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Search Results: 1 - 10 of 405136 matches for " Timothy M. Crombleholme "
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Pseudotyped AAV Vector-Mediated Gene Transfer in a Human Fetal Trachea Xenograft Model: Implications for In Utero Gene Therapy for Cystic Fibrosis
Sundeep G. Keswani, Swathi Balaji, Louis Le, Alice Leung, Anna B. Katz, Foong-Yen Lim, Mounira Habli, Helen N. Jones, James M. Wilson, Timothy M. Crombleholme
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043633
Abstract: Background Lung disease including airway infection and inflammation currently causes the majority of morbidities and mortalities associated with cystic fibrosis (CF), making the airway epithelium and the submucosal glands (SMG) novel target cells for gene therapy in CF. These target cells are relatively inaccessible to postnatal gene transfer limiting the success of gene therapy. Our previous work in a human-fetal trachea xenograft model suggests the potential benefit for treating CF in utero. In this study, we aim to validate adeno-associated virus serotype 2 (AAV2) gene transfer in a human fetal trachea xenograft model and to compare transduction efficiencies of pseudotyping AAV2 vectors in fetal xenografts and postnatal xenograft controls. Methodology/Principal Findings Human fetal trachea or postnatal bronchus controls were xenografted onto immunocompromised SCID mice for a four-week engraftment period. After injection of AAV2/2, 2/1, 2/5, 2/7 or 2/8 with a LacZ reporter into both types of xenografts, we analyzed for transgene expression in the respiratory epithelium and SMGs. At 1 month, transduction by AAV2/2 and AAV2/8 in respiratory epithelium and SMG cells was significantly greater than that of AAV2/1, 2/5, and 2/7 in xenograft tracheas. Efficiency in SMG transduction was significantly greater in AAV2/8 than AAV2/2. At 3 months, AAV2/2 and AAV2/8 transgene expression was >99% of respiratory epithelium and SMG. At 1 month, transduction efficiency of AAV2/2 and AAV2/8 was significantly less in adult postnatal bronchial xenografts than in fetal tracheal xenografts. Conclusions/Significance Based on the effectiveness of AAV vectors in SMG transduction, our findings suggest the potential utility of pseudotyped AAV vectors for treatment of cystic fibrosis. The human fetal trachea xenograft model may serve as an effective tool for further development of fetal gene therapy strategies for the in utero treatment of cystic fibrosis.
The Effects of Fetal Surgery on Retinopathy of Prematurity Development
Sudha Nallasamy, Stefanie L. Davidson, Lori J. Howell, Holly Hedrick, Alan W. Flake, Timothy M. Crombleholme, N. Scott Adzick and Terri L. Young
Ophthalmology and Eye Diseases , 2012,
Abstract: Background: Fetal surgery is selectively offered for severe or life-threatening fetal malformations. These infants are often born prematurely and are thus at risk for retinopathy of prematurity (ROP). It is not known whether fetal surgery confers an increased risk of developing severe ROP relative to published rates in standard premature populations ≤37 weeks of age grouped by birth weight (<1500 grams or ≥1500 grams). Design: This is a retrospective chart review. Methods: We reviewed the charts of 137 patients who underwent open fetal/fetoscopic surgery from 1996–2004. Surgical indications included twin-twin transfusion syndrome (TTTS), myelomeningocele (MMC), congenital diaphragmatic hernia (CDH), sacrococcygeal teratoma (SCT), cystic adenomatoid malformation of the lung (CCAM), and twin reversed arterial perfusion sequence (TRAP). Of these, 17 patients had local ROP examination data. Binomial tests were performed to assess whether rates of ROP in our fetal/fetoscopic surgery cohort were significantly different from published rates. Results: There were 5 patients each with an underlying diagnosis of TTTS and MMC, 2 patients each with CDH and TRAP, and 1 patient each with SCT, CCAM, and mediastinal teratoma. The mean gestational age at surgery was 234/7 ± 23/7 weeks, mean gestational age at birth was 30 ± 25/7 weeks, and mean birth weight was 1449 ± 510 grams (610–2485). Compared to published rates of ROP and threshold ROP, our fetal surgery patients had significantly higher rates of ROP and threshold ROP in both the <1500 grams and the ≥1500 grams group (all p-values < 0.05). Conclusions: Fetal/fetoscopic surgery appears to significantly increase the rate of ROP and threshold ROP development. Greater numbers are needed to confirm these observations.
Adenoviral-Mediated Placental Gene Transfer of IGF-1 Corrects Placental Insufficiency via Enhanced Placental Glucose Transport Mechanisms
Helen N. Jones, Timothy Crombleholme, Mounira Habli
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074632
Abstract: Previous work in our laboratory demonstrated that over-expression of human insulin-like growth factor -1 (hIGF-1) in the placenta corrects fetal weight deficits in mouse, rat, and rabbit models of intrauterine growth restriction without changes in placental weight. The underlying mechanisms of this effect have not been elucidated. To investigate the effect of intra-placental IGF-1 over-expression on placental function we examined glucose transporter expression and localization in both a mouse model of IUGR and a model of human trophoblast, the BeWo Choriocarcinoma cell line. Methods At gestational day 18, animals were divided into four groups; sham-operated controls, uterine artery branch ligation (UABL), UABL+Ad-hIGF-1 (108 PFU), UABL+Ad-LacZ (108 PFU). At gestational day 20, pups and placentas were harvested by C-section. For human studies, BeWo choriocarcinoma cells were grown in F12 complete medium +10%FBS. Cells were incubated in serum-free control media ±Ad-IGF-1 or Ad-LacZ for 48 hours. MOIs of 10:1 and 100:1 were utilized. The RNA, protein expression and localization of glucose transporters GLUT1, 3, 8, and 9 were analyzed by RT-PCR, Western blot and immunohistochemistry. Results In both the mouse placenta and BeWo, GLUT1 regulation was linked to altered protein localization. GLUT3, localized to the mouse fetal endothelial cells, was reduced in placental insufficiency but maintained with Ad-I GF-1 treatment. Interestingly, GLUT8 expression was reduced in the UABL placenta but up-regulated following Ad-IGF-1 in both mouse and human systems. GLUT9 expression in the mouse was increased by Ad-IGF-1 but this was not reflected in the BeWo, where Ad-IGF-1 caused moderate membrane relocalization. Conclusion Enhanced GLUT isoform transporter expression and relocalization to the membrane may be an important mechanism in Ad-hIGF-1mediated correction of placental insufficiency.
Simplified Model of a Layer of Interconnects under a Spiral Inductor  [PDF]
Sonia M. Holik, Timothy D. Drysdale
Journal of Electromagnetic Analysis and Applications (JEMAA) , 2011, DOI: 10.4236/jemaa.2011.36031
Abstract: An empirical effective medium approximation that provides a homogeneous equivalent for a layer of interconnects un-derneath a spiral inductor is presented. When used as part of a numerical 3D model of the inductor, this approach yields a faster simulation that uses less memory, yet still predicts the quality factor and inductance to within 1%. We expect this technique to find use in the electromagnetic modeling of System-on-Chip.
Rearing Velocity Impacts on Landlocked Fall Chinook Salmon (Oncorhynchus tshawytscha) Growth, Condition, and Survival  [PDF]
Timothy M. Parker, Michael E. Barnes
Open Journal of Animal Sciences (OJAS) , 2014, DOI: 10.4236/ojas.2014.45031
Abstract: Juvenile landlocked Chinook salmon (Oncorhynchus tshawytscha) (mean ± SD initial weight 2.6 ± 0.7 g, fork length 6.3 ± 0.5) were reared in three different water velocities [0.5, 1.5 and 3.0 body length/s (BL/s)] for four weeks to determine possible effects of water velocity on growth, condition, and survival. Fish were sampled for weight, fork length, condition factor, hepatosomatic index (HSI), viscerosomatic index (VSI), and fin erosion after four weeks of feeding to satiation. At the end of the feeding trial, the fish were handled and transported to simulate stocking, with survival observed over the following 10 d. Following four weeks of feeding, fish reared in 0.5 and 1.5 BL/s had the same growth and food conversion ratio, but fish reared at 3.0 BL/s had a significant reduction in both metrics. Furthermore, fish reared at 1.5 BL/s had a significantly higher condition factor than fish reared in other treatments. No significant differences were found for HSI, VSI, fin erosion, or survival. The results from this study indicate that a moderate velocity (1.5 BL/s), which is necessary for circular tanks to be self-cleaning, is not detrimental to fish growth or condition, but a faster water velocity (3.0 BL/s) negatively affects fish growth and food utilization.
Brain Signaling in Psychiatric Disorders: What Can They Tell Us in the Absence of Behavioral Differences?  [PDF]
Jodi M. Gilman, James M. Bjork, Timothy E. Wilens
Journal of Behavioral and Brain Science (JBBS) , 2015, DOI: 10.4236/jbbs.2015.58033
Abstract: This is a commentary on the often-observed phenomenon of observing task-based brain signaling differences between clinical populations and healthy control participants in the absence of any behavioral decrements in the clinical group. We offer several explanations for why brain-based differences amid normative performance may be of interest to researchers and clinicians. First, neural processing in the clinical group may not be as efficient as that in the control group. Second, differences in activation could reveal important differences in the cognition behind the (normative) behavior. Third, differences in activation may be prognostic biomarkers of injury or decline. In addition, we contend that similar behavior between groups is important in properly interpreting brain data. Finally, we offer caveats and future directions to further clarify brain mechanisms underlying behavior in clinical populations.
CODEHOP-mediated PCR – A powerful technique for the identification and characterization of viral genomes
Timothy M Rose
Virology Journal , 2005, DOI: 10.1186/1743-422x-2-20
Abstract: Only a very small fraction of the vast number of viral species belonging to the different virus families have been identified and characterized to date. The majority of these uncharacterized viral species are found in host organisms which have not been targeted in biomedical, plant or animal research. However, recent reports have noted an increase in the occurrence of viral diseases, not only in humans, but in animals and plants as well. While some of this rise may reflect more effective surveillance techniques, disease outbreaks caused by novel cross-species infections and/or subsequent virus recombination events have occurred [1]. Therefore, the development of tools for the detection of viruses, the characterization of their genomes and the study of their evolution, becomes important, not only for basic scientific study, but also for the protection of public health and the well-being of the plant and animal life that surrounds us.We have developed a novel technology to identify and characterize distantly related gene sequences based on consensus-degenerate hybrid oligonucleotide primers (CODEHOPs)[2]. CODEHOPs are designed from amino acid sequence motifs that are highly conserved within members of a gene family, and are used in PCR amplification to identify unknown related family members. We have developed and implemented a computer program that is accessible over the World Wide Web to facilitate the design of CODEHOPs from a set of related protein sequences [3]. This site is linked to the Block Maker multiple sequence alignment site [4] on the BLOCKS WWW server [5] hosted at the Fred Hutchinson Cancer Research Center, Seattle, WA.We have utilized the CODEHOP technique to develop novel assays to detect previously unknown viral species by targeting sequence motifs within stable housekeeping genes that are evolutionarily conserved between different members of virus families. Using CODEHOPs derived from conserved motifs within retroviral reverse transcriptases, we ha
Gaucher disease: clinical profile and therapeutic developments
Timothy M Cox
Biologics: Targets and Therapy , 2010, DOI: http://dx.doi.org/10.2147/BTT.S7582
Abstract: ucher disease: clinical profile and therapeutic developments Review (9612) Total Article Views Authors: Timothy M Cox Published Date December 2010 Volume 2010:4 Pages 299 - 313 DOI: http://dx.doi.org/10.2147/BTT.S7582 Timothy M Cox Department of Medicine, University of Cambridge, Cambridge, UK Abstract: Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme ), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential 'niche busters'. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.
Ethnic Forces in Collective Action: Diversity, Dominance, and Irrigation in Tamil Nadu
Timothy M. Waring
Ecology and Society , 2011, DOI: 10.5751/es-04265-160401
Abstract: Mounting evidence suggests that ethnic interactions damage cooperation in the provision of public goods, yet very few studies of collective action in common pool resource management have found strong evidence for the effects of ethnic diversity. Research on both public goods and common pool resource management that does find negative ethnic effects on cooperation tend to ignore the importance of interethnic relationships, particularly ethnic inequality, stratification, or dominance. This study presents data from agricultural villages in Tamil Nadu's Palani Hills to test the importance of a range of ethnic effects using caste interactions in a traditional irrigation system. I provide corroborating evidence of a negative cooperative effect of ethnic diversity, but also demonstrate that factors of ethnic dominance such as hierarchical stratification and demographic dominance strongly determine outcomes in collective irrigation management. I argue that the most important measure of equity, irrigation access, is socially, technologically, and institutionally embedded, and demonstrate that the distribution of irrigation channels is explained by measures of inequality, such as wealth inequality, Dalit status, and demographic dominance.
Preliminary phytochemistry and in vitro antimicrobial properties of aqueous and methanol extracts of Icacina trichantha Oliv. Leaf
O. TIMOTHY,M. IDU
International Journal of Medicinal and Aromatic Plants , 2011,
Abstract: Emergence of resistant strains of pathogenic microorganisms has continued to pose major health concern about the efficacy of several antibiotic therapies available in the market today. The search for new and effective antimicrobial substances from sources such as plants has become a necessary approach towards overcoming this medical challenge. This study was designed to determine the preliminary phytochemical composition and in vitro antimicrobial properties of aqueous and methanol extracts of Icacina trichantha Oliv. leaf. The fresh leaves of I. trichantha were collected in Jesse, Delta State, Nigeria cleaned, dried and extracted with distilled water and analytical methanol by maceration method. Standard qualitative screening revealed that the compounds of pharmacological interest present in the plant were alkaloids, tannins and saponins. Both extracts showed broad spectrum antimicrobial activities, which were clearly dose dependent. However, the methanol extract had preferable activity than corresponding concentrations of the aqueous extract. In the agar-well diffusion assay, highest inhibition zone diameters of 25.00 mm and 21.00 mm were recorded with Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli respectively. The broth micro-dilution assay gave minimal inhibitory concentration values ranging from 3.125 to 100 mg/ml and minimal bactericidal concentration values ranging from 6.25 to 100 mg/ml. The methanol extract, at higher concentrations, also compared favorably with pefloxacin, a positive control.
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