Academic potential and cognitive functioning of long-term survivors after childhood liver transplantation

This cross-sectional study assessed intellect, cognition, academic function, behaviour, and emotional health of long-term survivors after childhood liver transplantation. Eligible children were >5 yr post-transplant, still attending school, and resident in Queensland. Hearing and neurocognitive testing were performed on 13 transplanted children and six siblings including two twin pairs where one was transplanted and the other not. Median age at testing was 13.08 (range 6.52-16.99) yr; time elapsed after transplant 10.89 (range 5.16-16.37) yr; and age at transplant 1.15 (range 0.38-10.00) yr. Mean full-scale IQ was 97 (81-117) for transplanted children and 105 (87-130) for siblings. No difficulties were identified in intellect, cognition, academic function, and memory and learning in transplanted children or their siblings, although both groups had reduced mathematical ability compared with normal. Transplanted patients had difficulties in executive functioning, particularly in self-regulation, planning and organization, problem-solving, and visual scanning. Thirty-one percent (4/13) of transplanted patients, and no siblings, scored in the clinical range for ADHD. Emotional difficulties were noted in transplanted patients but were not different from their siblings. Long-term liver transplant survivors exhibit difficulties in executive function and are more likely to have ADHD despite relatively intact intellect and cognition.

Conserved gene structure and function of interleukin-10 in teleost fish

Interleukin-10 (IL-10) is an important immunoregulatory cytokine produced by various types of cells. Researchers describe here the isolation and characterization of olive flounder IL-10 (ofIL-10) cDNA and genomic organization. The ofIL-10 gene encodes a 187 amino acid protein and is composed of a five exon/four intron structure, similar to other known IL-10 genes. The ofIL-10 promoter sequence analysis shows a high level of homology in putative binding sites for transcription factors which are sufficient for transcriptional regulation ofIL-10. Important structural residues are maintained in the ofIL-10 protein including the four cysteines responsible for the two intra-chain disulfide bridges reported for human IL-10 and two extra cysteine residues that exist only in fish species. The phylogenetic analysis clustered ofIL-10 with other fish IL-10s and apart from mammalian IL-10 molecules. Quantitative real-time Polymerase Chain Reaction (PCR) analysis demonstrated ubiquitous ofIL-10 gene expression in the 13 tissues examined. Additionally, the induction of ofIL-10 gene expression was observed in the kidney tissue from olive flounder infected with bacteria (Edawardsiella tarda) or virus (Viral Hemorrhagic Septicemia Virus; VHSV). These data indicate that IL-10 is an important immune regulator that is conserved strictly genomic organization and function during the evolution of vertebrate immunity.

A Bruch’s membrane substitute fabricated from silk fibroin supports the function of retinal pigment epithelial cells in vitro

Silk fibroin provides a promising biomaterial for ocular tissue reconstruction including the damaged outer blood-retinal barrier of patients afflicted with age-related macular degeneration (AMD). The aim of the present study was to evaluate the function of retinal pigment epithelial (RPE) cells in vitro, when grown on fibroin membranes manufactured to a similar thickness as Bruch’s membrane (3 μm). Confluent cultures of RPE cells (ARPE-19) were established on fibroin membranes and maintained under conditions designed to promote maturation over 4 months. Control cultures were grown on polyester cell culture well inserts (Transwell). Cultures established on either material developed a cobblestoned morphology with partial pigmentation within 12 weeks. Immunocytochemistry at 16 weeks revealed a similar distribution pattern between cultures for F-actin, ZO-1, ezrin, cytokeratin pair 8/18, RPE-65 and Na+/K+-ATPase. Electron microscopy revealed that cultures grown on fibroin displayed a rounder apical surface with a more dense distribution of microvilli. Both cultures avidly ingested fluorescent microspheres coated with vitronectin and bovine serum albumin (BSA), but not controls coated with BSA alone. VEGF and PEDF were detected in the conditioned medium collected from above and below both membrane types. Levels of PEDF were significantly higher than for VEGF on both membranes and a trend was observed towards larger amounts of PEDF in apical compartments. These findings demonstrate that RPE cell functions on fibroin membranes are equivalent to those observed for standard test materials (polyester membranes). As such, these studies support advancement to studies of RPE cell implantation on fibroin membranes in a preclinical model.

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS. © 2015 Field et al.

Cuff tear arthropathy: Evidence of functional variation in pyrophosphate metabolism genes

We investigated the role of two genes, ANKH and TNAP, in patients with cuff tear arthropathy. These genes encode proteins which regulate the extracellular concentration of inorganic pyrophosphate, fluctuations of which can lead to calcium crystal formation. Variants were detected by direct sequencing of DNA and their frequencies compared with healthy controls. The effect of variants on protein function was further studied by in vitro approaches. Variant genotypes were observed more frequently in the cases when compared with controls in ANKH (45% and 20%) and TNAP (32% and 9%). Variants in ANKH altered inorganic pyrophosphate (PPi) concentrations in transfected human chondrocytes. There was a higher mean serum concentration of TNAP detected in female patients compared with normal ranges. Cuff tear arthropathy is associated with variants in ANKH and TNAP that alter extracellular inorganic pyrophosphate concentrations causing calcium crystal deposition. This supports a theory that genetic variants predispose patients to primary crystal deposition which when combined with a massive rotator cuff tear leads to the development of arthritis.

Comparison of visual status of Iranian military and commercial drivers

Background There is no legal requirement for Iranian military truck drivers to undergo regular visual checkups as compared to commercial truck drivers. Objectives This study aimed to evaluate the impact of drivers’ visual checkups by comparing the visual function of Iranian military and commercial truck drivers. Patients and Methods In this comparative cross-sectional study, two hundred military and 200 commercial truck drivers were recruited and their Visual Acuity (VA), Visual Field (VF), color vision and Contrast Sensitivity (CS) were assessed and compared using the Snellen chart, confrontation screening method, D15 test and Pelli-Robson letter chart, respectively. A questionnaire regarding driving exposure and history of motor-vehicle crashes (MVCs) was also filled by drivers. Results were analyzed using an independent samples t-test, one-way ANOVA (assessing difference in number of MVCs across different age groups), chi-square test and Pearson correlation at statistical significance level of P < 0.05. Results Mean age was 41.6 ± 9.2 for the military truck drivers and 43.4 ± 10.9 for commercial truck drivers (P > 0.05). No significant difference between military and commercial drivers was found in terms of driving experience, number of MVCs, binocular VA, frequency of color vision defects and CS scores. In contrast, the last ocular examination was significantly earlier in military drivers than commercial drivers (P < 0.001). In addition, 4% of military drivers did not meet the national standards to drive as opposed to 2% of commercial drivers. There was a significant but weak correlation between binocular VA and age (r = 0.175, P < 0.001). However, CS showed a significantly moderate correlation with age (r = -0.488, P < 0.001). Conclusions The absence of legal requirement for regular eye examination in military drivers caused the incompetent drivers to be missed in contrast to commercial drivers. The need for scientific revision of VA standard for Iranian drivers is also discussed. The CS measurement in visual checkups of older drivers deserves to be investigated more thoroughly.

Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis

BACKGROUND Bronchiectasis is a major contributor to chronic respiratory morbidity and mortality worldwide. Wheeze and other asthma-like symptoms and bronchial hyperreactivity may occur in people with bronchiectasis. Physicians often use asthma treatments in patients with bronchiectasis. OBJECTIVES To assess the effects of inhaled long-acting beta2-agonists (LABA) combined with inhaled corticosteroids (ICS) in children and adults with bronchiectasis during (1) acute exacerbations and (2) stable state. SEARCH METHODS The Cochrane Airways Group searched the the Cochrane Airways Group Specialised Register of Trials, which includes records identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other databases. The Cochrane Airways Group performed the latest searches in October 2013. SELECTION CRITERIA All randomised controlled trials (RCTs) of combined ICS and LABA compared with a control (placebo, no treatment, ICS as monotherapy) in children and adults with bronchiectasis not related to cystic fibrosis (CF). DATA COLLECTION AND ANALYSIS Two review authors extracted data independently using standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS We found no RCTs comparing ICS and LABA combination with either placebo or usual care. We included one RCT that compared combined ICS and LABA with high-dose ICS in 40 adults with non-CF bronchiectasis without co-existent asthma. All participants received three months of high-dose budesonide dipropionate treatment (1600 micrograms). After three months, participants were randomly assigned to receive either high-dose budesonide dipropionate (1600 micrograms per day) or a combination of budesonide with formoterol (640 micrograms of budesonide and 18 micrograms of formoterol) for three months. The study was not blinded. We assessed it to be an RCT with overall high risk of bias. Data analysed in this review showed that those who received combined ICS-LABA (in stable state) had a significantly better transition dyspnoea index (mean difference (MD) 1.29, 95% confidence interval (CI) 0.40 to 2.18) and cough-free days (MD 12.30, 95% CI 2.38 to 22.2) compared with those receiving ICS after three months of treatment. No significant difference was noted between groups in quality of life (MD -4.57, 95% CI -12.38 to 3.24), number of hospitalisations (odds ratio (OR) 0.26, 95% CI 0.02 to 2.79) or lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Investigators reported 37 adverse events in the ICS group versus 12 events in the ICS-LABA group but did not mention the number of individuals experiencing adverse events. Hence differences between groups were not included in the analyses. We assessed the overall evidence to be low quality. AUTHORS' CONCLUSIONS In adults with bronchiectasis without co-existent asthma, during stable state, a small single trial with a high risk of bias suggests that combined ICS-LABA may improve dyspnoea and increase cough-free days in comparison with high-dose ICS. No data are provided for or against, the use of combined ICS-LABA in adults with bronchiectasis during an acute exacerbation, or in children with bronchiectasis in a stable or acute state. The absence of high quality evidence means that decisions to use or discontinue combined ICS-LABA in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and consideration of adverse events associated with combined ICS-LABA.

The subordinated processes controlled by a family of subordinators and corresponding Fokker-Planck type equations

In this work, we consider subordinated processes controlled by a family of subordinators which consist of a power function of a time variable and a negative power function of an α-stable random variable. The effect of parameters in the subordinators on the subordinated process is discussed. By suitable variable substitutions and the Laplace transform technique, the corresponding fractional Fokker–Planck-type equations are derived. We also compute their mean square displacements in a free force field. By choosing suitable ranges of parameters, the resulting subordinated processes may be subdiffusive, normal diffusive or superdiffusive

Multifocal electroretinogram responses in Nepalese diabetic patients without retinopathy

Purpose To determine neuroretinal function with multifocal electroretinogram (mfERG) in diabetic subjects without retinopathy. Methods Multifocal electroretinogram (mfERG) was performed in 18 eyes of 18 diabetic subjects without retinopathy and 17 eyes of 17 age and gender-matched healthy control participants. Among 18 diabetic subjects, two had type 1 and 16 had type 2 diabetes. MfERG responses were averaged by the retinal areas of six concentric rings and four quadrants, and 103 retinal locations; N1–P1 amplitude and P1-implicit time were analysed. Results Average mfERG N1–P1 amplitude (in nv/deg2) of 103 retinal locations was 56.3 ± 17.2 (mean ± SD) in type 1 diabetic subjects, 47.2 ± 9.3 in type 2 diabetic subjects and 71.5 ± 12.7 in controls. Average P1-implicit time (in ms) was 43.0 ± 1.3 in type 1 diabetic subjects, 43.9 ± 2.3 in type 2 diabetic subjects and 41.9 ± 2.1 in controls. There was significant reduction in average N1–P1 amplitude and delay in P1-implicit time in type 2 diabetic subjects in comparison to controls. mfERG amplitude did not show any significant correlation with diabetes duration and blood sugar level. However, implicit time showed a positive correlation with diabetes duration in type 2 diabetic subjects with diabetes duration ≥5 years. Conclusions This is the first study in a Nepalese population with diabetes using multifocal electroretinography. We present novel findings that mfERG N1–P1 amplitude is markedly reduced along with delay in P1-implicit time in type 2 diabetic subjects without retinopathy. These findings indicate that there might be significant dysfunction of inner retina before the development of diabetic retinopathy in the study population, which have higher prevalence of diabetes than the global estimate and uncontrolled blood sugar level.

Post-transcriptional regulation in the nucleus and cytoplasm: study of mean time to threshold (MTT) and narrow escape problem

Messenger RNAs (mRNAs) can be repressed and degraded by small non-coding RNA molecules. In this paper, we formulate a coarsegrained Markov-chain description of the post-transcriptional regulation of mRNAs by either small interfering RNAs (siRNAs) or microRNAs (miRNAs). We calculate the probability of an mRNA escaping from its domain before it is repressed by siRNAs/miRNAs via cal- culation of the mean time to threshold: when the number of bound siRNAs/miRNAs exceeds a certain threshold value, the mRNA is irreversibly repressed. In some cases,the analysis can be reduced to counting certain paths in a reduced Markov model. We obtain explicit expressions when the small RNA bind irreversibly to the mRNA and we also discuss the reversible binding case. We apply our models to the study of RNA interference in the nucleus, examining the probability of mRNAs escaping via small nuclear pores before being degraded by siRNAs. Using the same modelling framework, we further investigate the effect of small, decoy RNAs (decoys) on the process of post-transcriptional regulation, by studying regulation of the tumor suppressor gene, PTEN : decoys are able to block binding sites on PTEN mRNAs, thereby educing the number of sites available to siRNAs/miRNAs and helping to protect it from repression. We calculate the probability of a cytoplasmic PTEN mRNA translocating to the endoplasmic reticulum before being repressed by miRNAs. We support our results with stochastic simulations

Frequency response function based damage identification using principal component analysis and pattern recognition technique

Pattern recognition is a promising approach for the identification of structural damage using measured dynamic data. Much of the research on pattern recognition has employed artificial neural networks (ANNs) and genetic algorithms as systematic ways of matching pattern features. The selection of a damage-sensitive and noise-insensitive pattern feature is important for all structural damage identification methods. Accordingly, a neural networks-based damage detection method using frequency response function (FRF) data is presented in this paper. This method can effectively consider uncertainties of measured data from which training patterns are generated. The proposed method reduces the dimension of the initial FRF data and transforms it into new damage indices and employs an ANN method for the actual damage localization and quantification using recognized damage patterns from the algorithm. In civil engineering applications, the measurement of dynamic response under field conditions always contains noise components from environmental factors. In order to evaluate the performance of the proposed strategy with noise polluted data, noise contaminated measurements are also introduced to the proposed algorithm. ANNs with optimal architecture give minimum training and testing errors and provide precise damage detection results. In order to maximize damage detection results, the optimal architecture of ANN is identified by defining the number of hidden layers and the number of neurons per hidden layer by a trial and error method. In real testing, the number of measurement points and the measurement locations to obtain the structure response are critical for damage detection. Therefore, optimal sensor placement to improve damage identification is also investigated herein. A finite element model of a two storey framed structure is used to train the neural network. It shows accurate performance and gives low error with simulated and noise-contaminated data for single and multiple damage cases. As a result, the proposed method can be used for structural health monitoring and damage detection, particularly for cases where the measurement data is very large. Furthermore, it is suggested that an optimal ANN architecture can detect damage occurrence with good accuracy and can provide damage quantification with reasonable accuracy under varying levels of damage.

The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause

STUDY QUESTION Can the number of oocytes retrieved in IVF cycles be predictive of the age at menopause? SUMMARY ANSWER The number of retrieved oocytes can be used as an indirect assessment of the extent of ovarian reserve to provide information on the duration of the reproductive life span in women of different ages. WHAT IS KNOWN ALREADY Menopause is determined by the exhaustion of the ovarian follicular pool. Ovarian reserve is the main factor influencing ovarian response in IVF cycles. As a consequence the response to ovarian stimulation with the administration of gonadotrophins in IVF treatment may be informative about the age at menopause. STUDY DESIGN, SIZE, DURATION In the present cross-sectional study, participants were 1585 infertile women from an IVF clinic and 2635 menopausal women from a more general population. PARTICIPANTS/MATERIALS, SETTING, METHODS For all infertile women, the response to ovarian stimulation with gonadotrophins was recorded. For menopausal women, relevant demographic characteristics were available for the analysis. MAIN RESULTS AND THE ROLE OF CHANCE A cubic function described the relationship between mean numbers of oocytes and age, with all terms being statistically significant. From the estimated residual distribution of the actual number of oocytes about this mean, a distribution of the age when there would be no oocytes retrieved following ovarian stimulation was derived. This was compared with the distribution of the age at menopause from the menopausal women, showing that menopause occurred about a year later. LIMITATIONS, REASONS FOR CAUTION The retrieved oocyte data were from infertile women, while the menopausal ages were from a more general population. WIDER IMPLICATIONS OF THE FINDINGS In the present study, we have shown some similarity between the distributions of the age when no retrieved oocytes can be expected after ovarian stimulation and the age at menopause. For a given age, the lower the ovarian reserve, the lower the number of retrieved oocytes would be and the earlier the age that menopause would occur.

Linear and weakly nonlinear stability analyses of cooperative car-following models

Stability analyses have been widely used to better understand the mechanism of traffic jam formation. In this paper, we consider the impact of cooperative systems (a.k.a. connected vehicles) on traffic dynamics and, more precisely, on flow stability. Cooperative systems are emerging technologies enabling communication between vehicles and/or with the infrastructure. In a distributed communication framework, equipped vehicles are able to send and receive information to/from other equipped vehicles. Here, the effects of cooperative traffic are modeled through a general bilateral multianticipative car-following law that improves cooperative drivers' perception of their surrounding traffic conditions within a given communication range. Linear stability analyses are performed for a broad class of car-following models. They point out different stability conditions in both multianticipative and nonmultianticipative situations. To better understand what happens in unstable conditions, information on the shock wave structure is studied in the weakly nonlinear regime by the mean of the reductive perturbation method. The shock wave equation is obtained for generic car-following models by deriving the Korteweg de Vries equations. We then derive traffic-state-dependent conditions for the sign of the solitary wave (soliton) amplitude. This analytical result is verified through simulations. Simulation results confirm the validity of the speed estimate. The variation of the soliton amplitude as a function of the communication range is provided. The performed linear and weakly nonlinear analyses help justify the potential benefits of vehicle-integrated communication systems and provide new insights supporting the future implementation of cooperative systems.

The function of the RNA-binding protein TEL1 in moss reveals ancient regulatory mechanisms of shoot development

The shoot represents the basic body plan in land plants. It consists of a repeated structure composed of stems and leaves. Whereas vascular plants generate a shoot in their diploid phase, non-vascular plants such as mosses form a shoot (called the gametophore) in their haploid generation. The evolution of regulatory mechanisms or genetic networks used in the development of these two kinds of shoots is unclear. TERMINAL EAR1-like genes have been involved in diploid shoot development in vascular plants. Here, we show that disruption of PpTEL1 from the moss Physcomitrella patens, causes reduced protonema growth and gametophore initiation, as well as defects in gametophore development. Leafy shoots formed on ΔTEL1 mutants exhibit shorter stems with more leaves per shoot, suggesting an accelerated leaf initiation (shortened plastochron), a phenotype shared with the Poaceae vascular plants TE1 and PLA2/LHD2 mutants. Moreover, the positive correlation between plastochron length and leaf size observed in ΔTEL1 mutants suggests a conserved compensatory mechanism correlating leaf growth and leaf initiation rate that would minimize overall changes in plant biomass. The RNA-binding protein encoded by PpTEL1 contains two N-terminus RNA-recognition motifs, and a third C-terminus non-canonical RRM, specific to TEL proteins. Removal of the PpTEL1 C-terminus (including this third RRM) or only 16–18 amino acids within it seriously impairs PpTEL1 function, suggesting a critical role for this third RRM. These results show a conserved function of the RNA-binding PpTEL1 protein in the regulation of shoot development, from early ancestors to vascular plants, that depends on the third TEL-specific RRM.