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PubMed1978

The torn or degenerated meniscus and its relationship to degeneration of the weight-bearing areas of the femur and tibia.

Data was collected on 300 cadaver knees dissected for the prime purpose of studying chondromalacia of the patella. Simultaneous observations were also made on the state of the meniscus and the articular cartilage in the tibio-femoral joint. The data did not seem to support the oft-repeated statement that the torn meniscus is the primary cause of unicompartmental osteoarthritis. Investigations were also carried out on 69 additional cadaver knees and 100 consecutive unselected arthroscoped knees in which there was damage either to the meniscus or the adjacent joint surfaces. In 60% of the combined series of cadaver and arthroscoped knees, the meniscal changes could not be correlated with the condition of the articular cartilage. In the remaining 40% in which there was coexisting pathology in the meniscus and the articular cartilage, a cause and effect relationship could not be established, but there was no evidence that a torn meniscus posed a significant threat to the articular cartilage.

Aged↗
PubMed2002

Retinal degeneration mutants in the mouse.

The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to look for genetically determined eye variations and disorders. Through ophthalmoscopy, electroretinography and histology, we have discovered disorders affecting all aspects of the eye including the lid, cornea, iris, lens and retina, resulting in corneal disorders, cataracts, glaucoma and retinal degenerations. Mouse models of retinal degeneration have been investigated for many years in the hope of understanding the causes of photoreceptor cell death. Sixteen naturally occurring mouse mutants that manifest degeneration of photoreceptors in the retina with preservation of all other retinal cell types have been found: retinal degeneration (formerly rd, identical with rodless retina, r, now Pde6b(rd1)); Purkinje cell degeneration (pcd); nervous (nr); retinal degeneration slow (rds, now Prph(Rd2)); retinal degeneration 3 (rd3); motor neuron degeneration (mnd); retinal degeneration 4 (Rd4); retinal degeneration 5 (rd5, now tub); vitiligo (vit, now Mitf(mi-vit)); retinal degeneration 6 (rd6); retinal degeneration 7 (rd7, now Nr2e3(rd7)); neuronal ceroid lipofuscinosis (nclf); retinal degeneration 8 (rd8); retinal degeneration 9 (Rd9); retinal degeneration 10 (rd10, now Pde6b(rd10)); and cone photoreceptor function loss (cpfl1). In this report, we first review the genotypes and phenotypes of these mutants and second, list the mouse strains that carry each mutation. We will also provide detailed information about the cpfl1 mutation. The phenotypic characteristics of cpfl1 mice are similar to those observed in patients with complete achromatopsia (ACHM2, OMIM 216900) and the cpfl1 mutation is the first naturally-arising mutation in mice to cause cone-specific photoreceptor function loss. cpfl1 mice may provide a model for congenital achromatopsia in humans.

Animals↗
PubMed1997

Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome.

Several cancers, especially lung, ovarian and breast, can cause paraneoplastic cerebellar degeneration. The presence of different antineuronal antibodies associated with different cancers and paraneoplastic cerebellar degeneration suggests that several immunological mechanisms may result in the same neurological disorder. In patients with small-cell lung cancer, paraneoplastic cerebellar degeneration may occur with or without Hu antineuronal antibodies (HuAb), indicating that patients with the same tumour can develop paraneoplastic cerebellar degeneration by different immunological mechanisms. Furthermore, paraneoplastic cerebellar degeneration sometimes occurs in association with the Lambert-Eaton myasthenic syndrome. In order to try to understand the clinical implication of antineuronal antibodies in patients with small-cell lung cancer, we examined the serum of 57 patients with presenting symptoms of paraneoplastic cerebellar degeneration for the presence of HuAb and P/Q- and N-type voltage-gated calcium channel antibodies. Patients with paraneoplastic cerebellar degeneration who were HuAb positive were compared with HuAb negative patients with respect to neurological symptoms, course of the neurological disorder, response to treatment, tumour prognosis, pathological findings, and cause of death. The tumour outcome and serological findings of these patients were also compared with those of 109 small-cell lung cancer patients without paraneoplastic syndromes of the CNS. Titres of HuAb were classified as 'high' (immunoblot titre > 1:10,000) or 'low' (< 1:10,000), the latter similar to the antibody titres detected in some small-cell lung cancer patients without paraneoplastic symptoms. Twenty-five patients with paraneoplastic cerebellar degeneration (44%) had high titres of HuAb, four (7%) had low titres of HuAb, and 28 (49%) were HuAb negative; for clinical comparisons with the patients with high titres of HuAb, the four patients with low antibody titres were included in the HuAb negative cohort. None of the 109 small-cell lung cancer patients without paraneoplastic symptoms had high titres of HuAb. The presence of high titres of HuAb defined a subset of patients who differed from the HuAb negative paraneoplastic cerebellar degeneration cohort, HuAb positive patients were more likely to be female (P < 0.01), to have multifocal neurological disease (brainstem encephalopathy and sensory neuropathy being common extracerebellar manifestations) (P < 0.002), and be severely disabled (P < 0.005). A total of nine patients (16%) from both paraneoplastic cerebellar degeneration groups developed electrophysiologically confirmed Lambert-Eaton myasthenic syndrome. Seven of these nine patients had serum available for P/Q-type voltage-gated calcium channel antibody testing and all seven were positive. In addition, 20% of HuAb negative paraneoplastic cerebellar degeneration patients without clinically identified Lambert-Eaton myasthenic syndrome had P/Q-type voltage-gated calcium channel antibodies, while only 2% of small-cell lung cancer patients without paraneoplastic symptoms had these antibodies. Treatment of the tumour and/or immunomodulation did not alter the course of paraneoplastic cerebellar degeneration, but improved Lambert-Eaton myasthenic syndrome symptoms. At the time of death, in 60% of HuAb positive and 20% of HuAb negative paraneoplastic cerebellar degeneration patients, the tumour was either not evident or localized to the chest (P < 0.007); neurological disease was the cause of death of 65% HuAb positive paraneoplastic cerebellar degeneration and 10% HuAb negative paraneoplastic cerebellar degeneration patients (P < 0.001). (ABSTRACT TRUNCATED)

Age Distribution↗
PubMed2000

The effect of disc degeneration and facet joint osteoarthritis on the segmental flexibility of the lumbar spine.

STUDY DESIGN: A biomechanical and imaging study of human cadaveric spinal motion segments. OBJECTIVE: To investigate the effect of both disc degeneration and facet joint osteoarthritis on lumbar segmental motion. SUMMARY OF BACKGROUND DATA: Spinal degeneration includes the osteoarthritic changes of the facet joint as well as disc degeneration. Disc degeneration has been reported to be associated with spinal motion. The association of facet joint osteoarthritis with lumbar segmental motion characteristics and the combined influence of disc degeneration and facet osteoarthritis has not yet been investigated. METHODS: A total of 110 lumbar motion segments (52 female, 58 male) from 44 human lumbar spines were studied (mean age = 69 years). Magnetic resonance images were used to assess the disc degeneration from Grade I (normal) to Grade V (advanced) and the osteoarthritic changes in the facet joints in terms of cartilage degeneration, subchondral sclerosis, and osteophytes. Disc height, endplate size, and facet joint orientation and width also were measured from the computed tomographic images. Rotational movements of the motion segment in response to the flexion, extension, lateral bending, and axial rotational moments were measured using a three-dimensional motion analysis system. RESULTS: Female motion segments showed significantly greater motion (lateral bending: P < 0. 001, flexion: P < 0.01, extension: P < 0.05) and smaller endplate size (P < 0.001) than male ones. The segmental motion increased with increasing severity of disc degeneration up to Grade IV, but decreased in both genders when the disc degeneration advanced to Grade V. In male segments, the disc degeneration-related motion changes were significant in axial rotation (P < 0.001), lateral bending (P < 0.05), and flexion (P < 0.05), whereas female segments showed significant changes only in axial rotation (P < 0.001). With cartilage degeneration of the facet joints, the axial rotational motion increased, whereas the lateral bending and flexion motion decreased in female segments. In male segments, however, motion in all directions increased with Grade 3 cartilage degeneration and decreased with Grade 4 cartilage degeneration. Subchondral sclerosis significantly decreased the motion (female: axial rotation, P < 0. 05; extension, P < 0.05 vs.- male:flexion,P < 0.05). Severity of osteophytes had no significant association with the segmental motion. CONCLUSION: Axial rotational motion was most affected by disc degeneration, and the effects of disc degeneration on the motion were similar between genders. Facet joint osteoarthritis also affected segmental motion, and the influence differed for male and female spines. Further studies are needed to clarify whether the degenerative process of facet joint osteoarthritis differs between genders and how facet joint osteoarthritis affects the stability of the spinal motion segment.

Cadaver↗
PubMed2005

Ultrastructural study of normal and degenerating nerve fibers in the protocerebral tract of the crab Ucides cordatus.

Wallerian degeneration is a very well described phenomenon in the vertebrate nervous system. In arthropods, and especially in crustaceans, nerve fiber degeneration has not been described extensively. In addition, literature shows that the events do not follow the same patterns as in vertebrates. In this study we report, by qualitative and quantitative ultrastructural analyses, the features and time course of the protocerebral tract degeneration following extirpation of the optic stalk. No remarkable changes were observed seven days after lesion. After 28 days the protocerebral tracts presented apparently preserved small and large diameter axons and some degenerating medium axons, with irregular contours and empty-looking aspect of the axoplasm. Forty days after the ablation of the optic stalks, both small (type I) and medium (type II and III) axons revealed signs of partial or total degeneration, but large nerve fibers (type IV) were still intact. After 45 days, the tract showed signs of advanced stage of degeneration and, apart from large axons, normal-looking fibers were almost absent. At these 3 last time points, degenerating axons displayed different electron densities and aspects, probably correlating to different onset times of the process. In addition, cells with granules in their cytoplasm, possibly hemocytes, were quite distinct, especially at 40 and 45 days after axotomy. These cells might share with glial cells the function of phagocytosis of cellular debris during the protocerebral tract degeneration. Quantitative analysis showed that the number of degenerating fibers increased significantly from 28 to 40 days after lesion, whereas the number of normal fibers decreased accordingly. Measurements of cross-sectional areas of normal and degenerating axons showed that types II and III (medium) start to degenerate before type I (small). Type IV (large) axons do not degenerate, even after 40 days. Therefore, we can conclude that degeneration in these afferent fibers starts late after axotomy, but proceeds at a faster rate afterwards until the complete degeneration of small and medium axons.

Animals↗
PubMedDate not supplied

Correlation of end plate shape on MRI and disc degeneration in surgically treated patients with degenerative disc disease and herniated nucleus pulposus.

BACKGROUND CONTEXT: The sagittal profile of the lumbar end plates on magnetic resonance imaging (MRI) has not been investigated in patients with degenerative disc disease (DDD) or herniated nucleus pulposus (HNP). PURPOSE: To examine the shape of the end plates in patients treated surgically for a) low back pain or b) radiculopathy with HNP. Furthermore, to investigate the correlation between end plate shape and disc degeneration on the one, and end plate shape and symptoms on the other. STUDY DESIGN/SETTING: Retrospective review of charts and radiographs. METHODS: The charts, operative reports, preoperative lateral plain radiographs, and MRI scans of 178 patients (85 with low back pain and 93 with HNP) were reviewed. End plate shape was determined on midsagittal MRI cuts, disc degeneration was graded on T2 sequences, and disc height was measured on lateral plain radiographs from L1 to S1 in all patients. Student t-test and chi(2) test were used to detect significant differences and associations. RESULTS: Flat and irregular levels were most common in the lower lumbar spine. The L5/S1 segment was flat in most cases, due to a flat sacral end plate. In DDD patients, disc degeneration on MRI and plain radiographs worsened from concave to flat, to irregular levels. In HNP patients, MRI demonstrated concave levels to be less degenerated, whereas no difference was detected between flat and irregular levels. Disc height of irregular levels was well preserved in HNP patients. Comparing the two groups, flat levels were more degenerated on MRI in HNP patients. Despite similar degrees of degeneration on MRI, concave and irregular levels in DDD patients had lower disc heights. A higher frequency of symptoms was found in flat and irregular levels for both patient groups. CONCLUSIONS: The sagittal profile of end plates in the lumbar spine was described for patients with DDD on the one and HNP on the other. A higher association with symptoms was observed for flat and irregular levels in both patient groups. In DDD patients, disck degeneration on both MRI and plain radiographs increased from concave to flat, to irregular levels. In HNP patients, MRI demonstrated concave levels to be less degenerated, whereas no difference was detected between flat and irregular levels. Disc height of irregular levels was well preserved in HNP patients. Comparing the two groups of patients, flat levels were more degenerated on MRI in HNP patients. Despite similar degrees of degeneration on MRI, concave and irregular levels in DDD patients had lower disc heights. The correlation of symptoms and disc degeneration with the end plate shapes is not definitive evidence of end plate remodeling around degenerated discs. It may simply represent the higher rate of disc degeneration in the lower lumbar levels. This analysis did not provide any hints as to which degenerated discs are more likely to herniated and cause leg symptoms or cause predominantly low back pain.

Adult↗
PubMed2002

Endplate degeneration observed on magnetic resonance imaging of the lumbar spine: correlation with pain provocation and disc changes observed on computed tomography diskography.

STUDY DESIGN: One hundred and three lumbar intervertebral discs (L3/4-L5/S1) of 36 patients with low back pain were examined with computed tomography (CT) diskography and magnetic resonance imaging (MRI). OBJECTIVES: To determine whether lumbar endplate degeneration correlates with the degree of disc degeneration or disc rupture and to determine if there is an association between pain provocation during diskography and lumbar endplate degeneration. SUMMARY OF BACKGROUND DATA: There have been numerous attempts to explain the pathogenesis of pain provocation during diskography, but the possibility of endplate degeneration as a source of pain has not been widely assessed. METHODS: One hundred and three lumbar intervertebral discs (36 L3/4, 36 L4/5, and 31 L5/S1 intervertebral discs) of 36 patients were examined. On the basis of MRI, the intervertebral discs were divided into four categories based on the degree of endplate degeneration. Based on pain provocation on diskography, the intervertebral discs were divided into three categories: no pain, indifferent/untypical pain, and familiar/typical pain. Based on disc degeneration and disc rupture, the intervertebral discs were divided into four categories in accordance with the Dallas Discogram Description: Grades 0-3 of both degeneration and rupture. RESULTS: There was a positive correlation between endplate degeneration and disc degeneration and a positive correlation between disc rupture and pain provocation, but there was no association between endplate degeneration and disc rupture and no correlation between endplate degeneration and pain provocation on diskography. CONCLUSIONS: This study showed a stronger association between endplate degeneration and disc degeneration than between endplate degeneration and disc rupture. The results indicate that the contrast injection during diskography reflects mainly pain of discogenic origin, whereas the possible pain associated with endplate damage cannot be depicted by CT diskography.

Adult↗
PubMed2004

Risk factors for adjacent segment degeneration after PLIF.

STUDY DESIGN: A retrospective study of 87 patients who underwent posterior lumbar interbody fusion (PLIF) at L4-L5 for L4 degenerative spondylolisthesis. OBJECTIVE: To clarify: 1) the correlation between radiologic degeneration of cranial adjacent segment and clinical results, 2) risk factors for radiologic degeneration of cranial adjacent segment, and 3) preoperative radiologic features of patients who underwent additional surgery with cranial adjacent segment degeneration. SUMMARY OF BACKGROUND DATA: Whereas PLIF with pedicle screw fixation has shown satisfactory clinical results, a solid fusion has been reported to accelerate a degenerative change at unfused adjacent levels, especially in the cranial level. Although several authors have reported the adjacent segment degeneration after PLIF, there are no previous reports of risk factors for adjacent segment degeneration after PLIF. MATERIALS AND METHODS: Eighty-seven patients who underwent PLIF for L4 degenerative spondylolisthesis and could be followed for at least 2 years were included in this study. We measured lumbar lordosis, scoliosis, laminar inclination angle at L3, facet sagittalization at L3-L4, facet tropism at L3-L4, preexisting disc degeneration at L3-L4, and lordosis at the fused segment. Progression of L3-L4 segment degeneration was defined as a condition in which disc narrowing, posterior opening, and progress of slippage in comparison with preoperative dynamic lateral radiographs. Patients were divided into three groups according to postoperative progression of L3-L4 degeneration: Group 1 with neither progression of L3-L4 degeneration nor neurologic deterioration, Group 2 with progression of L3-L4 degeneration but no neurologic deterioration, and Group 3 with an additional surgery required for neurologic deterioration. Correlation between clinical results and radiologic progression of L3-L4 degeneration, and risk factors for progression of radiologic degeneration were investigated. Further, preoperative radiologic features of Group 3 were studied to detect risk factors for clinical deterioration. RESULTS: There were 58 (67%) patients classified into Group 1, 25 (29%) patients into Group 2, and 4 (4%) patients into Group 3. There was no significant difference in average age in each group. No obvious difference was observed in recovery rate between Groups 1 and 2. Laminar inclination angle and facet tropism in Group 3 were more significant than those in Groups 1 and 2. Further, apparent lamina inclination and facet tropism coexisted in Group 3. There were no obvious differences in other factors between each group. CONCLUSION: 1) There was no correlation between radiologic degeneration of cranial adjacent segment and clinical results. 2) Risk factors for postoperative radiologic degeneration could not be detected in terms of each preoperative radiologic factor. 3) Coexistence of horizontalization of the lamina at L3 and facet tropism at L3-L4 may be one of the risk factors for neurologic deterioration resulting from accelerated L3-L4 degenerative change after L4-L5 PLIF.

Adult↗
PubMed2006

Lumbar disc degeneration: epidemiology and genetics.

Research conducted over the past decade has led to a dramatic shift in the understanding of disc degeneration and its etiology. Previously, heavy physical loading-often associated with occupation-was the main suspected risk factor for disc degeneration, which was commonly viewed as a wear-and-tear phenomenon exacerbated by the precarious nutritional status of the disc. However, results of studies on twins suggest that physical loading specific to occupation and sport plays a relatively minor role in disc degeneration. Recent research indicates that heredity has a dominant role in disc degeneration, which would explain the variance of up to 74% seen in adult populations that have been studied to date. Since 1998, genetic influences have been confirmed by the identification of several gene forms associated with disc degeneration. This research is paving the way for a better understanding of the biologic mechanisms through which disc degeneration occurs, including specific interactions between genes and environment. Research into disc degeneration and genetics has become more limited by phenotypes or definitions and measures of disc degeneration than by DNA analysis. Standardized, universally accepted definitions of disc degeneration are lacking, in part due to limited knowledge of the process. The measurements that are selected depend on the method used to evaluate the disc and are often qualitative ordinal rating scales, lacking in precision. Although it is generally agreed that disc degeneration is common, the prevalence of specific findings is unclear. A review of the epidemiology of disc degeneration reveals wide-ranging prevalence estimates for various signs of disc degeneration in samples of the general population and in patients with back symptoms. The extreme variations in prevalence rates are likely largely due to inconsistencies in the definitions and measurements of disc degeneration. Such inconsistencies and inaccuracies impede epidemiologic research on disc degeneration.

Age Distribution↗
PubMed2004

Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc.

The histological and biochemical changes that occur in the extracellular matrix of the intervertebral disc (IVD) during ageing and degeneration have been investigated extensively. However, the mechanisms behind these changes are not fully understood. A number of studies have suggested the involvement of matrix metalloproteinases (MMPs) and ADAMTS in IVD degeneration, but few have localized the site of production of these enzymes to the cells of the degenerate disc. This study uses immunohistochemical techniques to localize and quantify the production of degrading enzymes (MMPs 1, 3, and 13, and ADAMTS 4) and their inhibitors (TIMPS 1, 2, and 3) within non-degenerate and degenerate discs of varying severity of degeneration. In all discs investigated, the cells that produced the enzymes and their inhibitors were the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus (AF), with little immunopositivity in the outer AF. Non-degenerate discs showed low numbers of cells expressing the degradative enzymes MMP 1 and ADAMTS 4, suggesting a role for these enzymes in normal homeostasis. No MMP 3 or MMP 13 immunopositivity was observed in non-degenerate discs. In degenerate discs, the number of cells immunopositive for MMPs 1, 3, 13 and ADAMTS 4 increased with the severity of degeneration. This increase in degrading enzymes was also accompanied by increases in the number of cells immunopositive for TIMPs 1 and 2 but not TIMP 3. This study highlights that although the expression of a number of MMPs increases with degeneration, this is accompanied by an increase in their inhibitors. However, the increase in the number of cells immunoreactive for ADAMTS 4 with increasing degeneration was not paralleled by a rise in its inhibitor TIMP 3. This finding indicates that the aggrecanases, rather then the MMPs, are a possible therapeutic target for the inhibition of disc degeneration.

ADAM Proteins↗
PubMed1991

Striatopallidonigral degeneration in Pick's disease: a clinicopathological study of 41 cases.

The frequency and degree of stiatopallidonigral (SPN) degeneration were examined in 41 autopsy cases of Pick's disease. Based on the degree of SPN degeneration, these cases were arranged into four groups: 1) group I (severely degenerate; 19.5%), 2) group II (moderately degenerate; 22.0%), 3) group III (mildly degenerate; 36.5%), and 4) group IV (non-degenerate; 22.0%). 17 of the 41 cases had a definite (moderate to severe) SPN degeneration. The striatum, especially the caudate nucleus, was most frequently and most severely affected, while the internal segment of the globus pallidus was least frequently and least severely affected. In general, the oral portions of the SPN nuclei were more severely involved. In addition, in the putamen and globus pallidus the dorsomedial portions adjacent to the internal capsule were apt to be affected more markedly than the other portions. In the substantia nigra the degeneration tended to be more predominant in the pars reticulata than in the pars compacta, although both were usually involved. In addition, the medial to central portions of the substantia nigra were more vulnerable. In comparing the severely and moderately degenerate groups (groups I and II) with the mildly and non degenerate groups (groups III and IV), the former had more female cases, longer duration of illness, and more third-stage cases. In addition, the former contained more cases with lower brain weight and (predominant) frontal atrophy type, and more atypical cases without Pick bodies, or with symmetrical pyramidal tract degeneration or with combined traumatic lesions. It is notable that in all cases with definite SPN degeneration no extrapyramidal involuntary movements had been detected.

Adult↗
PubMed2005

Retinal degeneration and local oxygen metabolism.

Vision loss due to various forms of outer retinal degeneration remains a major problem in clinical ophthalmology. Most retinal degenerations are precipitated by genetic mutations affecting the retinal pigment epithelium and sensory retina, but it is becoming increasingly evident that resultant metabolic changes within the retina may also contribute to the further progression of photoreceptor cell loss. In particular, a role for the local oxygen environment within the retina has been proposed. The correct balance between retinal oxygen supply and oxygen consumption in the retina is essential for retinal homeostasis, and disruption of this balance is a factor in many retinal diseases. In animal models of photoreceptor degeneration, manipulation of environmental oxygen levels has been reported to be able to modulate the rate of photoreceptor degeneration. Clinically, hyperbaric oxygen therapy has already been used in retinitis pigmentosa patients and other types of oxygen therapy have been proposed. It therefore seems appropriate to review our current understanding of the oxygen environment in the normal and degenerating retina, and to build a clearer picture of how the retinal oxygen environment can be modulated. We focus on techniques that have been, or may be, applied clinically, such as modulation of systemic oxygen levels and modulation of retinal oxygen metabolism by light deprivation. Data from direct measurements of intraretinal oxygen distribution in rat models at different stages of photoreceptor degeneration will be reviewed. These models include the Royal College of Surgeons (RCS) rat, and the P23H rat model of outer retinal degeneration. Microelectrode based techniques have allowed the intraretinal oxygen distribution to be measured as a function of retinal depth under well-controlled systemic conditions at different stages of the degeneration process. Both models showed changes in the intraretinal oxygen distribution during the degenerative period, with the changes reflecting the gradual loss of oxygen metabolism of the degenerating photoreceptors. This results in higher than normal oxygen levels in the remaining outer retina and a significant alteration in the oxygen flux from the choroid to the inner retina. The maintenance of normal oxygen levels in the inner retina implies that inner retinal oxygen uptake is well preserved, and that there is also reduced oxygen input from the deeper capillary layer of the retinal circulation. Choroidal oxygen tension and the oxygen tension in the pre-retinal vitreous were unaffected at any of the time periods studied prior to, and during, the degeneration process. It is well known that both hypoxia and hyperoxia can cause neural cell stress and damage. Logically, any therapeutic intervention based on oxygen therapy should attempt to restore the oxygen environment of the remaining retinal cells to within the physiological range. Before any oxygen based therapies for the treatment of retinal degeneration should be seriously considered, the oxygen environment in the degenerating retina should be determined, along with clinically usable methods to restore the oxygen environment to the critical cell layers.

Animals↗
PubMed2001

The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6.

PURPOSE: To describe the system for grading age-related macular degeneration from fundus photographs in the Age-Related Eye Disease Study. This is a prospective multicenter cohort study of the course of age-related macular degeneration and a placebo-controlled clinical trial of the effect of high-dose vitamin and mineral supplements on development of advanced age-related macular degeneration. METHODS: Standardized stereoscopic 30-degree color fundus photographs are taken at 11 clinical centers and evaluated by graders at a reading center for quality and age-related macular degeneration abnormalities. Macular subfields are defined by a grid, and presence and severity of various age-related macular degeneration abnormalities are graded using standard/example photographs and measuring circles. Advanced age-related macular degeneration abnormalities (presence/absence) include retinal pigment epithelial detachment, serous (or hemorrhagic) sensory retinal detachment, hard exudates, subretinal/subretinal pigment epithelial hemorrhage, subretinal fibrous tissue, and photocoagulation scars. Other abnormalities (multistep scales) include retinal pigment epithelial abnormalities (geographic atrophy, depigmentation, and increased pigment), and drusen (size, type [hard versus soft distinct or indistinct], and total area). Contemporaneous variability is tested by having different graders evaluate samples of photographs, and temporal variability by annual regrading of a dedicated subset. RESULTS: In a cumulative sample of 1230 eyes for contemporaneous reproducibility, agreement on advanced age-related macular degeneration was 96% (kappa = 0.88) and for four-step age-related macular degeneration level was 83% (kappa = 0.77). Agreement was moderate for pigment epithelial detachment (kappa = 0.54) and substantial for serous sensory retinal detachment, hard exudates, subretinal/subretinal pigment epithelial hemorrhage, subretinal fibrous tissue, and central geographic atrophy (kappa = 0.73-0.82). For pigment abnormalities, agreement was substantial for geographic atrophy (kappa = 0.63; kappa(weighted) = 0.71, 0.75 weight for one-step disagreements), and moderate for depigmentation (kappa = 0.41, kappa(weighted) = 0.51) and increased pigment (kappa = 0.54, kappa(weighted) = 0.71). For drusen, agreement was moderate to substantial for presence/maximum size (kappa = 0.50, kappa(weighted) = 0.68), type (kappa = 0.61, kappa(weighted) = 0.69), and area (kappa = 0.56, kappa(weighted) = 0.77). Six annual regrades of 119 eyes showed little temporal drift in grading of various age-related macular degeneration abnormalities, except for drusen type. CONCLUSIONS: The Age-Related Eye Disease Study has demonstrated satisfactory reliability for detecting onset of advanced age-related macular degeneration in a cohort, and moderate to substantial agreement on various abnormalities across the age-related macular degeneration spectrum. The Age-Related Eye Disease Study system for classification of age-related macular degeneration is suitable for longitudinal multicenter studies.

Cohort Studies↗
PubMed1999

Color Doppler imaging discloses reduced ocular blood flow velocities in nonexudative age-related macular degeneration.

PURPOSE: To study ocular perfusion defects in age-related macular degeneration. METHODS: Twenty-five subjects with nonexudative age-related macular degeneration were compared with 25 age-matched control subjects in studies of flow velocities in several retrobulbar vessels. Color Doppler imaging, which was performed by an examiner who was masked to the subjects' assignment to the control or age-related macular degeneration group, measured peak systolic and end diastolic velocity in the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries of one eye. A resistive index was calculated from the peak systolic and end diastolic velocity. RESULTS: Subjects with nonexudative age-related macular degeneration showed a consistent trend toward lower peak systolic and end-diastolic velocities in the posterior ciliary arteries. For example, in the nasal posterior ciliary artery, the mean end diastolic velocity measured 1.45 +/- 0.34 cm per sec in the age-related macular degeneration group compared with 1.96 +/- 0.66 cm per sec in the control group, yielding a 26% decrease in the age-related macular degeneration group, which represented the largest difference and was highly statistically significant (P = .0012). The resistive index was not significantly altered in the nasal or temporal posterior ciliary artery. Subjects with nonexudative age-related macular degeneration did not differ from control subjects in peak systolic velocity, end diastolic velocity, or resistive index in the ophthalmic artery. In the central retinal artery, the end diastolic velocity was lower (1.37 +/- 1.95 cm per sec vs 1.95 +/- 0.66 cm per sec), whereas the resistive index was higher (0.83 +/- 0.05 vs 0.76 +/- 0.06 cm per sec), in the age-related macular degeneration group; these results were highly statistically significant (P = .0007 and P < .0001, respectively). CONCLUSIONS: Retrobulbar vascular changes in nonexudative age-related macular degeneration subjects include reduced flow velocities in the nasal and temporal posterior ciliary arteries. The reduced peak systolic velocity, combined with the reduced end diastolic velocity at a constant resistive index, seen in nonexudative age-related macular degeneration, is consistent with reduced bulk flow in these vessels, suggesting that choroidal perfusion is abnormal in this form of age-related macular degeneration. The changes in the central retinal artery suggest there may be a more generalized perfusion abnormality beyond the choroid in patients with age-related macular degeneration or that the central retinal artery exhibits a secondary autoregulatory response to a primary change elsewhere.

Aged↗
PubMed1996

Neural degeneration mutants in the zebrafish, Danio rerio.

Forty zebrafish mutants with localized or general neural degeneration are described. The onset and duration of degeneration and the distribution of ectopically dying cells are specific characteristics of each mutant. Mutants are classified into four groups by these parameters. Class I: late focal neural degeneration mutants. These 18 mutants have restricted cell death mainly in the tectum and the dorsal hindbrain after 36 hours. The degeneration does not spread and disappears at later stages of development. Class II: early focal neural degeneration mutants. Ten mutants in this class exhibit transient restricted degeneration affecting mainly the diencephalon, the hindbrain and the spinal cord at 20 hours. The midbrain is less affected. The degeneration shifts to the dorsal diencephalon and the tectum at 36 hours. Class III: late spreading neural degeneration mutants. The 8 mutants in this class display a degeneration that is first seen in the tectum and subsequently spreads throughout the nervous system from 36 hours on. Class IV: early general neural degeneration mutants. This class of four mutants already shows overall cell degeneration in the nervous system at the 15-somite stage. Three of the class I mutants show a change in the pattern of gene expression in the anlage of a brain structure prior to the onset of degeneration. These results suggest that focal cell death may be a useful clue for the detection of early patterning defects of the vertebrate nervous system in regions devoid of visible landmarks.

Animals↗