Functional central limit theorems for vicious walkers

We consider the diffusion scaling limit of the vicious walker model that is a system of nonintersecting random walks. We prove a functional central limit theorem for the model and derive two types of nonintersecting Brownian motions, in which the nonintersecting condition is imposed in a finite time interval $(0,T]$ for the first type and in an infinite time interval $(0,\infty)$ for the second type, respectively. The limit process of the first type is a temporally inhomogeneous diffusion, and that of the second type is a temporally homogeneous diffusion that is identified with a Dyson's model of Brownian motions studied in the random matrix theory. We show that these two types of processes are related to each other by a multi-dimensional generalization of Imhof's relation, whose original form relates the Brownian meander and the three-dimensional Bessel process. We also study the vicious walkers with wall restriction and prove a functional central limit theorem in the diffusion scaling limit.Comment: AMS-LaTeX, 20 pages, 2 figures, v6: minor corrections made for publicatio

Epigenetic Features of Human Mesenchymal Stem Cells Determine Their Permissiveness for Induction of Relevant Transcriptional Changes by SYT-SSX1

BACKGROUND: A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas, a malignant soft tissue tumor widely believed to originate from as yet unidentified pluripotent stem cells. The resulting fusion protein has no DNA binding motifs but possesses protein-protein interaction domains that are believed to mediate association with chromatin remodeling complexes. Despite recent advances in the identification of molecules that interact with SYT-SSX and with the corresponding wild type SYT and SSX proteins, the mechanisms whereby the SYT-SSX might contribute to neoplastic transformation remain unclear. Epigenetic deregulation has been suggested to be one possible mechanism. METHODOLOGY/PRINCIPAL FINDINGS: We addressed the effect of SYT/SSX expression on the transcriptome of four independent isolates of primary human bone marrow mesenchymal stem cells (hMSC). We observed transcriptional changes similar to the gene expression signature of synovial sarcoma, principally involving genes whose regulation is linked to epigenetic factors, including imprinted genes, genes with transcription start sites within a CpG island and chromatin related genes. Single population analysis revealed hMSC isolate-specific transcriptional changes involving genes that are important for biological functions of stem cells as well as genes that are considered to be molecular markers of synovial sarcoma including IGF2, EPHRINS, and BCL2. Methylation status analysis of sequences at the H19/IGF2 imprinted locus indicated that distinct epigenetic features characterize hMSC populations and condition the transcriptional effects of SYT-SSX expression. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that epigenetic features may define the cellular microenvironment in which SYT-SSX displays its functional effects

Blood test ordering for unexplained complaints in general practice: the VAMPIRE randomised clinical trial protocol. [ISRCTN55755886]

BACKGROUND: General practitioners (GPs) frequently order blood tests when they see patients presenting with unexplained complaints. Due to the low prevalence of serious pathology in general practice, the risk of false-positive test results is relatively high. This may result in unnecessary further testing, leading to unfavourable effects such as patient anxiety, high costs, somatisation and morbidity. A policy of watchful waiting is expected to lower both the number of patients to be tested and the risk of false-positive test results, without missing serious pathology. However, many general practitioners experience barriers when trying to postpone blood testing by watchful waiting. The objectives of this study are (1) to determine the accuracy of blood tests in patients presenting with unexplained complaints in terms of detecting pathology, (2) to determine the accuracy of a watchful waiting strategy and (3) to determine the effects of a quality improvement strategy to promote the postponement of blood test ordering by GPs for patients with unexplained complaints. DESIGN: General practices are randomised over three groups. Group 1 is instructed to order blood tests immediately, group 2 to apply a watchful waiting policy and group 3 also to postpone testing, but supported by our quality improvement strategy. The trial consists of two sub-studies: a diagnostic study at patient level (group 1 versus groups 2 and 3) and a quality improvement study at GP level (group 2 versus group 3). The diagnostic strategy to be used involves of both customary and innovative tests. The quality improvement strategy consists of two small-group meetings and a practice outreach visit. Patient follow-up ends at 12 months after the initial consultation. Primary outcome measures are the accuracy and added value of blood tests for detecting pathology, the effect of a 4-week postponement of test ordering on the blood test characteristics and the quantity of tests ordered. Secondary outcome measures are the course of complaints, quality of life, satisfaction with care, anxiety of patients and practitioners, determinants of physicians' behaviour, health care utilisation and costs. DISCUSSION: The innovative aspect of this trial is that it combines a clinical-epidemiological study and a quality of care study

5-a-day fruit and vegetable food product labels: reduced fruit and vegetable consumption following an exaggerated compared to a modest label.

BACKGROUND: Food product labels based on the WHO 5-a-day fruit and vegetable (FV) message are becoming increasingly common, but these labels may impact negatively on complementary or subsequent FV consumption. This study aimed to investigate the impact of a '3 of your 5-a-day' versus a '1 of your 5-a-day' smoothie product label on subsequent FV consumption. METHODS: Using an acute experimental design, 194 participants (90 males, 104 females) were randomised to consume a smoothie labelled as either '3 of your 5-a-day' (N = 97) or '1 of your 5-a-day' (N = 97) in full, following a usual breakfast. Subsequent FV consumption was measured for the rest of the day using 24-h recall. Usual FV consumption was also assessed via 24-h recall for the day before the study. RESULTS: Regression analyses revealed a significantly lower subsequent FV consumption following smoothies displaying the '3 of your 5-a-day' label compared to the '1 of your 5-a-day' label (Beta = - 0.15, p = 0.04). Secondary analyses revealed these effects to be driven mainly by changes to consumption in usual high FV consumers, in females and in vegetable as opposed to fruit consumption. CONCLUSIONS: These findings demonstrate a role for label information in food intake, and the potential negative impacts of an exaggerated food product label on healthy food consumption and healthy dietary profiles

Behavior Problems in Relation to Sustained Selective Attention Skills of Moderately Preterm Children

Attention skills may form an important developmental mechanism. A mediation model was examined in which behavioral problems of moderately preterm and term children at school age are explained by attention performance. Parents and teachers completed behavioral assessments of 348 moderately preterm children and 182 term children at 8 years of age. Children were administered a test of sustained selective attention. Preterm birth was associated with more behavioral and attention difficulties. Gestational age, prenatal maternal smoking, and gender were associated with mothers’, fathers’, and teachers’ reports of children’s problem behavior. Sustained selective attention partially mediated the relationship between birth status and problem behavior. Development of attention skills should be an important focus for future research in moderately preterm children

Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS

A Drosophila Model of ALS: Human ALS-Associated Mutation in VAP33A Suggests a Dominant Negative Mechanism

ALS8 is caused by a dominant mutation in an evolutionarily conserved protein, VAPB (vesicle-associated membrane protein (VAMP)-associated membrane protein B)/ALS8). We have established a fly model of ALS8 using the corresponding mutation in Drosophila VAPB (dVAP33A) and examined the effects of this mutation on VAP function using genetic and morphological analyses. By simultaneously assessing the effects of VAPwt and VAPP58S on synaptic morphology and structure, we demonstrate that the phenotypes produced by neuronal expression of VAPP58S resemble VAP loss of function mutants and are opposite those of VAP overexpression, suggesting that VAPP58S may function as a dominant negative. This is brought about by aggregation of VAPP58S and recruitment of wild type VAP into these aggregates. Importantly, we also demonstrate that the ALS8 mutation in dVAP33A interferes with BMP signaling pathways at the neuromuscular junction, identifying a new mechanism underlying pathogenesis of ALS8. Furthermore, we show that mutant dVAP33A can serve as a powerful tool to identify genetic modifiers of VAPB. This new fly model of ALS, with its robust pathological phenotypes, should for the first time allow the power of unbiased screens in Drosophila to be applied to study of motor neuron diseases

Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases