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Search Results: 1 - 10 of 212850 matches for " Susan L. Semple-Rowland "
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Increasing Hippocampal Estrogen Receptor Alpha Levels via Viral Vectors Increases MAP Kinase Activation and Enhances Memory in Aging Rats in the Absence of Ovarian Estrogens
Christine F. Witty, Thomas C. Foster, Susan L. Semple-Rowland, Jill M. Daniel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051385
Abstract: We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle-age exhibited increased levels of estrogen receptor alpha (ERα) in the hippocampus as well as enhanced hippocampal dependent memory as compared to aged rats that had not received mid-life estradiol treatment. These effects persisted long after the estradiol treatment had been terminated. The goal of the current experiment was to determine if increased expression of ERα in the hippocampus, in the absence of exogenously administered estrogens, can impact the hippocampus and cognitive function in aging ovariectomized rats. Middle-aged rats were trained for 24 days on an eight-arm radial maze spatial memory task. All rats were then ovariectomized. Forty days later, rats received either lentiviral delivery to the hippocampus of the gene encoding ERα (lenti-ERα) or a control virus. Rats were tested on delay trials in the radial-maze in which delays of varying lengths were imposed between the fourth and fifth arm choices. Following behavior testing, hippocampi were immunostained using western blotting for ERα, the ERα-regulated protein choline acetyltransferase, and phosphorylation of the ERα-regulated kinases, ERK/MAPK and Akt. Results revealed that aging ovariectomized rats that received delivery of lenti-ERα to the hippocampus exhibited enhanced spatial memory as indicated by increased arm-choice accuracy across delays as compared to ovariectomized rats that received control virus. Western blot data revealed that lenti-ERα delivery significantly increased levels of ERα and phosphorylated ERK/MAPK and had no impact on levels of ChAT or phosphorylation of Akt. Results indicate that increasing hippocampal levels of ERα in aging females in the absence of ovarian or exogenously administered estrogens leads to increases in phosphorylation of ERK/MAPK as well as in enhanced memory.
Bicistronic Lentiviruses Containing a Viral 2A Cleavage Sequence Reliably Co-Express Two Proteins and Restore Vision to an Animal Model of LCA1
Jonathan D. Verrier, Irina Madorsky, William E. Coggin, Mero Geesey, Michael Hochman, Elleanor Walling, Daniel Daroszewski, Kristofer S. Eccles, Rachel Ludlow, Susan L. Semple-Rowland
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020553
Abstract: The disease processes underlying inherited retinal disease are complex and are not completely understood. Many of the corrective gene therapies designed to treat diseases linked to mutations in genes specifically expressed in photoreceptor cells restore function to these cells but fail to stop progression of the disease. There is growing consensus that effective treatments for these diseases will require delivery of multiple therapeutic proteins that will be selected to treat specific aspects of the disease process. The purpose of this study was to design a lentiviral transgene that reliably expresses all of the proteins it encodes and does so in a consistent manner among infected cells. We show, using both in vitro and in vivo analyses, that bicistronic lentiviral transgenes encoding two fluorescent proteins fused to a viral 2A-like cleavage peptide meet these expression criteria. To determine if this transgene design is suitable for therapeutic applications, we replaced one of the fluorescent protein genes with the gene encoding guanylate cyclase -1 (GC1) and delivered lentivirus carrying this transgene to the retinas of the GUCY1*B avian model of Leber congenital amaurosis – 1 (LCA1). GUCY1*B chickens carry a null mutation in the GC1 gene that disrupts photoreceptor function and causes blindness at hatching, a phenotype that closely matches that observed in humans with LCA1. We found that treatment of these animals with the 2A lentivector encoding GC1 restored vision to these animals as evidenced by the presence of optokinetic reflexes. We conclude that 2A-like peptides, with proper optimization, can be successfully incorporated into therapeutic vectors designed to deliver multiple proteins to neural retinal. These results highlight the potential of this vector design to serve as a platform for the development of combination therapies designed to enhance or prolong the benefits of corrective gene therapies.
A Preclinical Assessment of Neural Stem Cells as Delivery Vehicles for Anti-Amyloid Therapeutics
eMalick G. Njie, Svetlana Kantorovich, Garrett W. Astary, Cameron Green, Tong Zheng, Susan L. Semple-Rowland, Dennis A. Steindler, Malisa Sarntinoranont, Wolfgang J. Streit, David R. Borchelt
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034097
Abstract: Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.
Lentiviral Expression of Retinal Guanylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness
Melissa L Williams equal contributor,Jason E Coleman equal contributor,Shannon E Haire,Tomas S Aleman,Artur V Cideciyan,Izabel Sokal,Krzysztof Palczewski,Samuel G Jacobson,Susan L Semple-Rowland
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030201
Abstract: Background Leber congenital amaurosis (LCA) is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans. Methods and Findings A lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration. Conclusions Blindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness.
Activation of Phospholipase C Mimics the Phase Shifting Effects of Light on Melatonin Rhythms in Retinal Photoreceptors
Susan Semple-Rowland, Irina Madorsky, Susan Bolch, Jonathan Berry, W. Clay Smith
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083378
Abstract: Many aspects of retinal photoreceptor function and physiology are regulated by the circadian clocks in these cells. It is well established that light is the primary stimulus that entrains these clocks; yet, the biochemical cascade(s) mediating light’s effects on these clocks remains unknown. This deficiency represents a significant gap in our fundamental understanding of photoreceptor signaling cascades and their functions. In this study, we utilized re-aggregated spheroid cultures prepared from embryonic chick retina to determine if activation of phospholipase C in photoreceptors in the absence of light can phase shift the melatonin secretion rhythms of these cells in a manner similar to that induced by light. We show that spheroid cultures rhythmically secrete melatonin and that these melatonin rhythms can be dynamically phase shifted by exposing the cultures to an appropriately timed light pulse. Importantly, we show that activation of phospholipase C using m-3M3FBS in the absence of light induces a phase delay in photoreceptor melatonin rhythms that mirrors that induced by light. The implication of this finding is that the light signaling cascade that entrains photoreceptor melatonin rhythms involves activation of phospholipase C.
Changes among US Cancer Survivors: Comparing Demographic, Diagnostic, and Health Care Findings from the 1992 and 2010 National Health Interview Surveys
Natasha D. Buchanan,Jessica B. King,Juan L. Rodriguez,Arica White,Katrina F. Trivers,Laura P. Forsythe,Erin E. Kent,Julia H. Rowland,Susan A. Sabatino
ISRN Oncology , 2013, DOI: 10.1155/2013/238017
Abstract: Background. Differences in healthcare and cancer treatment for cancer survivors in the United States (US) have not been routinely examined in nationally representative samples or studied before and after important Institute of Medicine (IOM) recommendations calling for higher quality care provision and attention to comprehensive cancer care for cancer survivors. Methods. To assess differences between survivor characteristics in 1992 and 2010, we conducted descriptive analyses of 1992 and 2010 National Health Interview Survey (NHIS) data. Our study sample consisted of 1018 self-reported cancer survivors from the 1992 NHIS and 1718 self-reported cancer survivors from the 2010 NHIS who completed the Cancer Control (CCS) and Cancer Epidemiology (CES) Supplements. Results. The prevalence of reported survivors increased from 1992 to 2010 (4.2% versus 6.3%). From 1992 to 2010, there was an increase in long-term cancer survivors and a drop in multiple malignancies, and surgery remained the most widely used treatment. Significantly fewer survivors (<10 years after diagnosis) were denied insurance coverage. Survivors continue to report low participation in counseling or support groups. Conclusions. As the prevalence of cancer survivors continues to grow, monitoring differences in survivor characteristics can be useful in evaluating the effects of policy recommendations and the quality of clinical care. 1. Introduction Advances in cancer detection, diagnosis, and treatment, along with the aging of the United States (US) population, have resulted in a large and growing number of cancer survivors. Recent estimates indicate that there are nearly 14 million cancer survivors in the US, more than the over 7 million cancer survivors reported in 1992 [1–3]. Although research examining sociodemographic and healthcare characteristics of nationally representative samples of cancer survivors has been conducted [4, 5], differences in these characteristics over time have rarely been examined in population-based studies. In 1992, the National Health Interview Survey (NHIS) examined characteristics of cancer survivors as part of its Cancer Control Supplement for the first time. Hewitt and colleagues published findings from the 1992 NHIS about numerous self-reported cancer survivor characteristics, including demographic information, cancer type, frequency of second opinion concerning type of cancer treatment, counseling and support group services, patient education, contact with cancer organizations, participation in clinical trials, health and life insurance coverage, and
Quality and availability of consumer information on heart failure in Australia
Agnes I Vitry, Susan M Phillips, Susan J Semple
BMC Health Services Research , 2008, DOI: 10.1186/1472-6963-8-255
Abstract: The availability of consumer information was assessed through a questionnaire-based survey of the major organisations in Australia known, or thought, to be producing or using consumer materials on heart failure, including hospitals. The questionnaire was designed to explore issues around the use, production and dissemination of consumer materials. Only groups that had produced consumer information on heart failure were asked to complete the totality of the questionnaire.The quality of information booklets was assessed by using a standardised checklist.Of 101 organisations which were sent a questionnaire, 33 had produced 61 consumer resources on heart failure including 21 information booklets, 3 videos, 5 reminder fridge magnets, 7 websites, 15 self-management diaries and 10 self-management plans. Questionnaires were completed for 40 separate information resources. Most had been produced by hospitals or health services. Two information booklets had been translated into other languages. There were major gaps in the availability of these resources as more than half of the resources were developed in 2 of the 8 Australian states and territories, New South Wales and Victoria.Quality assessment of 19 information booklets showed that most had good presentation and language. Overall eight high quality booklets were identified. There were gaps in terms of topics covered, provision of references, quantitative information about treatment outcomes and quality and level of scientific evidence to support medical recommendations. In only one case was there evidence that consumers had been involved in the production of the booklets.Key findings arising from the study included the need to develop a nationally coordinated approach for increasing the dissemination of information resources on heart failure. While the more recent publication of a booklet by the National Heart Foundation may have improved the situation, dissemination of written information materials may remain sub-optima
Making the Case for Using Informational Text in Preschool Classrooms  [PDF]
Susan L. Massey
Creative Education (CE) , 2014, DOI: 10.4236/ce.2014.56049
Abstract:

This article explores the use of informational text in preschool environments by reviewing the current literature related to the topic. While informational text is currently used on a limited basis in early childhood settings, the benefits of introducing young children to this genre through interactive shared reading or read-alouds can positively influence foundational literacy development. Through exposure to informational text, children enhance their vocabulary and language skills while developing conceptual background knowledge. Strong vocabulary and language skills are keys to the development of strong literacy skills upon entrance to formal schooling. Read-aloud routines scaffold the learning inherent in the language and literacy development resulting from interactions with informational text.

Randomised controlled trial of school-based humanistic counselling for emotional distress in young people: Feasibility study and preliminary indications of efficacy
Cooper Mick,Rowland Nancy,McArthur Katherine,Pattison Susan
Child and Adolescent Psychiatry and Mental Health , 2010, DOI: 10.1186/1753-2000-4-12
Abstract: Aims The purpose of this study was to test the feasibility of a randomised controlled trial comparing six weeks of humanistic school-based counselling versus waiting list in the reduction of emotional distress in young people, and to obtain initial indications of efficacy. Methods Following a screening procedure, young people (13 - 15 years old) who experienced emotional distress were randomised to either humanistic counselling or waiting list in this multi-site study. Outcomes were assessed using a range of self-report mental health measures, with the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ) acting as the primary outcome indicator. Results Recruitment procedures were successful, with 32 young people consenting to participate in the trial and 27 completing endpoint measures. Trial procedures were acceptable to all involved in the research. No significant differences were found between the counselling and waiting list groups in reductions in levels of emotional symptoms (Hedges' g = 0.03), but clients allocated to counselling showed significantly greater improvement in prosocial behaviour (g = 0.89) with an average effect size (g) across the nine outcome measures of 0.25. Participants with higher levels of depressive symptoms showed significantly greater change. Conclusion This study suggested that a randomised controlled trial of counselling in schools is acceptable and feasible, although initial indications of efficacy are mixed. Trial registration Current Controlled Trials ISRCTN68290510.
A genome-wide screen in human embryonic stem cells reveals novel sites of allele-specific histone modification associated with known disease loci
James G D Prendergast, Pin Tong, David C Hay, Susan M Farrington, Colin A M Semple
Epigenetics & Chromatin , 2012, DOI: 10.1186/1756-8935-5-6
Abstract: Using a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.These results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.In genome-wide studies of human chromatin, chromatin states are often assumed to be the same on both copies of a chromosome. However, an increasing number of studies has shown that a surprising level of heterogeneity can in fact exist between the chromatin states of different alleles. A recent study of allele-specific methylation (ASM) of DNA in various pluripotent and adult cell lines estimated that 23 to 37% of heterozygous single-nucleotide polymorphisms (SNPs) displayed differing levels of methylation between alleles, with most ASM sites attributable to heterozygote polymorphisms disrupting the guanine nucleotide in CpG motifs [1].Although DNA methylation is the best-characterized mechanism [2], it is not the only level of chromatin that has been shown to exhibit genome-wide allele-specific patterns in humans. For example, the nuclease DNaseI has been shown to cleave at sites of open chromatin and to preferentially target regulatory elements such as promoters and enhancers. Investigation of allele-specific patterns of DNaseI hypersensitivity has shown that 7% of DNaseI sites display allelic imbalances
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