores, and both showed statistically significant ocular discomfort score improvement. Subjects in the Rohto group reported significant improvements in visual tasking activities such as watching television and driving at night. There was also a tendency for diary symptom scores to worsen from morning to evening in the Systane group, but not in the Rohto group; this trend was not significant, but warrants further study. The two products, Rohto Dry-Aid and Systane Ultra, elicited comparable effects on the signs and symptoms of DED. While both products are designed to provide long-lasting relief, subjects in the Rohto group experienced a superior relief from discomfort associated with visual tasking activities and daily diaries, indicating that the Rohto drops may provide a longer duration of symptomatic relief over the course of the day.


Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease.
The lecithin:cholesterol acyltransferase (LCAT) enzyme is responsible for the synthesis of cholesteryl esters in human plasma and plays a critical role in high density lipoprotein (HDL) metabolism. Genetic LCAT deficiency is a rare metabolic disorder characterized by low HDL cholesterol levels. This paper reviews the genetic and biochemical features of LCAT deficiency, highlighting the absence of enhanced preclinical atherosclerosis in carriers, despite the remarkably low HDL cholesterol.


Encapsulating peritoneal sclerosis in children on chronic PD: a survey from the European Paediatric Dialysis Working Group.
Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that is associated with significant morbidity and mortality in adults. There are scarce data for children. We performed a 10-year survey to determine the prevalence, risk factors and outcome for EPS in children. Chronic PD patients in 14 dialysis units participating in the European Paediatric Dialysis Working Group between January 2001 and December 2010 were included in this study. Twenty-two cases of EPS were reported (prevalence 1.5%; 8.7 per 1000 patient-years on PD). Median PD vintage was 5.9 (1.6-10.2) in EPS and 1.7 (0.7-7.7) years in the remainder of the PD population (P<0.0001). EPS patients had a significantly higher peritonitis rate than non-EPS patients (P=0.2). EPS was diagnosed while the child was on PD in 17 (77%), after conversion to haemodialysis (HD) in 3 and after transplantation in 2. Fifteen of 17 (88%) developed ultrafiltration (UF) failure. The median interval between UF failure and presentation with bowel obstruction was 2.8 (0.02-5.8) months. Twenty (91%) had clinical and radiological signs of bowel obstruction. Enterolysis was performed in 14 and 19 received immunosuppression or tamoxifen. Nine required parenteral nutrition. At final follow-up 4.8 (1.3-8.7) years after EPS diagnosis, 3 patients died, 11 had a functioning transplant and 8 were on HD. The prevalence of EPS in European children on PD is comparable with that of adult PD patients, but mortality from paediatric EPS is significantly lower. A high index of suspicion is required for the diagnosis of EPS in children with longer dialysis duration, a high peritonitis rate and UF failure.


Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4.
IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders. Study of the relationship between human IL-17A-producing CD4(+) T(H) cells (T(H)17) and IL-4-producing CD4(+) T(H) (T(H)2) cells. T-cell clones generated from the CCR6(+)CD161(+) fraction of human circulating CD4(+) T cells, which contains virtually all T(H)17 cells, as well as circulating CD4(+) T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile. A small proportion of CCR6(+)CD161(+)CD4(+) T-cell clones showed the ability to produce both IL-17A and IL-4 (T(H)17/T(H)2). T(H)17/T(H)2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few T(H)17/T(H)2 cells were found among circulating CD4(+) T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. T(H)17/T(H)2 cells could not be derived from naive umbilical cord blood CD4(+) T cells under any experimental condition. However, when circulating memory CCR6(+)CD161(+)CD4(+) T cells were cloned under appropriate polarizing conditions, T(H)17/T(H)2 clones originated in the presence of IL-4, suggesting that an IL-4-rich microenvironment may induce the shifting of memory T(H)17 cells into T(H)17/T(H)2 cells. Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of T(H)17/T(H)2 cells may play some role in the pathogenesis of this disease.


Emerging role of pemetrexed in ovarian cancer.
The current treatment of choice of epithelial ovarian cancer involves aggressive tumor cytoreductive surgery followed by platinum- and taxane-based chemotherapy; however, despite the encouraging activity of these agents, most ovarian carcinomas relapse and many patients die from drug-resistant disease. After the failure of platinum- and taxane-based schedules, several cytotoxic agents have demonstrated activity in advanced ovarian cancer but none were able to induce significant and durable responses. Among the new cytotoxic agents, pemetrexed plays an emerging role in different tumors, demonstrating competitive activity and a promising safety profile. In ovarian cancer, pemetrexed has been investigated, with encouraging results, as a single agent and in association with platinum compounds; moreover, the drug has shown interesting activity both in platinum-sensitive and platinum-resistant ovarian cancer. According to these clinical results it appears reasonable to explore the combination of pemetrexed with other cytotoxic agents and also with targeted therapies in relapsed ovarian cancer patients.