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Search Results: 1 - 10 of 10332 matches for " Deborah Young "
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Gene Regulation Systems for Gene Therapy Applications in the Central Nervous System
Jerusha Naidoo,Deborah Young
Neurology Research International , 2012, DOI: 10.1155/2012/595410
Abstract: Substantial progress has been made in the development of novel gene therapy strategies for central nervous system (CNS) disorders in recent years. However, unregulated transgene expression is a significant issue limiting human applications due to the potential side effects from excessive levels of transgenic protein that indiscriminately affect both diseased and nondiseased cells. Gene regulation systems are a tool by which tight tissue-specific and temporal regulation of transgene expression may be achieved. This review covers the features of ideal regulatory systems and summarises the mechanics of current exogenous and endogenous gene regulation systems and their utility in the CNS. 1. Introduction Recent years have seen a plethora of potential gene therapy strategies for central nervous system (CNS) disorders. One of the major challenges gene therapy applications face clinically is the ability to control the level of expression or silencing of therapeutic genes in order to provide a balance between therapeutic efficacy and nonspecific toxicity due to overexpression of therapeutic protein or RNA interference-based sequences. Thus, the ability to regulate gene expression is essential as it reduces the likelihood of potentially initiating adverse events in patients. Although genes may be regulated at either the translational or posttranscriptional level, greatest success in gene regulation has been at the transcriptional level and as such gene regulation systems at a transcriptional level is the focus of this review. There are two classes of gene regulation systems—exogenously controlled gene regulation systems, which rely on an external factor (usually the administration of a drug) to turn transgene expression on or off, and endogenously controlled gene expression systems that rely on physiological stimuli to control transgene expression. This review covers the characteristics of an ideal regulatory system and summarises the mechanics of current gene regulation systems and their application to CNS disorders. 2. What Are the Characteristics of a Good Gene Regulation System? In order to be clinically effective, it has been proposed that regulatory systems should possess the following characteristics [1]:(i)Exhibit low basal expression. In the “off” state, transgene expression should be subphysiological. This would be crucial in the event of an adverse reaction to the treatment.(ii)Be positively induced. Induction of gene expression should be positive, through the presence, rather than the absence of an inducing stimulus so that patients can discontinue
Nucleic Acid-Based Therapy Approaches for Huntington's Disease
Tatyana Vagner,Deborah Young,Alexandre Mouravlev
Neurology Research International , 2012, DOI: 10.1155/2012/358370
Abstract: Huntington's disease (HD) is caused by a dominant mutation that results in an unstable expansion of a CAG repeat in the huntingtin gene leading to a toxic gain of function in huntingtin protein which causes massive neurodegeneration mainly in the striatum and clinical symptoms associated with the disease. Since the mutation has multiple effects in the cell and the precise mechanism of the disease remains to be elucidated, gene therapy approaches have been developed that intervene in different aspects of the condition. These approaches include increasing expression of growth factors, decreasing levels of mutant huntingtin, and restoring cell metabolism and transcriptional balance. The aim of this paper is to outline the nucleic acid-based therapeutic strategies that have been tested to date. 1. Introduction Huntington’s disease (HD is an inherited autosomal-dominant disorder characterised by loss of motor control, cognitive decline, psychiatric disturbances, and dementia, which progresses towards death within approximately 20 years of disease onset [1]. It is caused by an expansion of a CAG repeat in the huntingtin gene (Htt) that results in synthesis of an aberrant polyglutamine tract in huntingtin protein (HTT) and leads to neuronal dysfunction and neurodegeneration [2]. GABAergic medium-sized spiny neurons in the striatum are found to be most profoundly affected [3]; neuronal loss in the cerebral cortex, hippocampus, hypothalamus, substantia nigra, and in other brain structures has also been reported [4]. The mechanism by which the mutant huntingtin (mHtt) causes HD is still poorly understood. Normal HTT has been shown to have multiple distinct functions in cells, including antiapoptotic activity [5–7], roles in vesicular transport [8–11], neuronal gene transcription regulation [12, 13], and control of synaptic transmission [14, 15]. Consequently, the expression of long glutamine stretches either in the context of an N-terminal fragment or full-length HTT disrupts a wide variety of biological functions in cellular as well as animal models. To date, many animal models have been developed that closely mimic HD symptoms or pathology. Rodents (mouse, rat) and nonhuman primates have been used most extensively to test HD gene therapy strategies. In general, HD animal models can be divided into chemically induced and genetic models. The chemically induced HD models include excitotoxic lesion models (glutamate-, kainic acid-, quinolinic acid- (QA-) induced) [16–19] and mitochondrial dysfunction models (3-nitroprionic acid (3-NP), malonate induced) [20–22].
Factors and Home- and Community-Based Services (HCBS) that Predict Older Adults’ Residential Transitions  [PDF]
Ya-Mei Chen, Elaine Adams Thompson, Bobbie Berkowitz, Heather M. Young, Deborah Ward
Journal of Service Science and Management (JSSM) , 2011, DOI: 10.4236/jssm.2011.43043
Abstract: Objectives: This study identified specific personal factors and home- and community-based services (HCBS) that predict older adults’ residential transitions between community and institutional settings. Method: Logistic regression of interview data from 5294 participants in the Second Longitudinal Study of Aging identified predictors of three residential transition patterns and of frequency and duration of institutional services use. Results: Different HCBS services differently affected residential transitions. Informal support and paid personal care services (PCS) were the main factors affecting older adults’ ability to reside in community settings or to remain in community longer. Frequency of HCBS use and quantity of paid PCS used indicated direction of transitions: from communities into institutions or vice versa. Discussion: Integration of informal and formal care systems and attention to community-dwelling older adults’ HCBS use and paid PCS use, as a guide for possible future transitions, are tasks for community care professionals.
Atypical Clinical and Diagnostic Features in Ménétrier's Disease in a Child
Michael Chung,Jaime Pittenger,Deborah Flomenhoft,Jeffrey Bennett,Eun-Young Lee,Harohalli Shashidhar
Case Reports in Gastrointestinal Medicine , 2011, DOI: 10.1155/2011/480610
Abstract: Ménétrier's disease is one of the rarest protein-losing gastropathies in childhood. It is characterized clinically by non-specific gastrointestinal symptoms and edema, biochemically by hypoalbuminemia, and pathologically by enlarged gastric folds. In adults, this disease can be devastating with significant morbidity and mortality. In childhood, it is a self-limiting, transient and benign illness. Its treatment is largely supportive with total parenteral nutrition (TPN) while oral intake is encouraged. Acute onset of vomiting in healthy school age children can be initially explained by acute viral gastroenteritis. However, persistent vomiting associated with hematemesis and severe abdominal pain should warrant further work-up. This case report illustrates a self-limiting and rare cause of protein-losing enteropathy called Ménétrier's disease that presented with several variant clinical features not typically described in association with this entity.
Demographic, social cognitive and social ecological predictors of intention and participation in screening for colorectal cancer
Tess A Gregory, Carlene Wilson, Amy Duncan, Deborah Turnbull, Stephen R Cole, Graeme Young
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-38
Abstract: People aged 50 to 74 years recruited from the electoral roll completed a baseline survey (n = 376) and were subsequently invited to complete an immunochemical faecal occult blood test (iFOBT).Multivariate analyses revealed five predictors of intention to screen and two predictors of participation. Perceived barriers to CRC screening and perceived benefits of CRC screening were the only predictor of both outcomes. There was little support for social ecological factors, but measurement problems may have impacted this finding.This study has confirmed that the predictors of intention to screen for CRC and screening behaviour, although overlapping, are not the same. Research should focus predominantly on those factors shown to predict participation. Perceptions about the barriers to screening and benefits of screening are key predictors of participation, and provide a focus for intervention programs.Colorectal Cancer (CRC) is the most commonly diagnosed internal cancer in Australia affecting both men and women, and the second most common cause of cancer-related death in the Western world [1]. Given the slow progression of the disease, strategies currently focus on the early detection of curable lesions through screening, using endoscopic means or faecal occult blood tests (FOBTs). FOBTs detect minute amounts of blood in the stool; this facilitates the detection of neoplasia at early, curable stages [2]. Population screening with FOBT has been shown to reduce mortality by 15-35% assessed on an intention-to-screen basis relative to an unscreened population [3]. Moreover, the newer immunochemical FOBTs achieve better overall performance than conventional guaiac-based tests [4], making them more effective for use in colorectal cancer screening. Nonetheless, the efficacy of these screening programs depends in part on high participation rates and in many cases, this has not been achieved. For instance, the participation rate in the initial roll-out of the Australian National B
The evolutionary history of mitochondrial porins
Matthew J Young, Denice C Bay, Georg Hausner, Deborah A Court
BMC Evolutionary Biology , 2007, DOI: 10.1186/1471-2148-7-31
Abstract: In this work, the wealth of recent sequence information was used to perform a comprehensive analysis of the evolutionary history of mitochondrial porins. Fungal porin sequences were well represented, and newly-released sequences from stramenopiles, alveolates, and seed and flowering plants were analyzed. A combination of Neighbour-Joining and Bayesian methods was used to determine phylogenetic relationships among the proteins. The aligned sequences were also used to reassess the validity of previously described eukaryotic porin motifs and to search for signature sequences characteristic of VDACs from plants, animals and fungi. Secondary structure predictions were performed on the aligned VDAC primary sequences and were used to evaluate the sites of intron insertion in a representative set of the corresponding VDAC genes.Our phylogenetic analysis clearly shows that paralogs have appeared several times during the evolution of VDACs from the plants, metazoans, and even the fungi, suggesting that there are no "ancient" paralogs within the gene family. Sequence motifs characteristic of the members of the crown groups of organisms were identified. Secondary structure predictions suggest a common 16 β-strand framework for the transmembrane arrangement of all porin isoforms. The GLK (and homologous or analogous motifs) and the eukaryotic porin motifs in the four representative Chordates tend to be in exons that appear to have changed little during the evolution of these metazoans. In fact there is phase correlation among the introns in these genes. Finally, our preliminary data support the notion that introns usually do not interrupt structural protein motifs, namely the predicted β-strands. These observations concur with the concept of exon shuffling, wherein exons encode structural modules of proteins and the loss and gain of introns and the shuffling of exons via recombination events contribute to the complexity of modern day proteomes.Mitochondrial porins were first ide
JNK activation is responsible for mucus overproduction in smoke inhalation injury
Won-II Choi, Olga Syrkina, Kun Young Kwon, Deborah A Quinn, Charles A Hales
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-172
Abstract: We intubated mice and exposed them to smoke from burning cotton for 15 min. Their lungs were then isolated 4 and 24 h after inhalation injury. Three groups of mice were subjected to the smoke inhalation injury: (1) wild-type (WT) mice, (2) mice lacking JNK1 (JNK1-/- mice), and (3) WT mice administered a JNK inhibitor. The JNK inhibitor (SP-600125) was injected into the mice 1 h after injury.Smoke exposure caused an increase in the production of mucus in the airway epithelium of the mice along with an increase in MUC5AC gene and protein expression, while the expression of MUC5B was not increased compared with control. We found increased MUC5AC protein expression in the airway epithelium of the WT mice groups both 4 and 24 h after smoke inhalation injury. However, overproduction of mucus and increased MUC5AC protein expression induced by smoke inhalation was suppressed in the JNK inhibitor-treated mice and the JNK1 knockout mice. Smoke exposure did not alter the expression of MUC1 and MUC4 proteins in all 3 groups compared with control.An increase in epithelial MUC5AC protein expression is associated with the overproduction of mucus in smoke inhalation injury, and that its expression is related on JNK1 signaling.Smoke inhalation injury is a serious threat to victims of house fires, explosions, and other disasters involving fire and smoke. This type of injury alone can be lethal as shown in the Cocoanut Grove fire, in which 492 people died, most without burns [1]. In the Rhode Island nightclub fire, 95 people died (out of 350 victims and survivors of this tragedy), and 187 people were treated for smoke inhalation lung injury and burns [2]. Autopsy series from fire victims show sloughed mucosal cells and a collection of proteinaceous debris obstructing the airways [3]. There are multiple case reports in adults and children of airway obstruction due to these tracheobronchial casts [3]. The airway microenvironment is significantly altered by smoke inhalation with lung par
Glycemic index and glycemic load are associated with some cardiovascular risk factors among the PREMIER study participants
Pao-Hwa Lin,Chuhe Chen,Deborah R. Young,Diane Mitchell
Food & Nutrition Research , 2012, DOI: 10.3402/fnr.v56i0.9464
Abstract: Background: The clinical significance of glycemic index (GI) and glycemic load (GL) is inconclusive. Objective : This study was conducted to examine the association of GI and GL with clinical cardiovascular disease (CVD) risk factors including body weight, blood pressure (BP), serum lipids, fasting glucose, insulin and homocysteine over time among the PREMIER participants. Design: PREMIER was an 18-month randomized lifestyle intervention trial, conducted from 2000 to 2002, designed to help participants reduce BP by following the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, losing weight, reducing sodium and increasing physical activity. GI and GL were estimated from 24 h diet recall data at baseline, 6 and 18 months after intervention. PROC MIXED model was used to examine the association of changes in GI or GL with changes in CVD risk factors. Results: A total of 756 randomized participants, 62% females and 34% African Americans and who averaged 50.0±0.3 years old and 95.3±0.7 kg, were included in this report. Neither GI nor GL changes was associated with changes in any risk factors at 6 months. At 18 months, however, the GI change was significantly and positively associated with total cholesterol (TC) change only (p<0.05, β = 23.80±12.11 mg/dL or 0.62±0.31 mmol/L) with a significant age interaction. The GL change was significantly associated with TC (p=0.02, β = 0.28±0.15 mg/dL or 0.01±0.00 mmol/L) positively and with low density lipoprotein cholesterol (LDL-C) changes negatively (p=0.03, β = 0.01±0.00 mg/dL or 0.00±0.00 mmol/L), and significant age interactions were observed for both. Conclusion: GI and GL was associated with TC and LDL-C after controlling for energy, fat and fiber intake and other potential confounders and the associations were modified by age. Further investigation into this relationship is important because of its potential clinical impact.
Identifying Adolescent Metabolic Syndrome Using Body Mass Index and Waist Circumference
Sarah M. Camhi, PhD,JoAnn Kuo, MPH,Deborah R. Young, PhD
Preventing Chronic Disease , 2008,
Abstract: IntroductionMetabolic syndrome is increasing among adolescents. We examined the utility of body mass index (BMI) and waist circumference to identify metabolic syndrome in adolescent girls.MethodsWe conducted a cross-sectional analysis of 185 predominantly African American girls who were a median age of 14 years. Participants were designated as having metabolic syndrome if they met criteria for 3 of 5 variables: 1) high blood pressure, 2) low high-density lipoprotein cholesterol level, 3) high fasting blood glucose level, 4) high waist circumference, and 5) high triglyceride level. We predicted the likelihood of the presence of metabolic syndrome by using previously established cutpoints of BMI and waist circumference. We used stepwise regression analysis to determine whether anthropometric measurements significantly predicted metabolic syndrome.ResultsOf total participants, 18% met the criteria for metabolic syndrome. BMI for 118 (64%) participants was above the cutpoint. Of these participants, 25% met the criteria for metabolic syndrome, whereas only 4% of participants with a BMI below the cutpoint met the criteria for metabolic syndrome (P <.001). Girls with a BMI above the cutpoint were more likely than girls with a BMI below the cutpoint to have metabolic syndrome (P = .002). The waist circumference for 104 (56%) participants was above the cutpoint. Of these participants, 28% met the criteria for metabolic syndrome, whereas only 1% of participants with a waist circumference below the cutpoint met the criteria for metabolic syndrome (P <.001). Girls with a waist circumference above the cutpoint were more likely than girls with a waist circumference below the cutpoint to have metabolic syndrome (P = .002). Stepwise regression showed that only waist circumference significantly predicted metabolic syndrome.ConclusionBoth anthropometric measures were useful screening tools to identify metabolic syndrome. Waist circumference was a better predictor of metabolic syndrome than was BMI in our study sample of predominantly African American female adolescents living in an urban area.
AAV-Mediated Overexpression of Neuroserpin in the Hippocampus Decreases PSD-95 Expression but Does Not Affect Hippocampal-Dependent Learning and Memory
Vicky W. K. Tsang, Deborah Young, Matthew J. During, Nigel P. Birch
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091050
Abstract: Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno-associated virus (AAV) vector expression system to investigate the effect of neuroserpin on hippocampal-dependent learning and memory in the young adult rat. A FLAG-tagged neuroserpin construct was initially characterized by in vitro transcription/translation and transfection into HEK293 cells and shown to interact with tPA and be targeted to the secretory pathway. Targeted injection of a chimeric AAV1/2 vector expressing FLAG-neuroserpin resulted in localized overexpression in the dorsal hippocampus. Neuroserpin overexpression led to the appearance of an unstable neuroserpin:tPA complex in zymographic assays consistent with interaction with endogenous tPA in vivo. Rats overexpressing neuroserpin also showed a significant decrease in the levels of postsynaptic density protein 95, a major postsynaptic scaffolding protein. Three weeks after injection, a range of behavioural tests was performed to measure spatial and associative learning and memory, as well as innate and acquired fear. These tests provided no evidence of a role for neuroserpin in hippocampal-dependent learning and memory. In summary this study does not support a role for neuroserpin in hippocampal-dependent learning and memory in young adult rats but does suggest an involvement of neuroserpin in hippocampal synaptic plasticity.
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