Biomedical subjects
Publications and source records attributed to Michael Sheldon.
We demonstrate optical waveguiding of a probe beam at 980 nm by a soliton beam at 780 nm in an organic photorefractive monolithic glass. Both planar and circular waveguides induced by one- and two-dimensional spatial solitons formed as a result of orientationally enhanced photorefractive nonlinearity are produced in the organic glass. Possibilities for increasing the speed of waveguide formation are discussed.
Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures through the VLDLR and ApoER2 receptors and the adaptor protein Dab1. In addition to cellular disorganization, dendrite abnormalities are present in the brain of reeler mice lacking Reelin. It is unclear whether these defects are due primarily to cellular ectopia or the absence of Reelin. Here we examined dendrite development in the hippocampus of normal and mutant mice and in dissociated cultures. We found that dendrite complexity is severely reduced in homozygous mice deficient in Reelin signaling both in vivo and in vitro, and it is also reduced in heterozygous mice in the absence of cellular ectopia. Addition of Reelin interfering antibodies, receptor antagonists, and Dab1 phosphorylation inhibitors prevented dendrite outgrowth from normal neurons, whereas addition of recombinant Reelin rescued the deficit in reeler cultures. Thus, the same signaling pathway controls both neuronal migration and dendrite maturation.
Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.
Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. Here, we demonstrate that Reelin functions postnatally to regulate the development of the neuromuscular junction. Reelin is required for motor end-plate maturation and proper nerve-muscle connectivity, and it directly promotes synapse elimination. Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity.
In developing mammalian (mouse) brain, Reelin (Reln) is secreted by the Cajal-Retzius (CR) neurons in the marginal zone, binds apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (Vldlr), and induces the phosphorylation of the downstream cytoplasmic molecule disabled-1 (Dab1) in cortical plate neurons. Although this is a well-characterized signaling pathway in mice, it has not been well defined in human brain. In this paper we examined the expression of RELN, APOER2, VLDLR, and DAB1 in the developing human brain by RT-PCR. We further determined the cellular expression of the proteins RELN and DAB1 in 50 human brains ranging in age from 10 gestational weeks (GW) to 62 years using immunochemistry. We found that the pattern of expression of RELN and DAB1 in the human brain isnot identical to that observed in the mouse brain. In particular, we report the novel finding that human DAB1and RELN are coexpressed in CR neurons during cortical development and in cortical pyramidal neurons after neuronal migration is complete. Thus, in the human brain, the whole RELN signaling pathway is present within selected populations of cortical neurons throughout life. We speculate that RELN and DAB1 coexpression in these neurons is necessary for both normal cortical development and mature function.
Thirty patients (30 knees) who underwent total knee arthroplasty at age </=50 were reviewed. These patients were operated on between July 1, 1991, and May 1, 1995, with final follow-up evaluation at a mean of 86 months (range, 60-107 months). At final evaluation, 18 knees (60%) had excellent Knee Society objective scores, 11 knees (37%) had good scores, and 1 knee (3%) had a poor score. There were no statistically significant differences in Knee Society objective scores among the cemented group (mean, 88 points), hybrid group (mean, 88 points), and noncemented group (mean, 90 points). One patient (3%) had a revision because of unexplained pain. In the other knees, there was no radiographic evidence of progressive loosening, lucencies, or change in position or alignment of the prosthesis. Total knee arthroplasty of this design, at least for the time period studied (7-year mean follow-up), has a high rate of success in patients who are </=50 years old.
BACKGROUND: A patient with collapse of a femoral condyle caused by osteonecrosis has few treatment options other than total knee arthroplasty. The purpose of this study was to report the clinical and radiographic outcome of total knee arthroplasty for osteonecrosis. METHODS: Between 1987 and 1996, thirty-two total knee arthroplasties were performed with cement in thirty patients with osteonecrosis of the femoral condyle and/or tibial plateau. The study group included twenty-forty women and five men with a mean age of fifty-four years (range, thirty-one to seventy-seven years) at the time of the arthroplasty. Twenty-two patients had atraumatic osteonecrosis associated with corticosteroid use, and eight had spontaneous osteonecrosis. All patients had a complete clinical and radiographic evaluation at a mean of 108 months (range, forty-eight to 144 months) postoperatively. RESULTS: Overall, thirty-one (97%) of the thirty-two knees had a successful clinical outcome. The mean Knee Society score improved from 54 points preoperatively to 95 points at the time of the latest follow-up. No evidence of progressive radiolucency was found around any prosthetic component. CONCLUSIONS: Previous studies have demonstrated less-than-optimal results following total knee arthroplasty in patients with osteonecrosis. The excellent results found in the present study may have been secondary to the use of cemented implants in all cases and ancillary stems when appropriate.