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103. Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.

Author

Turner, S. M. F., Falk, D. J., Byrne, B. J., and Fuller, D. D.

Subjects
*GLYCOGEN storage disease type II, *ALPHA-glucosidases, *SPINAL cord physiology, *NEUROLOGICAL disorders, *MOTOR neurons, *APOPTOSIS, *THERAPEUTICS
Abstract

Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa−/−) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa−/− mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa−/− spinal cord. Third, many signal transduction pathways in the Gaa−/− cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were “synaptic plasticity pathways” including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system. [ABSTRACT FROM AUTHOR]

Published
2016
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106. Neurostimulation for Parkinson's disease with early motor complications

Author

Schuepbach, W.M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., Halbig, T.D., Hesekamp, H., Navarro, S.M., Meier, N., Falk, D., Mehdorn, M., Paschen, S., Maarouf, M., Barbe, M.T., Fink, G.R., Kupsch, A., Gruber, D., Schneider, G.H., Seigneuret, E., Kistner, A., Chaynes, P., Ory-Magne, F., Brefel Courbon, C., Vesper, J., Schnitzler, A., Wojtecki, L., Houeto, J.L., Bataille, B., Maltete, D., Damier, P., Raoul, S., Sixel-Doering, F., Hellwig, D., Gharabaghi, A., Kruger, R., Pinsker, M.O., Amtage, F., Regis, J.M., Witjas, T., Thobois, S., Mertens, P., Kloss, M., Hartmann, A., Oertel, W.H., Post, B., Speelman, H., Agid, Y., Schade-Brittinger, C., Deuschl, G., et al., Schuepbach, W.M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., Halbig, T.D., Hesekamp, H., Navarro, S.M., Meier, N., Falk, D., Mehdorn, M., Paschen, S., Maarouf, M., Barbe, M.T., Fink, G.R., Kupsch, A., Gruber, D., Schneider, G.H., Seigneuret, E., Kistner, A., Chaynes, P., Ory-Magne, F., Brefel Courbon, C., Vesper, J., Schnitzler, A., Wojtecki, L., Houeto, J.L., Bataille, B., Maltete, D., Damier, P., Raoul, S., Sixel-Doering, F., Hellwig, D., Gharabaghi, A., Kruger, R., Pinsker, M.O., Amtage, F., Regis, J.M., Witjas, T., Thobois, S., Mertens, P., Kloss, M., Hartmann, A., Oertel, W.H., Post, B., Speelman, H., Agid, Y., Schade-Brittinger, C., Deuschl, G., and et al.

Abstract

Item does not contain fulltext, BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-thera

Published
2013

107. Neurostimulation for Parkinson's disease with early motor complications.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Schuepbach, W. M. M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., Halbig, T. D., Hesekamp, H., Navarro, S. M., Meier, N., Falk, D., Mehdorn, M., Paschen, S., Maarouf, M., Barbe, M. T., Fink, G. R., Kupsch, A., Gruber, D., Schneider, G.-H., Seigneuret, E., Kistner, A., Chaynes, P., Ory-Magne, F., Brefel Courbon, C., Vesper, J., Schnitzler, A., Wojtecki, L., Houeto, J.-L., Bataille, B., Maltete, D., Damier, P., Raoul, S., Sixel-Doering, F., Hellwig, D., Gharabaghi, A., Krüger, Rejko, Pinsker, M. O., Amtage, F., Regis, J.-M., Witjas, T., Thobois, S., Mertens, P., Kloss, M., Hartmann, A., Oertel, W. H., Post, B., Speelman, H., Agid, Y., Schade-Brittinger, C., Deuschl, G., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Schuepbach, W. M. M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., Halbig, T. D., Hesekamp, H., Navarro, S. M., Meier, N., Falk, D., Mehdorn, M., Paschen, S., Maarouf, M., Barbe, M. T., Fink, G. R., Kupsch, A., Gruber, D., Schneider, G.-H., Seigneuret, E., Kistner, A., Chaynes, P., Ory-Magne, F., Brefel Courbon, C., Vesper, J., Schnitzler, A., Wojtecki, L., Houeto, J.-L., Bataille, B., Maltete, D., Damier, P., Raoul, S., Sixel-Doering, F., Hellwig, D., Gharabaghi, A., Krüger, Rejko, Pinsker, M. O., Amtage, F., Regis, J.-M., Witjas, T., Thobois, S., Mertens, P., Kloss, M., Hartmann, A., Oertel, W. H., Post, B., Speelman, H., Agid, Y., Schade-Brittinger, C., and Deuschl, G.

Abstract

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-thera

Published
2013

108. Ecological Restoration of Southwestern Ponderosa Pine Ecosystems: A Broad Perspective

Author

Allen, C. D., Savage, M., Falk, D. A., Suckling, K. F., Swetnam, T. W., Schulke, T., Stacey, P. B., Morgan, P., Hoffman, M., Klingel, J. T., and Ecological Society of America

Subjects
Ecology and Evolutionary Biology, Forest Biology, Entomology, Forest Management, Forest Sciences
Abstract

The purpose of this paper is to promote a broad and flexible perspective on ecological restoration of Southwestern (U.S.) ponderosa pine forests. Ponderosa pine forests in the region have been radically altered by Euro-American land uses, including livestock grazing, fire suppression, and logging. Dense thickets of young trees now abound, old-growth and biodiversity have declined, and human and ecological communities are increasingly vulnerable to destructive crown fires. A consensus has emerged that it is urgent to restore more natural conditions to these forests. Efforts to restore Southwestern forests will require extensive projects employing varying combinations of young-tree thinning and reintroduction of low-intensity fires. Treatments must be flexible enough to recognize and accommodate: high levels of natural heterogeneity; dynamic ecosystems; wildlife and other biodiversity considerations; scientific uncertainty; and the challenges of on-the-ground implementation. Ecological restoration should reset ecosystem trends toward an envelope of “natural variability,” including the reestablishment of natural processes. Reconstructed historic reference conditions are best used as general guides rather than rigid restoration prescriptions. In the long term, the best way to align forest conditions to track ongoing climate changes is to restore fire, which naturally correlates with current climate. Some stands need substantial structural manipulation (thinning) before fire can safely be reintroduced. In other areas, such as large wilderness and roadless areas, fire alone may suffice as the main tool of ecological restoration, recreating the natural interaction of structure and process. Impatience, overreaction to crown fire risks, extractive economics, or hubris could lead to widespread application of highly intrusive treatments that may further damage forest ecosystems. Investments in research and monitoring of restoration treatments are essential to refine restoration methods. We support the development and implementation of a diverse range of scientifically viable restoration approaches in these forests, suggest principles for ecologically sound restoration that immediately reduce crown fire risk and incrementally return natural variability and resilience to Southwestern forests, and present ecological perspectives on several forest restoration approaches.

Published
2002
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111. Evolution of hominin cranial ontogeny

Author

Hofmann, Michael A, Falk, Dean, Hofmann, M A ( Michael A ), Falk, D ( Dean ), Zollikofer, Christoph P E, Hofmann, Michael A, Falk, Dean, Hofmann, M A ( Michael A ), Falk, D ( Dean ), and Zollikofer, Christoph P E

Published
2012

112. The Addressees of 4QInstruction

Author

Tigchelaar, E.J.C., García Martínez, F., Schuller, E.M., Falk, D, and Faculteit Godgeleerdheid en Godsdienstwetenschap

Published
2000

114. 4Q446

Author

Tigchelaar, E.J.C., Qimron, E, Schuller, E.M., Chazon, E, Elgvin, T, Eshel, E, Falk, D, Nitzan, B, Seely, D, Weinfeld, M, and Faculteit Godgeleerdheid en Godsdienstwetenschap

Published
1999

115. Qumran Cave 4 XX

Author

Weinfeld, M, Seely, D, Schuller, E.M., Qimron, E, Nitzan, B, Falk, D, Eshel, E, Elgvin, T, Chazon, E, and Rijksuniversiteit Groningen

Published
1999

118. The type specimen (LB1) of Homo floresiensis did not have Laron Syndrome

Author

Sutikna, T., Saptomo, E.W., Jatmiko,, Morwood, Michael J, Larson, Susan G, Jungers, William L, Falk, D, Prior, Fred, Smith, Kirk, Hildebolt, Charles, Sutikna, T., Saptomo, E.W., Jatmiko,, Morwood, Michael J, Larson, Susan G, Jungers, William L, Falk, D, Prior, Fred, Smith, Kirk, and Hildebolt, Charles

Published
2009

133. Pompe disease gene therapy

Author

Byrne, B. J., primary, Falk, D. J., additional, Pacak, C. A., additional, Nayak, S., additional, Herzog, R. W., additional, Elder, M. E., additional, Collins, S. W., additional, Conlon, T. J., additional, Clement, N., additional, Cleaver, B. D., additional, Cloutier, D. A., additional, Porvasnik, S. L., additional, Islam, S., additional, Elmallah, M. K., additional, Martin, A., additional, Smith, B. K., additional, Fuller, D. D., additional, Lawson, L. A., additional, and Mah, C. S., additional

Published
2011
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150. Dilemmas in international and cross-cultural social work education

Author

Nagy, Geza, Falk, D., Nagy, Geza, and Falk, D.

Abstract

The authors summarize the dramatic impact that ongoing global processes are having on the social work profession. They review the literature on international and cross-cultural social work education, citing the rationales for and barriers to incorporating such content, and discussing models of introducing international content into social work education. They suggest the need for developing new approaches to bring international/crosscultural perspectives and content into the mainstream of social work education, and to create more specialized professional programmes.

Published
2000

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