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PubMed1995

Patterns of degeneration in the human cochlear nerve.

The patterns of neural degeneration of the spiral ganglion were studied in 12 human pathologic specimens and 2 normal neonatal specimens. Morphometric analysis of spiral ganglion cells included the maximum cross-sectional areas of both large (type 1) and small (type II) spiral ganglion cells. The organ of Corti in segments corresponding to the spiral ganglion, was evaluated for the presence or absence of inner (IHC) and outer (OHC) hair cells and supporting cells. The relationship between degeneration of spiral ganglion cells and degeneration in the organ of Corti, the age, sex, duration of deafness, cochlear location and delay between death and fixation was evaluated statistically. Both primary and secondary degeneration of the spiral ganglion were more severe in the basal than apical half of the cochlea. Degeneration of the spiral ganglion was most severe when both IHCs and OHCs were absent in the organ of Corti. No survival advantage was identified for type II ganglion cells as has been previously reported. That is, there was no correlation between the degree of degeneration of the spiral ganglion and the prevalence of type II ganglion cells. In fact, there was more severe degeneration of type II cells when the corresponding organ of Corti was severely degenerated. These findings in the human were compared with animal models of degeneration of the spiral ganglion, and the implications for cochlear implantation were discussed.

Aged↗

PubMed2004

Suppressive silver methods--a tool for identifying axotomy-induced neuron degeneration.

Suppressive silver methods evolved from empirical observations about 50 years ago that argyrophilia of normal nerve fibers can be suppressed by a short period of oxidation of tissue sections, whereas degenerating nerve fibers in the same preparations were still clearly visible. Based on this property, suppressive silver impregnation became the main technique for investigating pathways in the central nervous system until the early 1970s. Suppressive silver methods were also found to visualize degenerating nerve cell bodies, in addition to degenerating nerve fibers. This possibility has given these methods an important place among current tools for identifying neuronal degeneration in trauma, disease and toxicity. In this article we demonstrate and review the usefulness of suppressive silver methods in identifying neurons undergoing degeneration as a result of peripheral or central axon injury in immature animals. The documentation is based on previously published data from experiments in which silver impregnation was used to demonstrate degeneration of motoneurons following pure motor axon injury or mixed peripheral nerve injury, as well as on new results on degeneration-induced argyrophilia in the inferior olive following cerebellar lesions. We find that silver precipitates resulting from these injuries are localized either to the entire neuronal cytoplasm, to a few (typically two) intranuclear bodies, or to both sites. The findings are discussed in relation to morphological features of apoptosis, necrosis and retrograde neuronal responses. We suggest that suppressive silver methods allow visualization of different processes of neuronal degeneration, and therefore may be a useful adjunct for identifying axotomy-induced neuronal degeneration.

Animals↗

PubMed2001

Translocation of the macula for management of subfoveal choroidal neovascularization: comparison of results in age-related macular degeneration and degenerative myopia.

PURPOSE: To report the results of limited macular translocation in subfoveal choroidal neovascularization resulting from age-related macular degeneration or degenerative myopia. METHODS: The first consecutive 32 patients (23 age-related macular degeneration eyes and nine myopic eyes) were operated on with the limited macular translocation technique described by de Juan. Before and after surgery, a complete examination included fluorescein and indocyanine-green angiographies and optical coherence tomography. Mean follow-up was 9 months in the age-related macular degeneration group (range, 6 to 14 months) and 10 months in the myopic group (range, 6 to 15 months). RESULTS: The improvement in visual acuity was better in the myopic group than in the age-related macular degeneration group and was correlated with younger age in the myopic group (P <.05). At the end of follow-up, visual acuity improved by 2 lines or more in seven age-related macular degeneration eyes (30%), including four eyes (13%) with an improvement of 6 lines or more, and in six myopic eyes (67%), including two eyes (22%) with an improvement of 6 lines or more. Final visual acuity was unchanged in four age-related macular degeneration eyes (17%) and three myopic eyes (33%), and decreased in 12 age-related macular degeneration eyes (52%). Conversely, the mean foveal displacement was greater in age-related macular degeneration than in myopia (1,105 microm and 685 microm, respectively; P <.05). Main complications were retinal detachment (six eyes), neovascularization at the injection site (two eyes), and recurrence of neovascularization (43% of the age-related macular degeneration group and 11% of the myopic group). CONCLUSIONS: Limited macular translocation allowed a significant improvement in visual acuity in some eyes with subfoveal neovascularization and resulted in a moderate rate of complications. Longer follow-up and additional studies are required to confirm these findings.

Adult↗

PubMed1999

Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration.

PURPOSE: To test the hypothesis that neovascular age-related macular degeneration is related to oxidative stress involving the macular retinal pigment epithelium. This study investigated, as a function of age, levels of enzymes that defend tissues against oxidative stress in the macular retinal pigment epithelium of human eyes with this disease. METHODS: Surgical specimens of macular choroidal neovascular membranes from eyes with age-related macular degeneration and the macular regions of whole donor eyes with neovascular age-related macular degeneration or without evident ocular disease were studied by quantitative electron microscopic immunocytochemistry with colloidal gold-labeled second antibodies. Relative levels in retinal pigment epithelium cell cytoplasm and lysosomes were determined of five enzymes believed to protect cells from oxidative stress, as well as levels of the retinal pigment epithelium marker cytoplasmic retinaldehyde-binding protein, for comparison with the enzymes. RESULTS: Copper, zinc superoxide dismutase immunoreactivity increased and catalase immunoreactivity decreased with age in cytoplasm and lysosomes from macular retinal pigment epithelium cells of normal eyes and eyes with age-related macular degeneration. Cytoplasmic retinaldehyde-binding protein immunoreactivity showed no significant relationship to age or the presence of neovascular age-related macular degeneration. Glutathione peroxidase immunoreactivity was absent from human retinal pigment epithelium cells. Both heme oxygenase-1 and heme oxygenase-2 had highly significantly greater immunoreactivity in retinal pigment epithelium cell lysosomes than in cytoplasm, differing from the much greater cytoplasmic immunoreactivity of the other proteins studied. This immunoreactivity decreased with age, particularly in the lysosomes of retinal pigment epithelium cells from eyes with neovascular age-related macular degeneration. These decreases were of borderline significance (P = .067 for heme oxygenase-1; P = .12 for heme oxygenase-2) when eyes with age-related macular degeneration were compared with normal eyes by multivariable logistic regression. CONCLUSIONS: The high heme oxygenase-1 and heme oxygenase-2 lysosomal antigen levels in macular retinal pigment epithelium cells of eyes with neovascular age-related macular degeneration suggest that oxidative stress causes a pathologic upregulation of these enzymes. Increased lysosomal disposal may indicate that the reparative functions of these enzymes are accompanied by deleterious effects, necessitating their rapid removal from the cell. The much higher heme oxygenase-1 and heme oxygenase-2 antigen levels in macular retinal pigment epithelium cells from younger individuals suggest that protective mechanisms against oxidation and, hence, presumably to the development of age-related macular degeneration, decrease with age.

Adult↗

PubMed1984

Metabolic studies on retinal tissue from a donor with a dominantly inherited chorioretinal degeneration resembling sectoral retinitis pigmentosa.

Protein synthesis, glycosylation, RNA synthesis, and neurotransmitter uptake were monitored using biochemical and autoradiographic techniques following in vitro labeling of retinal tissue from a 79-year-old female with sectoral retinitis pigmentosa (RP). Comparisons were made between degenerate and non-degenerate regions of the RP retina, and normal retinal tissues from an age- and postmortem-matched donor. Autoradiographs of non-degenerate retina from the RP eye following 3H-uridine incubation revealed virtually identical silver grain density over nuclei in all retinal strata as compared to normal control retinas. In contrast, a photoreceptor-specific reduction in silver grain density in the non-degenerate RP retina was noted following 3H-leucine incubation. In the normal retina, rod photoreceptor labeling with 3H-mannose was always greater than cone photoreceptor labeling. This pattern of incorporation was reversed in the non-degenerate region of the RP retina where rod photoreceptor labeling was less pronounced than that observed for cone photoreceptors. In non-degenerate regions of the RP retina, a marked accumulation of 3H-GABA by the Müller's cells was observed. Few cells exhibited selective uptake of 3H-muscimol, a GABA analog, indicating that few GABAergic neurons remained in the degenerate retina. 3H-dopamine-accumulating cell terminals were observed in the usual positions in the non-degenerate RP retina. In the degenerate region of the RP retina, heavy and diffuse uptake of 3H-GABA and 3H-muscimol, respectively, into broad cellular processes were noted, whereas 3H-dopamine was accumulated by only a few punctate terminals.

Aged↗

PubMedDate not supplied

Accumulation of calcium in degenerating photoreceptors of several Drosophila mutants.

The hypothesis that a large, possibly toxic, increase in cellular calcium accompanies photoreceptor cell degeneration in several different Drosophila mutants was tested. The calcium content of wild type and mutant photoreceptors of Drosophila was measured using rapid freezing of the eyes and energy-dispersive x-ray analysis (e.d.x.) of cryosections and semithin sections of cryosubstituted material. Light- and dark-raised mutants of the following strains were studied: retinal degeneration B (rdgB); retinal degeneration C (rdgC); neither inactivation nor afterpotential C (ninaC), and no receptor potential A (norpA). These are light-dependent retinal degeneration mutants in which the affected gene products had been previously shown as myosin-kinase (ninaC), calcium-dependent phosphoprotein phosphatase (rdgC), phosphoinositide transfer protein (rdgB), and phospholipase C (norpA). In light-raised mutants, ommatidia of variable degrees of degeneration were observed. Mass-dense globular bodies of 200-500 nm diameter in relatively large quantities were found in the degenerating photoreceptor of all the mutants tested. These subcellular globules were found to have a very high calcium content, which was not found in wild type or in nondegenerating photoreceptors of the mutants. Nondegenerating photoreceptors were found not only in dark-raised mutants, but in smaller quantities also in light-raised mutants. Usually these globular structures contained high levels of phosphorus, indicating that at least part of the calcium in the mutant photoreceptors is precipitated as calcium phosphate. The results indicate that a large increase in cellular calcium accompanies light-induced photoreceptor degeneration in degenerating Drosophila mutants even when induced by very different mutations, suggesting that the calcium accumulation is a secondary rather than a primary effect in the degeneration process.

Animals↗

PubMed1994

Increased retinal synthesis of heparan sulfate proteoglycan and HNK-1 glycoproteins following photoreceptor degeneration.

In an earlier analysis of the retinal biosynthesis of proteoglycan, we noted that, following photoreceptor degeneration in the rd (retinal degeneration) mouse, the remaining inner retina exhibited a marked elevation in synthesis of heparan sulfate proteoglycan (HSPG), well above the level observed in the normal (nondegenerate) retina, as well as a pronounced increase in sulfation of protein substrates. Biochemical and autoradiographic results of 35S-amino acid utilization reported here confirm that the 35SO4(2-) differences seen previously are accompanied by increased protein synthesis in the rd retina. An intact photoreceptor cell layer is neither a barrier to nor a sink for the amino acid precursor. Further, we have examined sulfate utilization in four other rodent strains with photoreceptor degenerations. In each of the models examined, an increase in retinal synthesis of 35SO4(2-)-labeled HSPG and glycoproteins occurs following photoreceptor degeneration. We have metabolically labeled with Na2(35)SO4 isolated retinal cultures from the following: (a) mice with light-induced photoreceptor degeneration; (b) rd mice; (c) transgenic mice with photoreceptor degeneration; (d) RCS rats; and (e) rats with light-induced photoreceptor degeneration. Comparisons were made with concurrent cultures of control nondegenerate retinal tissues. Protein and proteoglycan-enriched fractions were prepared from the incubation media and guanidine HCl/detergent extracts of the retinas by ion-exchange chromatography. The 35SO4(2-)-proteoglycans were identified by chondroitinase ABC and nitrous acid treatments. Retinas lacking photoreceptors produced at least five times the amount of 35SO4(2-)-HSPG found in control incubations. The RCS and light-damaged rats also showed increased synthesis of 35SO4(2-)-chondroitin sulfate proteoglycan relative to the control, through the increase was of lesser magnitude than the HSPG effect. 35SO4(2-)-protein in degenerate and light-damaged retinas always contained at least twice the radioactivity found in comparable control preparations. The bulk of the increased radiolabeling was found in N-linked oligosaccharides, including several recognized by the HNK-1 antibody. These data suggest that a sustained increase in HSPG and HNK-1 glycoprotein synthesis is a consistent response of inner retinal cells following loss of photoreceptors and is independent of the cause of photoreceptor degeneration.

Animals↗

PubMed2005

A local mechanism mediates NAD-dependent protection of axon degeneration.

Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. Important insight into the mechanisms of axon degeneration arose from findings that the degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wld(s) and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures, the underlying mechanism for Nmnat1- and NAD-mediated axon protection remains largely unclear. We demonstrate that NAD levels decrease in degenerating axons and that preventing this axonal NAD decline efficiently protects axons from degeneration. In support of a local protective mechanism, we show that the degeneration of axonal segments that have been separated from their soma could be prevented by the exogenous application of NAD or its precursor nicotinamide. Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration.

Adenosine Triphosphate↗

PubMed1996

rdgE: a novel retinal degeneration mutation in Drosophila melanogaster.

We report isolating the Drosophila retinal degeneration E (rdgE) mutation. The hypomorphic rdgE1 allele causes rapid photoreceptor degeneration in light and a slower rate of degeneration when the flies are raised in constant darkness. The rdgE1 flies exhibited an electrophysiological light response that decreased with age, coinciding with the degeneration. This suggests that degeneration caused the loss of the light response. We determined that the ninaE (rhodopsin) mutation, but not norpA [phospholipase C (PLC)], slowed the rdgE-dependent degeneration. This was consistent with the light-enhanced degeneration, but revealed that the degeneration is independent of the PLC-mediated phototransduction cascade. Transmission electron microscopy revealed that rdgE1 photoreceptors exhibited a number of vesicular transport defects including unpacking/vesiculation of rhabdomeres, endocytosis of novel vesicles by photoreceptors, a buildup of very large multivesicular bodies, and an increased amount of rough endoplasmic reticulum. We determined that the rdgE null phenotype is a late embryonic lethality. Therefore, rdgE+ is required in cells outside of the retina, quite possibly in a large number of neurons. Thus, rdgE may define a mutational class that exhibits both light-enhanced retinal degeneration and a recessive null lethality by perturbing neuronal membrane biosynthesis and/or recycling.

Alleles↗

PubMed2004

Identification of gene expression changes associated with the progression of retinal degeneration in the rd1 mouse.

PURPOSE: One approach to gaining insight into the biological pathways contributing to rod and cone photoreceptor death is to identify patterns of gene expression changes. In the present study, a custom retinal microarray was developed to analyze the rd1 mouse, a well-characterized animal model of human retinal degeneration. METHODS: A microarray was constructed containing cDNA fragments corresponding to genes known or postulated to be involved in normal retinal function, development, and disease. Gene expression in rd1 retina was compared with age-matched control retinas at three time points: the peak of rod degeneration (postnatal day [P]14), early in cone degeneration (P35), and during cone degeneration (P50). Selected microarray results were confirmed with real-time PCR. The cellular distribution of one of the differentially expressed genes, dickkopf 3 (Dkk3), was assessed by in situ hybridization. RESULTS: At each stage of degeneration, there was only limited overlap of the genes that showed increased expression, suggesting the involvement of temporally distinct molecular pathways. Genes active in transport mechanisms and in signaling pathways were differentially expressed during rod degeneration, whereas genes with functions in protein modification and cellular metabolism were differentially expressed during cone degeneration. Increased expression of genes involved in cell proliferation pathways and oxidative stress was observed at each time point. CONCLUSIONS: These microarray results provide clues to understanding the molecular pathways underlying photoreceptor degeneration and indicate directions for future studies. In addition, comparisons of normal and degenerated retina identified numerous genes and ESTs that are potentially enriched in rod photoreceptors.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Early-onset macular degeneration with drusen in a cynomolgus monkey (Macaca fascicularis) pedigree: exclusion of 13 candidate genes and loci.

PURPOSE: To describe hereditary macular degeneration observed in the cynomolgus monkey (Macaca fascicularis), which shares phenotypic features with age-related macular degeneration in humans, and to test the involvement of candidate gene loci by mutation screening and linkage analysis. METHODS: Ophthalmic examinations with fundus photography, fluorescein angiography (FA), indocyanine green angiography (IA), electroretinography (ERG), and histologic studies were performed on both affected and unaffected monkeys in the pedigree. The monkey orthologues of the human ABCA4, VMD2, EFEMP1, TIMP3, and ELOVL4 genes were cloned and screened for mutations by single-strand conformation polymorphism (SSCP) analysis or denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in six affected and five unaffected monkeys from the pedigree and in six unrelated, unaffected monkeys. Subsequently, 13 human macular degeneration loci including these five genes were analyzed to test for linkage with the disease. Nineteen affected and seven unaffected monkeys in the pedigree were analyzed by using human microsatellite markers linked to the 13 loci. RESULTS: Yellowish white spots were observed in the macula and fovea centralis, and in some cases the spots scattered to the peripheral retina along the blood vessels. FA showed hyperfluorescence corresponding to the dots except in the foveola. No anomalies were found by IA and ERG. Histologic studies demonstrated that the spots were drusen. Mutation analysis of the ABCA4, VMD2, EFEMP1, TIMP3, and ELOVL4 genes identified a few sequence variants, but none of them segregated with the disease. Linkage analysis with markers linked to these five genes and an additional eight human macular degeneration loci failed to establish linkage. Haplotype analysis excluded the involvement of the 13 candidate loci for harboring the gene associated with macular degeneration in the monkeys. CONCLUSIONS: Significant homology was identified between monkey and human orthologues of the five macular degeneration genes. Thirteen loci associated with macular degeneration in humans or harboring macular degeneration genes were excluded as causal of early-onset macular degeneration in the monkeys. It is likely that none of these loci, but rather a novel gene, is involved in causing the observed phenotype in this monkey pedigree.

ATP-Binding Cassette Transporters↗

PubMed2005

[Age-related macular degeneration: analysis in two ophthalmological centers in Pernambuco-Brazil].

PURPOSE: To evaluate age-related macular degeneration (AMD) prevalence and its risk factors in two different populations, with distinct socioeconomic conditions, at two ophthalmological centers in Pernambuco state, Brazil. METHODS: A cross-sectional study was performed in 200 volunteers aged 55 years or older. One hundred were cared for by the Public Health System (in the Fundação Altino Ventura FAV-SUS) and 100 were cared for at a private hospital (Hospital de Olhos de Pernambuco-HOPE). There were 400 eyes altogether. Age-related macular degeneration was graded using fundoscopic examination using AREDS classification (Age-Related Eye Disease Study). RESULTS: Presence of age-related macular degeneration was observed in 61 eyes (30%) of the patients of the Fundação Altino Ventura and in 46 eyes (23%) of the patients of the Hospital de Olhos de Pernambuco. The age-related macular degeneration frequency difference between these populations, that are not similar regarding their socioeconomic level, was not significant (p=0.113). There was a positive association between aging and the age-related macular degeneration frequency (p<0.0001). This association was also present in the female gender (p=0.0451), the presence of cataract (p=0.0447), cataract surgery (p=0.0432) and obesity (p<0.0001). No age-related macular degeneration association with race (p=0.1367), hypertension (p=0.1985), diabetes (p=0.6712), smoking (p=0.6374), alcohol intake (p=0.7359), ocular sunlight exposure (p=0.9399), light-colored iris (p=0.1691), hyperopia (p=0.5098) and the usage of antioxidants (p=0.8251) was observed. CONCLUSIONS: The age-related macular degeneration frequency in the two studied ophthalmological centers varied from 23 to 30%. Age-related macular degeneration association with age; female gender; cataract; cataract surgery; and obesity was observed. No age-related macular degeneration association with socioeconomic level was found in this study.

Aged↗

PubMed1999

Temperature modulation reveals three distinct stages of Wallerian degeneration.

After peripheral nerve transection, axons distal to the cut site rapidly degenerate, a process termed Wallerian degeneration. In wild-type mice the compound action potential (CAP) disappears by 3 d. Previous studies have demonstrated that cold temperatures and lower extracellular calcium ion (Ca2+) concentrations can slow the rate of Wallerian degeneration. We have incubated isolated sciatic nerve segments from wild-type and C57BL/Wld mice (which carry a gene slowing Wallerian degeneration) in vitro at 25 and 37 degrees C. At 25 degrees C we found that the degeneration rate of wild-type axons was slowed dramatically, with the CAP preserved up to 7 d post-transection. In contrast, at 37 degrees C the CAPs were minimal at 2 d. When the temperature of wild-type nerves was raised to 37 degrees C after 24-72 hr at 25 degrees C, degeneration occurred within the subsequent 24 hr. Wld nerves, too, were preserved longer at 25 degrees C but, on return to 37 degrees C, degenerated promptly. Cooling the nerve within 12 hr after axotomy enhanced axonal preservation. Neither wild-type nor Wld nerves showed different degeneration rates when they were incubated with 250 microM or 5 or 10 mM extracellular Ca2+ for 1-2 d, suggesting that an abrupt increase in intracellular Ca2+ occurs at the time of axonal destruction. Wallerian degeneration, thus, appears to progress through three distinct stages. Initiation occurs at the time of injury with subsequent temperature-dependent and -independent phases. Nerves appear to remain intact and are able to exclude Ca2+ from entering until an as yet unknown process finally increases axolemmal permeability.

Animals↗

PubMed2001

Subretinally transplanted embryonic stem cells rescue photoreceptor cells from degeneration in the RCS rats.

The Royal College of Surgeons (RCS) rat is an animal model for retinal degeneration such as the age-related macular degeneration. The RCS rat undergoes a progressive retinal degeneration during the early postnatal period. A potential treatment to prevent this retinal degeneration is the transplantation into the subretinal space of cells that would replace functions of the degenerating retinal pigment epithelium (RPE) cells or may form neurotrophic factors. In this study we have investigated the potential of subretinally transplanted embryonic stem cells to prevent the genetically determined photoreceptor cell degeneration in the RCS rat. Embryonic stem cells from the inner cell mass of the mouse blastocyst were allowed to differentiate to neural precursor cells in vitro and were then transplanted into the subretinal space of 20-day-old RCS rats. Transplanted and sham-operated rats were sacrificed 2 months following cell transplantation. The eyes were enucleated and photoreceptor degeneration was quantified by analyzing and determining the thickness of the outer nuclear layer by light and electron microscopy. In the eyes transplanted with embryonic cells up to 8 rows of photoreceptor cell nuclei were observed, whereas in nontreated control eyes the outer nuclear layer had degenerated completely. Transplantation of embryonic stem cells appears to delay photoreceptor cell degeneration in RCS rats.

Animals↗

PubMed1996

Apoptosis in human retinal degenerations.

PURPOSE: This paper examined the role of apoptosis in human retinal degenerations including pathologic myopia, age-related macular degeneration, serous retinal detachment, retinal lattice, and paving stone degenerations. METHOD: Thirty-seven enucleated human eyes with 1 of the above-mentioned retinal degenerations were studied by histopathology and by TdT-mediated biotin-dUTP nicked-end labelling (TUNEL) technique. RESULTS: Tunnel labelling characteristic DNA fragmentation of apoptosis was observed in photoreceptor cells in 2 of the 4 eyes with pathologic myopia and in 4 of 16 eyes with age-related macular degeneration, 2 of which were exudative and 2 of which were atrophic. However, only a few scattered photoreceptor cells were labelled in 4 of 8 eyes with serous retinal detachment secondary to malignant melanoma of the choroid. Moreover, none of the photoreceptors cells in the 4 eyes with retinal lattice degeneration and 6 eyes with retinal paving stone degeneration were labelled. CONCLUSIONS: Apoptosis is 1 of the important pathways of photoreceptor cell degeneration in pathologic myopia and age-related macular degeneration.

Aged↗

PubMed2003

Indentation testing of human cartilage: sensitivity to articular surface degeneration.

OBJECTIVE: To determine, for clinical indentation testing of human articular cartilage, the effects of aging and degeneration on indentation stiffness and traditional indices of cartilage degeneration; the relationship between indentation stiffness and indices of degeneration; and the sensitivity and specificity of indentation stiffness to cartilage degeneration. METHODS: Osteochondral cores from femoral condyles of cadaveric human donors were harvested. Samples were distributed into experimental groups based on donor age (young [20-39 years], middle [40-59 years], and old [>/=60 years]), and a macroscopic articular surface appearance that was either normal or mildly degenerate, without deep erosion. Samples were analyzed for indentation stiffness, cartilage thickness, India ink staining (quantitated as the reflected light score), and Mankin-Shapiro histopathology score. RESULTS: Indentation stiffness, India ink staining, and the histopathology score each varied markedly between normal-sample and degenerate-sample groups but varied relatively little between normal samples obtained from different age groups. A decrease in indentation stiffness (softening) correlated with a decrease in the reflectance score and an increase in the overall histopathology score, especially the surface irregularity component of the histopathology score. Receiver operating characteristic analysis suggested that the indentation testing could accurately detect cartilage degeneration as indicated by macroscopic appearance, India ink staining, and histopathology score. CONCLUSION: The indentation stiffness of the normal to mildly degenerate samples tested in this study was sensitive to mild degeneration at the articular surface and was insensitive to changes associated with normal aging or to slight variations in cartilage thickness. This suggests that indentation testing may be a useful clinical tool for the evaluation of early-stage degenerative changes in articular cartilage.

Adult↗

PubMed1977

Patterns of degeneration in the external cuneate nucleus after multiple dorsal rhizotomies.

Unilateral, intradural dorsal rhizotomies (C3-Cs) were performed on adult rats to study the patterns of synaptic organization of ascending dorsal root fibers in the external cuneate nucleus (ECN). Animals were permitted to survive for periods of time ranging from 3 hours to 12 days. Sham-operated animals presented a morphology indistinguishable from that of normal, unoperated animals. In rhizotomized animals, degeneration was observed ipsilaterally at all survival periods. After postoperative survivals of 3 to 14 hours some terminal boutons displayed clumping and diminution in numbers of synaptic vesicles and, in addition, degeneration myelinated axons were observed at this time. There was considerable degeneration in the neuropil between 24 and 48 hours postoperative. Two forms of degeneration occurred in axons and terminal boutons with comparable frequency: electron lucent degeneration and electron opaque degeneration. Reactive phagocytic glial cells contained degenerated masses, lipoid droplets, lysosome-like structures and myelin fragments. After postoperative survivals of four to six days, lucent and opaque degenerating terminals were less numerous. Neurofilamentous degeneration was observed only occasionally. Unaltered synaptic membrane specializations were present and were usually abutted by glia. At 12 days postoperative, synaptic glomeruli and serial synapses were not seen. Invaginating dendritic spines were rarely seen. Bouton populations that remained unualtered were: small (0.3-3.0 micron) boutons that contact dendritic shafts and somata, nodal synaptic boutons and boutons containing granular vesicles (80-100 nm).

Animals↗

PubMed1982

Lesion-induced synaptogenesis in the dentate gyrus of aged rats: II. Demonstration of an impaired degeneration clearing response.

Previously we reported that a delayed onset in the reinnervation of the outer two-thirds of the dentate molecular layer occurred in aged rats after an entorhinal lesion. Several factors associated with formation of new synaptic contacts and removal of degenerative debris may affect the reinnervation process. In this study the appearance and removal of degeneration was analyzed and evaluated with respect to the delayed reinnervation process in aged rats. After a complete lesion of the entorhinal cortex, 85-90% of the input to the outer two-thirds of the ipsilateral molecular layer is lost. Electron-dense and electron-lucent degeneration are present throughout the outer two-thirds of the denervated molecular layer. In both aged and young adult rats, the electron-lucent degeneration disappears by 10 days postlesion. The predominant electron dense degeneration, however, is removed at a different rate by young adult and aged rats. Young adults demonstrate a biphasic degeneration removal process, with almost half of this degeneration rapidly lost by 10 days postlesion, and nearly all by 60 days postlesion. Aged animals in contrast, have lost only 16% of the dense degeneration at 10 days postlesion, with about 30% of the degeneration remaining at 60 days postlesion. The impaired removal of the degeneration from the denervated zone appears to be reciprocally related to the reinnervation response in both age groups and may be related to the normal astrocyte hypertrophy and elevated corticosteroid levels in aged rats.

Age Factors↗