35 results on '"Schmelzer L"'
Search Results
2. Dermal Pesticide Exposure During Seed Corn Production
- Author
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Hughes, B. J., Olsen, L. G., Schmelzer, L., Hite, P., and Bills, P.
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- 2005
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3. Sodium Sesqui Carbonate—a New Chemical for Swimming Pool pH-Alkalinity Control
- Author
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Coleman, R. B., Gates, J. M., Grove, J. H., and Schmelzer, L. L.
- Published
- 1971
4. Geringe diagnostische Wertigkeit des CRP bei low-grade Infektionen von Hüftendoprothesen
- Author
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Dobrindt, O, Schmelzer, L, Müller, M, and Perka, CF
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Fragestellung: Der Ausschluss einer periprothetischen Infektion sollte vor jedem Revisionseingriff in der Hüftendoprothetik erfolgen. Dies erfolgt üblicherweise durch die klinischen Untersuchung, Bestimmung der Entzündungsparameter und Gelenkpunktion. Das C-reaktive Protein (CRP) hat [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2014)
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- 2014
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5. Alpha1-antitrypsin and alpha2-macroglobulin in newborn infants: I. The Influence of Perinatal Complications
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Göbel, U., Petrich, C., von Voss, H., and Schmelzer, L.
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- 1978
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6. CASE STUDY: Reducing cheatgrass (Bromus tectorum L.) fuel loads using fall cattle grazing
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Schmelzer, L., primary, Perryman, B., additional, Bruce, B., additional, Schultz, B., additional, McAdoo, K., additional, McCuin, G., additional, Swanson, S., additional, Wilker, J., additional, and Conley, K., additional
- Published
- 2014
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7. O.8 Intrathecal delivery of AAV9 vectors to model and rescue a large animal model of SMA
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Duque, S., primary, Porensky, P., additional, William, D.A., additional, Odermatt, P., additional, Nlend, R. Nlend, additional, Bevan, A.K., additional, Foust, K., additional, Braun, L., additional, Schmelzer, L., additional, Schumperli, D., additional, Kaspar, B.K., additional, and Burghes, A.H.M., additional
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- 2013
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8. Alpha1-antitrypsin and alpha2-macroglobulin in newborn infants
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Göbel, U., Petrich, C., Voss, H., and Schmelzer, L.
- Abstract
The levels of alpha
1 -antitrypsin and alpha2 -macroglobulin in the plasma of 129 newborns were determined. The infants were divided into 3 groups according to their perinatal history.- Published
- 1978
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9. Exposure factors in occupational coccidioidomycosis.
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Schmelzer, L L, primary and Tabershaw, I R, additional
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- 1968
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10. CONTROL OF RADIATION HAZARDS. ROLE OF THE ENVIRONMENTAL HEALTH SCIENTIST.
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Schmelzer, L
- Published
- 1969
11. O.8 Intrathecal delivery of AAV9 vectors to model and rescue a large animal model of SMA.
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Porensky, P., William, D.A., Odermatt, P., Nlend, R. Nlend, Bevan, A.K., Foust, K., Braun, L., Schmelzer, L., Schumperli, D., Kaspar, B.K., and Burghes, A.H.M.
- Subjects
- *
SPINAL muscular atrophy , *ADENO-associated virus , *GENETIC vectors , *MOTOR neurons , *DISEASE vectors , *GENETIC transformation , *INFANT death - Abstract
Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants and results in the loss of motoneurons (MNs). Gene transfer based on systemic delivery of scAAV9 viral vector expressing human SMN (hSMN) has successfully rescued severe SMA mice and lead to the development of clinical trials. We have previously demonstrated that intrathecal delivery of scAAV9 in the pig results in efficient transduction of MNs and thus is an alternative to intravenous delivery. We now propose (1) to create a large animal model of SMA by knocking down SMN in MNs with a scAAV9 vector expressing shRNA (2) to correct the SMA phenotype using a second injection of scAAV9 vector expressing hSMN. We injected 5-day old piglets with a single intrathecal dose of scAAV9-shRNA (6.5×10e12vg/kg, n=6). A few weeks following injection, piglets developed symptoms resembling SMA (abnormal gait and posture) with hind limbs being particularly affected. The phenotype progressed rapidly to a general weakness with posterior paralysis. EMG analysis showed evidence of an active denervation process. We also observed a decrease in both the compound muscle action potential amplitude and the estimated number of MNs. This is remarkably similar to what is observed in SMA patients. Next, we investigated correction of the SMA phenotype. 5-day old piglets (n=4) received both scAAV9-shRNA (6.5×10e12 vg/kg) and scAAVV9-hSMN (8×10e12 vg/kg) with a 24hrs interval between injections. Two piglets showed no phenotype whereas the other two developed weakness that did not progress. Importantly, no EMG abnormality was observed. We have demonstrated that knockdown of SMN in the pig results in a phenotype displaying the key features of SMA. Furthermore we showed that early reintroduction of SMN significantly alters the phenotype. We are now determining whether later reintroduction of SMN at the first sign of symptoms has a therapeutic benefit as this more closely mimics what will occur in a human clinical trial. [ABSTRACT FROM AUTHOR]
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- 2013
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12. Examining the Relationship Between Meaningful Engagement and Well-Being Across Men and Women.
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Schmelzer L, Peters S, Mosiniak G, and Raina KD
- Abstract
While engagement in meaningful activities is associated with well-being, the influence of gender on this relationship is unknown. The study aims to (a) examine the difference between meaningful engagement and well-being for individuals who identify as men and women and (b) explore the association between engagement and well-being in men and women. In this observational study, 256 community-dwelling individuals completed meaningful engagement and well-being measures. Between-group t tests indicated no significant differences between men and women for engagement ( t = 0.595, p = .552) and well-being ( t = 0.818, p = .414). There were fair, positive correlations ( r s = .376; p < .01) between engagement and well-being for men and moderate positive correlations ( r s = .567; p < .01) between engagement and well-being for women. Self-identified gender may influence the relationship between engagement in meaningful activities and the sense of well-being it provides., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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13. DNA methylation-based organ tissue identification: Marker identification, SNaPshot multiplex assay development, and interlaboratory comparison.
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Kim BM, Park SU, Schmelzer L, Yang SB, Lee SD, Kim MY, Naue J, and Lee HY
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- Female, Humans, Male, Brain metabolism, CpG Islands genetics, DNA Primers, Forensic Genetics methods, Genetic Markers, Kidney chemistry, Liver chemistry, Lung chemistry, Multiplex Polymerase Chain Reaction, Muscle, Skeletal chemistry, Muscle, Skeletal metabolism, Organ Specificity, Polymerase Chain Reaction, Republic of Korea, East Asian People, DNA Methylation
- Abstract
Identifying body fluids and organ tissues is highly significant as they can offer crucial evidence in criminal investigations and aid the court in making informed decisions, primarily through evaluating the biological source and possibly at the activity level up to death or fatal damage. In this study, organ tissue-specific CpG markers were identified from Illumina's methylation EPIC array data of nine organ tissues, including epidermis, dermis, heart, skeletal muscle, blood, kidney, brain, lung, and liver, from autopsies of 10 Koreans. Through the validation test using 43 samples, 18 hypomethylation markers, with two markers for each organ tissue type, were selected to construct a SNaPshot assay. Two multiplex assays involving forward and reverse SBE primers were designed to help investigators accurately determine the organ origin of the analyzed tissue samples through repeated analysis of the same PCR products for markers. The developed multiplex demonstrated high accuracy, achieving 100.0 % correct detection of the presence of nine organ tissue types in 88 samples from autopsies of 10 Asians. However, two lung samples showed additional positive indications of the presence of blood. An interlaboratory comparison using 80 autopsy samples (heart, skeletal muscle, blood, kidney cortex, kidney medulla, brain, lung, and liver) from 10 individuals in Germany revealed overall comparable results with correct detection of the presence of eight organ tissue types in 92.5 % samples (74 of 80 samples). In the case of six samples, it was impossible to determine the correct tissue successfully due to drop-outs of unmethylation signals at target tissue marker loci. One of these lung samples revealed only non-intended off-target signals for blood. The observed differences might be due to differences in sample collection during routine autopsy, technical differences due to the PCR cycler, and the threshold used for signal calling. Indicating the presence of additional tissue type and off-target unmethylation signals seems alleviated by applying more stringent hypomethylation thresholds. Therefore, the developed SNaPshot multiplex assays will be valuable for forensic investigators dealing with organ tissue identification, as well as for prosecutors and defense aiming to establish the circumstances that occurred at the crime scene., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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14. Meaningful Engagement as a Predictor of Psychological Well-Being for Adults With Low Income.
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Schmelzer L and Raina KD
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- Humans, Adult, Cross-Sectional Studies, Poverty, Surveys and Questionnaires, Psychological Well-Being, Occupational Therapy
- Abstract
Importance: The activities that people engage in influence their well-being. Adults with low income have limited resources, which can affect their engagement in meaningful activities. Exploring the connection between meaningful engagement and well-being is an important step in providing occupational justice for this marginalized population., Objective: To examine whether engagement in meaningful activities uniquely contributes to well-being for adults with low income after controlling for demographic variables., Design: Cross-sectional exploratory study design., Setting: Community agencies serving adults with low income, a local library, and a university union hall in northwest Ohio., Participants: Adults with low income (N = 186)., Outcomes and Measures: Participants completed a demographic questionnaire, the Engagement in Meaningful Activities Survey (EMAS), and the World Health Organization-5 Wellbeing Index (WHO-5). We examined the influence of demographics and EMAS on the WHO-5., Results: We identified a moderate correlation between the EMAS and WHO-5 (r = .52, p ≤ .05). Linear regression revealed an R2 = .27, F(7, 164) = 8.75, p < .001, with the EMAS and participant attributes as predictor variables. The R2 changed to .02 (p = .85) without the EMAS in the model., Conclusions and Relevance: Findings support the need for and use of meaningful activities to support well-being and health for adults with low income. What This Article Adds: Findings build on the evidence supporting the role of engagement in meaningful activities by drawing connections to a well-known and widely used measure of subjective psychological well-being and applying these connections to adults with low income. Occupational therapy practitioners can use measures such as the EMAS to strategically infuse aspects of meaning that promote engagement and foster well-being., (Copyright © 2023 by the American Occupational Therapy Association, Inc.)
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- 2023
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15. The Development and Validation of the Planning to Make Meals Performance Measure.
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Schmelzer L, Stanger H, and Hughes R
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- Cross-Sectional Studies, Humans, Poverty, Psychometrics, Cooking, Meals
- Abstract
The Planning to Make Meals Performance Measure (PMMPM) was initially created as an outcome measure for an occupation-based program dedicated to helping individuals living in poverty maximize their food resources. This article briefly describes the PMMPM and the results of a cross-sectional study examining construct validity. Forty-two participants completed the PMMPM, Food Skills Confidence Measure (FSCM), and Cooking Skills Confidence Measure (CSCM). Analysis using Spearman's correlations revealed that one or more PMMPM score significantly correlated with the FSCM ( r = .37-.50, p ≤ .05) and the CSCM ( r = .44-.49, p = .01). These findings add to the psychometric properties of the PMMPM, promoting its usefulness as an alternative to self-report measures for programs seeking to enhance food, cooking, or resource management skills. Creating authentic and direct performance measures that assess complex constructs or skills is another way occupational therapy can contribute to health and well-being.
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- 2022
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16. Promoting Health Through Engagement in Occupations That Maximize Food Resources.
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Schmelzer L and Leto T
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- Community-Based Participatory Research, Health Promotion organization & administration, Humans, Program Evaluation, Food Services, Food Supply statistics & numerical data, Health Promotion methods, Occupations, Poverty
- Abstract
Poverty is a complex problem in the United States with far-reaching consequences, often leading to a lack of food or lack of access to food. Proper nutrition and food intake are foundational to health and well-being. This participatory action research (PAR) project explored the challenges associated with living in poverty and managing food resources. Stakeholders engaged in a multiphase PAR process, which resulted in the development and implementation of a 7-wk occupation-based program. The program promotes graded learning of specific skills for managing food resources and emphasizes empowering each participant. Preliminary results indicate statistically significant improvements in participants' ability to make meals with certain food items and in perceived satisfaction and performance in self-identified activities related to food resource management. These findings support the feasibility of the program and the need for participant-driven, occupation-based approaches to improving food security., (Copyright © 2018 by the American Occupational Therapy Association, Inc.)
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- 2018
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17. Variable clinical phenotype in two siblings with Aicardi-Goutières syndrome type 6 and a novel mutation in the ADAR gene.
- Author
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Schmelzer L, Smitka M, Wolf C, Lucas N, Tüngler V, Hahn G, Tzschach A, Di Donato N, Lee-Kirsch MA, and von der Hagen M
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- Adolescent, Child, Preschool, Female, Humans, Male, Mutation, Phenotype, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations diagnosis, Nervous System Malformations genetics, RNA-Binding Proteins genetics
- Abstract
Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)
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- 2018
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18. A large animal model of spinal muscular atrophy and correction of phenotype.
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Duque SI, Arnold WD, Odermatt P, Li X, Porensky PN, Schmelzer L, Meyer K, Kolb SJ, Schümperli D, Kaspar BK, and Burghes AH
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- Animals, Biomarkers, Dependovirus genetics, Electromyography, Genetic Vectors therapeutic use, Humans, Motor Neurons pathology, Muscular Atrophy, Spinal etiology, Muscular Atrophy, Spinal pathology, Muscular Atrophy, Spinal physiopathology, Phenotype, RNA, Small Interfering therapeutic use, SMN Complex Proteins genetics, Swine, Disease Models, Animal, Genetic Therapy methods, Motor Neurons metabolism, Muscular Atrophy, Spinal therapy, SMN Complex Proteins metabolism
- Abstract
Objectives: Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers., Methods: Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed., Results: Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology., Interpretation: High SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset., (© 2014 American Neurological Association.)
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- 2015
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19. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates.
- Author
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Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V, Likhite S, Michels O, Govoni A, Fitzgerald J, Morales P, Foust KD, Mendell JR, Burghes AH, and Kaspar BK
- Subjects
- Animals, Animals, Newborn, Brain Stem metabolism, Cerebral Cortex metabolism, DNA, Complementary administration & dosage, DNA, Complementary genetics, DNA, Complementary metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Gene Expression, Genetic Vectors pharmacokinetics, Injections, Epidural, Macaca fascicularis, Mice, Mice, Knockout, Motor Neurons metabolism, Motor Neurons pathology, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal metabolism, Muscular Atrophy, Spinal pathology, Spinal Cord pathology, Survival of Motor Neuron 1 Protein metabolism, Transduction, Genetic, Transgenes, Dependovirus genetics, Genetic Therapy methods, Genetic Vectors administration & dosage, Muscular Atrophy, Spinal therapy, Spinal Cord metabolism, Survival of Motor Neuron 1 Protein genetics
- Abstract
Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.
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- 2015
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20. Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis.
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Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, Popovich PG, Guttridge DC, and Kaspar BK
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- Age Factors, Amyotrophic Lateral Sclerosis metabolism, Animals, Animals, Newborn, Astrocytes cytology, Astrocytes metabolism, Cell Communication physiology, Coculture Techniques, Disease Models, Animal, Female, Mice, Mice, Inbred Strains, Mice, Transgenic, Microglia metabolism, Motor Neurons metabolism, NF-kappa B antagonists & inhibitors, Primary Cell Culture, Signal Transduction physiology, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis pathology, Cell Death physiology, Microglia cytology, Motor Neurons cytology, NF-kappa B metabolism
- Abstract
Neuroinflammation is one of the most striking hallmarks of amyotrophic lateral sclerosis (ALS). Nuclear factor-kappa B (NF-κB), a master regulator of inflammation, is upregulated in spinal cords of ALS patients and SOD1-G93A mice. In this study, we show that selective NF-κB inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-κB activity and subsequent deletion of NF-κB signaling in microglia rescued MNs from microglial-mediated death in vitro and extended survival in ALS mice by impairing proinflammatory microglial activation. Conversely, constitutive activation of NF-κB selectively in wild-type microglia induced gliosis and MN death in vitro and in vivo. Taken together, these data provide a mechanism by which microglia induce MN death in ALS and suggest a novel therapeutic target that can be modulated to slow the progression of ALS and possibly other neurodegenerative diseases by which microglial activation plays a role., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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21. Exploring complexities of promoting health in families in an obesogenic environment.
- Author
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Schmelzer L and Krishnagiri S
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- Child, Female, Food Preferences, Humans, Obesity psychology, Parenting, Perception, Time Management, Family Health, Feeding Behavior, Health Promotion, Mothers psychology, Obesity prevention & control, Social Environment
- Abstract
Childhood obesity is a serious public health concern, and although the complexity of this issue is now recognized, programming has yet to consider the interconnected nature of the contributing factors. This study, guided by grounded theory, sought to discover how mothers are attempting to promote health in a seemingly obesogenic environment. Data were collected via 22 semi-structured interviews, 55 personal diary entries, and 11 parenting style questionnaires. Constant comparative analysis occurred until theoretical saturation, and strategies to increase trustworthiness were used. Themes included (a) Managing Time, Managing Chaos; (b) Cultural Infatuation with Food; (c) Managing Health from a Distance; (d) Fluctuating Challenges and Supports; (e) Strategies; and (f) Resulting Actions/Interactions. Additionally, a substantive-level theory was developed. Findings highlight the importance of developing contextually relevant, family-based interventions for overweight children and their families, and propose a shift in current program development for this population.
- Published
- 2014
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22. Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.
- Author
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Mergler S, Derckx R, Reinach PS, Garreis F, Böhm A, Schmelzer L, Skosyrski S, Ramesh N, Abdelmessih S, Polat OK, Khajavi N, and Riechardt AI
- Subjects
- Benzoxazines pharmacology, Capsaicin pharmacology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunohistochemistry, Ion Channel Gating drug effects, Models, Biological, Morpholines pharmacology, Naphthalenes pharmacology, Pyrimidinones pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, Cannabinoid, CB1 metabolism, Transient Receptor Potential Channels agonists, Transient Receptor Potential Channels metabolism, Calcium metabolism, Melanoma genetics, Melanoma pathology, Temperature, Transient Receptor Potential Channels genetics, Uveal Neoplasms genetics, Uveal Neoplasms pathology
- Abstract
Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia. We determined in malignant human UM and healthy uvea and four different UM cell lines whether there is gene and functional expression of TRP subtypes and CB1 since they could serve as drug targets to either prevent or inhibit initiation and progression of UM. RT-PCR, Ca(2+) transients, immunohistochemistry and planar patch-clamp analysis probed for their gene expression and functional activity, respectively. In UM cells, TRPV1 and TRPM8 gene expression was identified. Capsaicin (CAP), menthol or icilin induced Ca(2+) transients as well as changes in ion current behavior characteristic of TRPV1 and TRPM8 expression. Such effects were blocked with either La(3+), capsazepine (CPZ) or BCTC. TRPA1 and CB1 are highly expressed in human uvea, but TRPA1 is not expressed in all UM cell lines. In UM cells, the CB1 agonist, WIN 55,212-2, induced Ca(2+) transients, which were suppressed by La(3+) and CPZ whereas CAP-induced Ca(2+) transients could also be suppressed by CB1 activation. Identification of functional TRPV1, TRPM8, TRPA1 and CB1 expression in these tissues may provide novel drug targets for treatment of this aggressive neoplastic disease., (© 2013.)
- Published
- 2014
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23. Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept.
- Author
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Arnold WD, Porensky PN, McGovern VL, Iyer CC, Duque S, Li X, Meyer K, Schmelzer L, Kaspar BK, Kolb SJ, Kissel JT, and Burghes AH
- Abstract
Objective: Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model., Methods: Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3-13 days and at 21 days in mice with SMN selectively reduced in motor neurons ( ChAT
Cre ). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy., Results: CMAP was significantly reduced in SMNΔ7 mice at days 6-13 (p<0.01), and MUNE was reduced at days 7-13 (p<0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (p=0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN., Interpretation: These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.- Published
- 2014
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24. Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model.
- Author
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Rodino-Klapac LR, Janssen PM, Shontz KM, Canan B, Montgomery CL, Griffin D, Heller K, Schmelzer L, Handy C, Clark KR, Sahenk Z, Mendell JR, and Kaspar BK
- Subjects
- Animals, Dependovirus genetics, Disease Models, Animal, Dystrophin metabolism, Follistatin metabolism, Gene Expression, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors administration & dosage, Genetic Vectors genetics, Mice, Mice, Inbred mdx, Muscle Contraction genetics, Muscle Strength genetics, Muscle, Skeletal pathology, Muscular Dystrophy, Animal, Muscular Dystrophy, Duchenne therapy, Dystrophin genetics, Follistatin genetics, Muscle, Skeletal metabolism, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne metabolism
- Abstract
Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promising therapies: micro-dystrophin gene replacement and muscle enhancement with follistatin, a potent myostatin inhibitor. Individual treatments with micro-dystrophin and follistatin demonstrated marked improvement in mdx mice but were insufficient to fully restore muscle strength and response to injury to wild-type levels. Strikingly, when combined, micro-dystrophin/follistatin treatment restored force generation and conferred resistance to contraction-induced injury in aged mdx mice. Pre-clinical studies with miniature dystrophins have failed to demonstrate full correction of the physiological defects seen in mdx mice. Importantly, the addition of a muscle enhancement strategy with delivery of follistatin in combination with micro-dystrophin gene therapy completely restored resistance to eccentric contraction-induced injury and improved force. Eccentric contraction-induced injury is a pre-clinical parameter relevant to the exercise induced injury that occurs in DMD patients, and herein, we demonstrate compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.
- Published
- 2013
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25. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS.
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Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, and Kaspar BK
- Subjects
- Administration, Intravenous, Amyotrophic Lateral Sclerosis genetics, Animals, COS Cells, Chlorocebus aethiops, Disease Models, Animal, Disease Progression, Female, Genetic Vectors, HEK293 Cells, Humans, Injections, Spinal, Macaca fascicularis, Mice, Motor Neurons pathology, Neuroglia pathology, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis pathology, Amyotrophic Lateral Sclerosis therapy, Dependovirus genetics, Genetic Therapy, Motor Neurons metabolism, Neuroglia metabolism, RNA, Small Interfering genetics, Superoxide Dismutase genetics
- Abstract
Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.
- Published
- 2013
- Full Text
- View/download PDF
26. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.
- Author
-
Bevan AK, Duque S, Foust KD, Morales PR, Braun L, Schmelzer L, Chan CM, McCrate M, Chicoine LG, Coley BD, Porensky PN, Kolb SJ, Mendell JR, Burghes AH, and Kaspar BK
- Subjects
- Animals, Brain metabolism, Dependovirus genetics, Gene Expression Regulation, Genetic Vectors administration & dosage, Genetic Vectors genetics, HEK293 Cells, Humans, Injections, Epidural, Injections, Intra-Arterial, Macaca, Male, Motor Neurons metabolism, Muscle, Skeletal metabolism, Muscular Atrophy, Spinal genetics, Neuroglia metabolism, Spinal Cord metabolism, Swine, Time Factors, Transduction, Genetic, Transgenes genetics, Gene Transfer Techniques, Genetic Therapy, Muscular Atrophy, Spinal therapy
- Abstract
Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.
- Published
- 2011
- Full Text
- View/download PDF
27. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery.
- Author
-
Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH, and Kaspar BK
- Subjects
- Animals, Cardiomyopathy, Dilated pathology, Cardiomyopathy, Dilated physiopathology, Disease Models, Animal, Echocardiography, Electrocardiography, Genetic Therapy, Heart Failure pathology, Heart Failure therapy, Mice, Mice, Transgenic, Motor Neurons metabolism, Muscular Atrophy, Spinal complications, Myocardial Contraction, Nerve Tissue Proteins, SMN Complex Proteins, Ventricular Function, Left, Bradycardia genetics, Bradycardia physiopathology, Bradycardia therapy, Dependovirus genetics, Gene Transfer Techniques, Heart Failure physiopathology, Muscular Atrophy, Spinal physiopathology, Survival of Motor Neuron 1 Protein genetics
- Abstract
Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse.
- Published
- 2010
- Full Text
- View/download PDF
28. [A manually operated micro-aspiration system for extracapsular cataract extraction].
- Author
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Friedburg D, Kramp H, and Schmelzer L
- Subjects
- Humans, Cataract Extraction instrumentation, Drainage instrumentation, Microsurgery instrumentation, Therapeutic Irrigation instrumentation
- Published
- 1984
29. Gastroenteritis from an orange juice preparation. II. Field and laboratory investigation.
- Author
-
Schmelzer LL, Gates JM, Redfearn MS, and Tabershaw IR
- Subjects
- California epidemiology, Feces microbiology, Gastroenteritis etiology, Gastroenteritis microbiology, Humans, Prevalence, Water Microbiology, Water Supply analysis, Beverages poisoning, Citrus poisoning, Gastroenteritis epidemiology
- Published
- 1967
- Full Text
- View/download PDF
30. A rapid x-ray diffraction method for the determination of quartz in industrial dusts.
- Author
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SCHMELZER LL
- Subjects
- Humans, X-Rays, Dust, Industry, Occupational Health, Quartz, X-Ray Diffraction
- Published
- 1951
31. George Washington University Hospital.
- Author
-
HEWES H and SCHMELZER LG
- Subjects
- District of Columbia, Humans, Washington, Hospitals, Hospitals, University
- Published
- 1948
32. Gastroenteritis from an orange juice preparation. I. Clinical and epidemiological aspects.
- Author
-
Tabershaw IR, Schmelzer LL, and Bruyn HB
- Subjects
- California epidemiology, Humans, Interviews as Topic, Beverages poisoning, Citrus poisoning, Disease Outbreaks, Gastroenteritis epidemiology
- Published
- 1967
- Full Text
- View/download PDF
33. The origin of industrial dusts; an x-ray diffraction method for determination.
- Author
-
SCHMELZER LL
- Subjects
- Dust analysis, Industry, X-Ray Diffraction
- Published
- 1955
- Full Text
- View/download PDF
34. [THE MILITARY SANATORIUM AT AMERSFOORT].
- Author
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SCHMELZER L
- Subjects
- Netherlands, Hospitals, Military Medicine, Military Personnel
- Published
- 1964
35. Control of radiation hazards. Role of the environmental health scientist.
- Author
-
Schmelzer LL
- Subjects
- Environmental Health, Radiation Protection
- Published
- 1969
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