Studies on neural stem cells and neuropathology in an inherited lysosomal storage disease animal model

The mucopolysaccharidoses (MPS) are lysosomal storage diseases that result from inherited deficiencies in enzymes involved in the degradative pathway of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs in lysosomes leads to cellular and organ dysfunction, which in the brain manifests as variable mental retardation. Little is known about the cellular and molecular mechanisms that underlie CNS dysfunction in these diseases. Animal models of Mucopolysaccharidosis type VII (MPS VII) were studied to elucidate the connection between storage and neurologic dysfunction. First, the effect of GAG storage on the neural progenitor cells (NPCs) was analyzed to determine if cellular developmental processes were affected by the disease. NPCs were isolated from MPS VII mice and normal littermates. After growth in culture, approximately 90% of cells from both genotypes were nestin positive, a marker for NPCs, and lacked markers associated with lineage commitment. The mutant NPCs contained elevated levels of undegraded glycosaminoglycans (GAGs), the substrate for the deficient enzyme, β-glucuronidase (GUSB). We tested whether the alterations in GAG metabolism affected MPS VII NPC properties regulated by GAG-containing molecules. MPS VII NPC cultures had growth rates in response to FGF-2 that were similar to normal cultures and the efficiency of differentiation into neurons was the same as with normal cells. Thus, even though isolated NPCs accumulate abnormally high levels of GAGs, these two key developmental properties were not altered when the cells were examined outside the milieu of the diseased brain. Additionally, NPCs were able to engraft and produce GUSB in the brains of donor animals. Second, the MPS brain was analyzed to determine if regional specific pathology, particularly neurodegeneration, was present in the mutant brain. We have determined that MPS VII mice undergo a progressive and selective neurodegeneration characterized by ubiquitin inclusions. The pattern of degeneration exhibited a regional specific pattern that was most prominent in the hippocampus and neocortex. The pattern was similar among diseased animals and completely absent from normal animals. Treatment with a recombinant viral-vector quantitatively reversed the neurodegeneration in targeted regions in the brains of mutant mice

Studies on neural stem cells and neuropathology in an inherited lysosomal storage disease animal model

The mucopolysaccharidoses (MPS) are lysosomal storage diseases that result from inherited deficiencies in enzymes involved in the degradative pathway of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs in lysosomes leads to cellular and organ dysfunction, which in the brain manifests as variable mental retardation. Little is known about the cellular and molecular mechanisms that underlie CNS dysfunction in these diseases. Animal models of Mucopolysaccharidosis type VII (MPS VII) were studied to elucidate the connection between storage and neurologic dysfunction. First, the effect of GAG storage on the neural progenitor cells (NPCs) was analyzed to determine if cellular developmental processes were affected by the disease. NPCs were isolated from MPS VII mice and normal littermates. After growth in culture, approximately 90% of cells from both genotypes were nestin positive, a marker for NPCs, and lacked markers associated with lineage commitment. The mutant NPCs contained elevated levels of undegraded glycosaminoglycans (GAGs), the substrate for the deficient enzyme, β-glucuronidase (GUSB). We tested whether the alterations in GAG metabolism affected MPS VII NPC properties regulated by GAG-containing molecules. MPS VII NPC cultures had growth rates in response to FGF-2 that were similar to normal cultures and the efficiency of differentiation into neurons was the same as with normal cells. Thus, even though isolated NPCs accumulate abnormally high levels of GAGs, these two key developmental properties were not altered when the cells were examined outside the milieu of the diseased brain. Additionally, NPCs were able to engraft and produce GUSB in the brains of donor animals. Second, the MPS brain was analyzed to determine if regional specific pathology, particularly neurodegeneration, was present in the mutant brain. We have determined that MPS VII mice undergo a progressive and selective neurodegeneration characterized by ubiquitin inclusions. The pattern of degeneration exhibited a regional specific pattern that was most prominent in the hippocampus and neocortex. The pattern was similar among diseased animals and completely absent from normal animals. Treatment with a recombinant viral-vector quantitatively reversed the neurodegeneration in targeted regions in the brains of mutant mice

Asymmetries and visual field summaries as predictors of glaucoma in the ocular hypertension treatment study

PURPOSE. To evaluate whether baseline visual field data and asymmetries between eyes predict the onset of primary open-angle glaucoma (POAG) in Ocular Hypertension Treatment Study (OHTS) participants. METHODS. A new index, mean prognosis (MP), was designed for optimal combination of visual field thresholds, to discriminate between eyes that developed POAG from eyes that did not. Baseline intraocular pressure (IOP) in fellow eyes was used to construct measures of IOP asymmetry. Age-adjusted baseline thresholds were used to develop indicators of visual field asymmetry and summary measures of visual field defects. Marginal multivariate failure time models were constructed that relate the new index MP, IOP asymmetry, and visual field asymmetry to POAG onset for OHTS participants. RESULTS. The marginal multivariate failure time analysis showed that the MP index is significantly related to POAG onset (P &lt; 0.0001) and appears to be a more highly significant predictor of POAG onset than either mean deviation (MD; P = 0.17) or pattern standard deviation (PSD; P = 0.046). A 1-mm Hg increase in IOP asymmetry between fellow eyes is associated with a 17% increase in risk for development of POAG. When threshold asymmetry between eyes existed, the eye with lower thresholds was at a 37% greater risk of development of POAG, and this feature was more predictive of POAG onset than the visual field index MD, though not as strong a predictor as PSD. CONCLUSIONS. The MP index, IOP asymmetry, and binocular test point asymmetry can assist in clinical evaluation of eyes at risk of development of POAG.</p

Public COAPI Toolkit of Open Access Policy Resources

The Coalition of Open Access Policy Institutions (COAPI, https://sparcopen.org/coapi ) is committed to sharing information and resources to assist in the development and implementation of institutional Open Access (OA) policies. The COAPI Toolkit includes a diverse collection of resources that COAPI members have developed in the course of their OA policy initiatives. These resources are openly accessible and published here under Creative Commons Attribution 4.0 licenses, unless otherwise noted on the resources themselves