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Search Results: 1 - 10 of 503529 matches for " David A Loeffler "
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Using animal models to determine the significance of complement activation in Alzheimer's disease
David A Loeffler
Journal of Neuroinflammation , 2004, DOI: 10.1186/1742-2094-1-18
Abstract: A variety of inflammatory processes are increased in regions of pathology in the Alzheimer's disease (AD) brain [1-4]. There is a reciprocal relationship between this local inflammation and senile plaques (SPs) and neurofibrillary tangles (NFTs); both SPs and NFTs, as well as damaged neurons and neurites, stimulate inflammatory responses [5], and inflammatory processes exert multiple effects, some of which promote neuropathology [6-8]. Numerous retrospective studies have shown that long-term administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to individuals with arthritis significantly reduces the risk for these individuals for developing AD [9]. These findings, together with the demonstration of elevated glial cell activation [10-12], complement activation [13-15], and increased acute phase reactant production [16-19] at sites of pathology in the AD brain, support the hypothesis that local inflammation may contribute to the development of this disorder [20]. Although a short-term trial of AD patients with the NSAID indomethacin suggested protection from cognitive decline [21], subsequent trials with other anti-inflammatory drugs have found no evidence for slowing of the dementing process [22-25]. These findings underscore the current perception of CNS inflammation as a "double edged sword" [26,27], with neuroprotective roles for some inflammatory components and neurotoxic effects for others [28-30].The significance of complement activation, a major inflammatory mechanism, in AD is particularly problematic. The complement system is composed of more than 30 plasma and membrane-associated proteins which function as an inflammatory cascade. Complement activation promotes the removal of microorganisms and the processing of immune complexes. The liver is the main source of these proteins in peripheral blood, but they are also synthesized in other organs including the brain [31]. Protein fragments generated during activation of the system enzymatically cleave
Plaque complement activation and cognitive loss in Alzheimer's disease
David A Loeffler, Dianne M Camp, David A Bennett
Journal of Neuroinflammation , 2008, DOI: 10.1186/1742-2094-5-9
Abstract: iC3b, C9, Bielschowsky, and Gallyas staining was performed on aged normal (n = 17), mild cognitively impaired (n = 12), and AD (n = 17–18) inferior temporal gyrus specimens. Plaques were counted in 10× fields with high numbers of Bielschowsky-stained plaques. One-way ANOVA was used to determine between-group differences for plaque counts and measures of cognitive function, and linear regression was used to evaluate global cognition as a function of Bielschowsky-stained plaques. Terms for iC3b- and C9-stained plaques were then added sequentially as additional predictors in a "mediation analysis" model.Complement was detected on plaques in all groups, and on neurofibrillary tangles only in AD specimens. iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD vs. other groups (all p ≤ 0.01). C9 staining was present on some diffuse plaques, as well as on neuritic plaques. Bielschowsky-stained and complement-stained plaque counts were highly correlated, and were negatively correlated with cognitive measures. When the Bielschowsky plaque count was used as a predictor, its correlations with cognitive measures were statistically significant, but when iC3b and C9 plaque counts were added as additional predictors, these correlations were no longer significant. This loss of significance was attributed to multicollinearity, i.e., high correlations between Bielschowsky-stained and complement-stained plaque counts.Both early-stage (iC3b) and late-stage (C9) complement activation occurs on neocortical plaques in subjects across the cognitive spectrum; contrary to previous reports, C9 is present on some diffuse plaques. Because of high correlations between complement-stained and Bielschowsky-stained plaque counts, quantitative assessment of the extent to which complement activation may mediate the relationship between plaques and cognitive function could not be performed. Additional studies with animal models of AD (if late-stage complement activation can be
Complement activation in the Parkinson's disease substantia nigra: an immunocytochemical study
David A Loeffler, Dianne M Camp, Stephanie B Conant
Journal of Neuroinflammation , 2006, DOI: 10.1186/1742-2094-3-29
Abstract: Substantia nigra specimens from young normal subjects (n = 11–13), aged normal subjects (n = 24–28), and subjects with PD (n = 19–20), Alzheimer's disease (AD; n = 12–13), and dementia with Lewy bodies (DLB; n = 9) were stained for iC3b and C9, representing early- and late-stage complement activation, respectively. Numbers of iC3b+, C9+, and total melanized neurons in each section were counted in a blinded fashion. Nonparametric analyses were used to evaluate differences between groups and to evaluate correlations between complement staining, numbers of melanized neurons, and the duration of PD.Lewy bodies in both PD and DLB specimens stained for iC3b and C9. Staining was also prominent on melanized neurons. The percentage of iC3b+ neurons was significantly increased in PD vs. aged normal and AD specimens, and in young normal vs. aged normal specimens. C9 immunoreactivity was significantly increased in PD vs. AD specimens, but unlike iC3b, the increased C9 staining in PD and young normal specimens did not achieve statistical significance vs. aged normal specimens. iC3b and C9 staining in PD specimens was not correlated with the numbers of remaining melanized neurons, nor with the duration of PD.Complement activation occurs on Lewy bodies and melanized neurons in the PD substantia nigra. Early complement activation (iC3b) is increased on melanized neurons in PD vs. aged normal specimens, and late-stage complement activation (C9) also tends to increase. This latter finding suggests that complement activation may contribute to loss of dopaminergic neurons in some individuals with PD. Complement activation on melanized neurons appears to decrease with normal aging, suggesting a possible neuroprotective role for this process in the normal substantia nigra.Multiple neurotoxic processes have been described in the Parkinson's disease (PD) brain including inflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction [1]. The evidence for inflammation in PD in
Spectral expansions of overconvergent modular functions
David Loeffler
Mathematics , 2007, DOI: 10.1093/imrn/rnm050
Abstract: The main result of this paper is an instance of the conjecture made by Gouvea and Mazur (Math. Res. Lett., 1995) which asserts that for certain values of r the space of r-overconvergent p-adic modular forms of tame level N and weight k should be spanned by the finite slope Hecke eigenforms. Using methods adapted from the work of Buzzard and Calegari I show that for p=2, k = 0, N = 1, this holds for all r in (5/12, 7/12). The proof relies on a certain factorisation of the U_p operator which is known in this case but I conjecture also holds for p = 3 and 5; this conjecture also implies exact formulae for the set of slopes similar to those proved for p=2 by Buzzard and Calegari. The same methods also provide an efficient approach to explicit computations of q-expansions of small slope overconvergent eigenforms, extending the computations of Gouvea and Mazur.
Explicit calculations of automorphic forms for definite unitary groups
David Loeffler
Mathematics , 2008, DOI: 10.1112/S1461157000000620
Abstract: I give an algorithm for computing the full space of automorphic forms for definite unitary groups over Q, and apply this to calculate the automorphic forms of level $G(Z-hat)$ and various small weights for an example of a rank 3 unitary group. This leads to some examples of various types of endoscopic lifting from automorphic forms for U_1 x U_1 x U_1 and U_1 x U_2, and to an example of a non-endoscopic form of weight (3,3) corresponding to a family of 3-dimensional irreducible l-adic Galois representations. I also compute the 2-adic slopes of some automorphic forms with level structure at 2, giving evidence for the local constancy of the slopes.
Overconvergent algebraic automorphic forms
David Loeffler
Mathematics , 2009, DOI: 10.1112/plms/pdq019
Abstract: I present a general theory of overconvergent p-adic automorphic forms and eigenvarieties for connected reductive algebraic groups G whose real points are compact modulo centre, extending earlier constructions due to Buzzard, Chenevier and Yamagami for forms of GL(n). This leads to some new phenomena, including the appearance of intermediate spaces of "semi-classical" automorphic forms; this gives a hierarchy of interpolation spaces (eigenvarieties) interpolating classical automorphic forms satisfying different finite slope conditions (corresponding to a choice of parabolic subgroup of G at p). The construction of these spaces relies on methods of locally analytic representation theory, combined with the theory of compact operators on Banach modules.
Density of classical points in eigenvarieties
David Loeffler
Mathematics , 2010,
Abstract: In this short note, we study the geometry of the eigenvariety parametrising p-adic automorphic forms for GL(1) over a number field K, as constructed by Buzzard. We show that if K is not totally real and contains no CM subfield, points in this space arising from classical automorphic forms (i.e. algebraic Grossencharacters of K) are not Zariski-dense in the eigenvariety (as a rigid space); but the eigenvariety posesses a natural formal scheme model, and the set of classical points is Zariski-dense in the formal scheme. We also sketch the theory for GL(2) over an imaginary quadratic field, following Calegari and Mazur, emphasising the strong formal similarity with the case of GL(1) over a general number field.
P-adic integration on ray class groups and non-ordinary p-adic L-functions
David Loeffler
Mathematics , 2013, DOI: 10.1007/978-3-642-55245-8_12
Abstract: We study the theory of finite-order p-adic functions and distributions on ray class groups of number fields, and apply this to the construction of (possibly unbounded) p-adic L-functions for automorphic forms on GL(2) which may be non-ordinary at the primes above p. As a consequence, we obtain a "plus-minus" decomposition of the p-adic L-functions of automorphic forms for GL(2) over an imaginary quadratic field with p split and Hecke eigenvalues 0 at the primes above p, confirming a conjecture of B.D. Kim.
Images of adelic Galois representations for modular forms
David Loeffler
Mathematics , 2014,
Abstract: We show that the image of the adelic Galois representation attached to a non-CM modular form is open in the adelic points of a suitable algebraic group. We also show a similar result for the adelic Galois representation attached to a finite set of modular forms.
Cellular immune response to intrastriatally implanted allogeneic bone marrow stromal cells in a rat model of Parkinson's disease
Dianne M Camp, David A Loeffler, Diane M Farrah, Jade N Borneman, Peter A LeWitt
Journal of Neuroinflammation , 2009, DOI: 10.1186/1742-2094-6-17
Abstract: 5-Bromo-2-deoxyuridine (BrdU) – labeled MSC from two allogeneic sources (Wistar and ACI rats) were implanted into the striatum of adult Wistar rats at the same time as 6-OHDA was administered into the substantia nigra. Behavioral tests were administered one to two weeks before and 16–20 days after 6-OHDA lesioning and MSC transplantation. Immunocytochemical staining for T helper and T cytotoxic lymphocytes, microglia/macrophages, and major histocompatibility class I and II antigens was performed on post-transplantation days 22–24. MSC were detected with an anti-BrdU antibody.Tissue injury due to the transplantation procedure produced a localized cellular immune response. Unexpectedly, both sources of allogeneic MSC generated robust cellular immune responses in the host striatum; the extent of this response was similar in the two allograft systems. Despite these immune responses, BrdU+ cells (presumptive MSC) remained in the striatum of all animals that received MSC. The numbers of remaining MSC tended to be increased (p = 0.055) in rats receiving Wistar MSC versus those receiving ACI MSC. MSC administration did not prevent behavioral deficits or dopamine depletion in the 6-OHDA-lesioned animals.MSC, when implanted into the striatum of allogeneic animals, provoke a marked immune response which is not sufficient to clear these cells by 22–24 days post-transplantation. In the experimental paradigm in this study, MSC did not prevent nigrostriatal dopamine depletion and its associated behavioral deficits. Additional studies are indicated to clarify the effects of this immune response on MSC survival and function before initiating trials with these cells in patients with PD or other neurodegenerative disorders.The standard treatment for Parkinson's disease (PD) for several decades has been the dopamine precursor levodopa. However, long-term administration of levodopa eventually results in decreased efficacy and the emergence of side effects including dyskinesias and psych
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