A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome.

BackgroundAngelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 - 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain.ResultsA potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events.ConclusionsThis study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies.Trial registrationNCT00348933 . Registered 6 July 2006

EP4 and EP2 Receptor Activation of Protein Kinase A by Prostaglandin E 2 Impairs Macrophage Phagocytosis of Clostridium sordellii

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102186/1/aji12153.pd

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141717/1/jlb0219.pd

Protein kinase A inhibition of macrophage maturation is accompanied by an increase in DNA methylation of the colonyâ stimulating factor 1 receptor gene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134212/1/imm12641.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134212/2/imm12641_am.pd

Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Crossâ Linking as a Therapeutic Concept in Airway Fibrosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136664/1/ajt14103-sup-0002-FigureS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136664/2/ajt14103-sup-0003-FigureS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136664/3/ajt14103.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136664/4/ajt14103_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136664/5/ajt14103-sup-0001-FigureS1.pd

NADPH oxidase deficiency results in reduced alveolar macrophage 5â lipoxygenase expression and decreased leukotriene synthesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141933/1/jlb1585.pd

Moon Shadow by Cosmic Rays under the Influence of Geomagnetic Field and Search for Antiprotons at Multi-TeV Energies

We have observed the shadowing of galactic cosmic ray flux in the direction of the moon, the so-called moon shadow, using the Tibet-III air shower array operating at Yangbajing (4300 m a.s.l.) in Tibet since 1999. Almost all cosmic rays are positively charged; for that reason, they are bent by the geomagnetic field, thereby shifting the moon shadow westward. The cosmic rays will also produce an additional shadow in the eastward direction of the moon if cosmic rays contain negatively charged particles, such as antiprotons, with some fraction. We selected 1.5 x10^{10} air shower events with energy beyond about 3 TeV from the dataset observed by the Tibet-III air shower array and detected the moon shadow at $\sim 40 \sigma$ level. The center of the moon was detected in the direction away from the apparent center of the moon by 0.23$^\circ$ to the west. Based on these data and a full Monte Carlo simulation, we searched for the existence of the shadow produced by antiprotons at the multi-TeV energy region. No evidence of the existence of antiprotons was found in this energy region. We obtained the 90% confidence level upper limit of the flux ratio of antiprotons to protons as 7% at multi-TeV energies.Comment: 13pages,4figures; Accepted for publication in Astroparticle Physic