Diagnosis of a popliteal venous aneurysm by venous duplex imaging.
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Adult↗
Biomedical subjects
M L Katz
Publications and source records attributed to M L Katz.
Juvenile ceroid lipofuscinosis. Evidence for methylated lysine in neural storage body protein.
Juvenile ceroid lipofuscinosis, or Batten disease, is a hereditary disorder characterized by progressive visual loss, seizures, cognitive and psychomotor deterioration, and early death, usually between 15 and 35 years of age. Individuals with this disease have massive deposits of autofluorescent inclusion bodies in cells of most tissues. The accumulation of these intracellular deposits suggests that juvenile ceroid-lipofuscinosis is a storage disease resulting from the inability of cells to metabolize some normal cellular constituent. It has been reported that the storage material is largely protein, much of which is a specific mitochondrial protein that apparently is not properly metabolized in subjects with Batten disease. The storage bodies were partially purified from the retinas of two siblings who died as a result of juvenile ceroid lipofuscinosis, as well as from the cerebral cortex of an unrelated individual with this disorder. Chromatographic analysis of storage body protein acid hydrolysates indicated that they contained a large amount of the modified amino acid epsilon-N-trimethyllysine. The abundance of this amino acid in the storage protein suggests that the disease may result from excessive methylation or from a failure to demethylate intermediate forms of the stored proteins. Acid hydrolysis also solubilized a fluorescent component from the retinal storage material, suggesting that the stored protein has a bound fluorescent adduct.
Adult↗
Maintenance of opsin density in photoreceptor outer segments of retinoid-deprived rats.
Dietary deficiency in the retinoid precursors of the visual pigment chromophore 11-cis-retinal eventually results in selective degeneration of the photoreceptor cells of the vertebrate retina. Early effects of retinoid deficiency are depletion of rhodopsin from the retina and vesiculation of the photoreceptor outer segment disc membranes. Experiments were conducted to determine whether these early changes were accompanied by an alteration of the opsin content of the disc membranes. After being fed a retinoid-deficient diet containing retinoic acid for 26 weeks, the rhodopsin content of rat retinas was reduced by over 85%. Both the diameters and the lengths of the outer segments decreased significantly. However, immunocytochemical and freeze-fracture analyses indicated that retinoid deficiency did not lower opsin density in the outer-segment disc membranes. These findings indicate that in the rat, opsin synthesis and disc assembly are coordinated processes that remain coupled despite reduced availability of the vitamin A chromophore. The fact that disc size decreases and disc synthesis eventually ceases in retinoid-deprived rats indicates that specific retinoids are essential for disc morphogenesis. The mechanism by which these retinoids regulate disc assembly remains to be determined.
Analysis of Variance↗
Storage protein in hereditary ceroid-lipofuscinosis contains S-methylated methionine.
Hereditary ceroid-lipofuscinoses are neurodegenerative disorders characterized by the accumulation in numerous tissues of a storage material with lipofuscin-like fluorescence properties. Investigations were undertaken to determine the chemical nature of this storage material isolated from the cerebral cortex of human subjects with the late infantile form of the disease. The storage material was mainly protein that consisted of a mixture of polypeptides ranging in apparent molecular weight from 13 to 67 kDa. Protein-bound fluorophores apparently were largely responsible for the autofluorescence of the storage bodies. The disease-related storage body protein was rich in S-methylmethionine [(3-amino-3-carboxypropyl) dimethyl sulfonium ion], an amino acid that does not normally occur in animal proteins. Methylation of proteins to form this unusual charged amino acid may impair proteolytic degradation or other aspects of protein metabolism, and account for the accumulation of protein-filled inclusions in cells of individuals with ceroid-lipofuscinoses. Similar amino acid modifications that block proteolysis could be involved in age pigment accumulation.
Amino Acids↗
Venous duplex imaging: should it replace hemodynamic tests for deep venous thrombosis?
Noninvasive diagnosis of deep venous thrombosis has traditionally relied on detection of alterations in venous hemodynamics. Although phleborheography is among the most sensitive tests, it is inadequate for diagnosing infrapopliteal and nonocclusive proximal thrombi and for surveillance of patients at high risk for deep venous thrombosis. Venous duplex imaging is a new technique being rapidly accepted, however, without the same critical analysis given to previous diagnostic modalities. The purpose of this study is to evaluate the diagnostic acumen of venous duplex imaging compared to phleborheography and ascending phlebography in two distinct patient groups, and to determine whether patient selection, and thus the location or magnitude of thrombi have significant influence on these diagnostic tests. One hundred ten extremities in 103 patients were prospectively evaluated with venous duplex imaging, phleborheography, and ascending phlebography within the same 24-hour period. Patients were categorized into one of two groups: Diagnostic--patients evaluated because of clinical suspicion of acute deep venous thrombosis; and Surveillance--patients at high risk of postoperative deep venous thrombosis after total joint replacement, but not symptomatic. Patients in the diagnostic group had a greater frequency of deep venous thrombosis (p less than 0.001) and significantly more occluding above-knee thrombi (p = 0.054) compared to those in the surveillance group. Phleborheography detected 73% (27/37) of above-knee thrombi in the diagnostic group compared to 29% (2/7) in the surveillance group (p = 0.036). This difference was not noted with venous duplex imaging, which detected 100% of above-knee thrombi in both diagnostic and surveillance groups and 78% (7/9) of all below-knee thrombi.(ABSTRACT TRUNCATED AT 250 WORDS)
Humans↗
The preoperative diagnosis of the ulcerated carotid atheroma.
Arteriography and carotid duplex imaging accurately quantify the degree of stenosis caused by carotid atheroma. Since arteriography is inconsistent in identifying carotid ulceration, and controversy exists regarding the diagnostic accuracy of carotid B-mode imaging, a prospective study was performed comparing the two techniques to 126 carotid endarterectomy specimens. Sixty percent (76/126) of specimens contained ulcers. The diagnostic sensitivity for B-mode imaging and arteriography was 47% (36/76) and 53% (40/76), respectively (p = NS). Importantly, the degree of stenosis caused by the plaque significantly affected diagnostic sensitivities. B-mode sensitivity was 77% (10/13) in plaques less than or equal to 50% and 41% (26/63) for plaques greater than 50% (p = 0.03). Arteriography likewise detected 77% (10/13) of ulcers in plaques less than or equal to 50% stenosis and 48% (30/63) in plaques with greater than 50% stenosis (p = 0.07). In patients with focal symptoms, 100% (10/10) of plaques with less than or equal to 50% stenosis contained ulcers, whereas in plaques with greater than 50% stenosis 63% (36/57) contained ulcers (p = 0.02). These data indicate that the diagnostic sensitivity for carotid ulceration is not significantly different between B-mode carotid imaging and arteriography. Since most B-mode errors occur with high-grade stenoses this short-coming is unlikely to adversely affect patient care. Previous studies investigating the ability of carotid B-mode imaging to detect ulceration failed to address quantitative aspects of the carotid plaque. These data appear to resolve the previously existing controversy.
Arteriosclerosis↗
Development of lipofuscin-like fluorescence in the retinal pigment epithelium in response to protease inhibitor treatment.
Experiments were conducted to determine whether photoreceptor outer segment components contain precursors for lipofuscin fluorophores that accumulate in the retinal pigment epithelium (RPE) during senescence. Intravitreal injection of the lysosomal protease inhibitor leupeptin caused a rapid accumulation of inclusions with lipofuscin-like autofluorescence in the RPE of albino rats. These inclusions appeared to be derived from photoreceptor outer segments, which are normally phagocytosed and degraded by the RPE. The tripeptide leu-gly-gly, which is similar to leupeptin except that it does not inhibit proteolysis, had no effect on RPE autofluorescent pigment content. Likewise, netilmicin, a purported inhibitor of lysosomal phospholipases, did not enhance autofluorescent pigment deposition in the RPE. These findings are consistent with other experiments suggesting that RPE age-pigment fluorophores are derived from molecular components of the photoreceptor outer segments. The effect of leupeptin suggests that outer segment proteins may be among the precursors for these fluorophores. The RPE appears to differ from other cell types that accumulate lipofuscin in that the majority of the precursors for this pigment in the RPE are taken up by phagocytosis rather than being generated within the cells themselves.
Aging↗
The autofluorescent products of lipid peroxidation may not be lipofuscin-like.
The fluorescent molecules of cellular age pigment granules (lipofuscin) are commonly thought to be end products of membrane lipid autoxidation. Lipofuscin fluorophores of the retinal pigment epithelium (RPE) appear to be derived from photoreceptor outer segment membranes. Experiments were therefore conducted to determine whether the in vitro oxidation of retinal homogenates would generate fluorophores similar to the naturally occurring lipofuscin fluorophores of the RPE. Neural retina and RPE-choroid homogenates from young (2-3 month old) albino rats were subjected to an iron-ascorbate-air pro-oxidant reaction medium, and compared to unoxidized control samples from young age-matched animals as well as senescent (24 month old) rats. In addition, neural retina and RPE-choroid homogenates from 3 month old albino rats were subjected to a 100% oxygen atmosphere to test whether the fluorescent products of autoxidation differ substantially from those generated in the pro-oxidant medium. The chloroform-soluble fluorophores of chloroform-methanol sample extracts were analyzed by corrected fluorescence spectroscopy and thin-layer chromatography (TLC). In vitro pro-oxidation of both the neural retina and the RPE from young rats produced blue-emitting fluorophores which differed from the orange- and yellow-emitting fluorophores extracted from the RPE of senescent rats. Corrected fluorescence spectroscopy of aged tissue extracts revealed vitamin A-related fluorescence (330 nm excitation maximum; 515 nm emission maximum) and a spectrally resolvable age-related fluorescence (420 nm excitation maximum; 600 nm emission maximum). Only the vitamin A-related fluorescence could be measured in the control of young samples.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Incomplete proteolysis may contribute to lipofuscin accumulation in the retinal pigment epithelium.
A substantial amount of experimental evidence indicates that the bulk of retinal pigment epithelial (RPE) lipofuscin is derived from components of the photoreceptor outer segments. Antioxidant nutrient deficiency promotes RPE lipofuscin deposition, suggesting that oxidation of outer segment components is involved in the formation of this pigment. However, the fluorescent products of in vitro oxidation of retinal constituents differ from the fluorophores associated with lipofuscin. Thus, the role of nonenzymatic oxidation in lipofuscin formation is probably indirect; it may inhibit proteolysis, which in turn allows nonoxidative amino acid modifications to accumulate. Direct inhibition of proteolysis by the RPE in vivo results in a rapid appearance of lipofuscin-like fluorescence in the undegraded proteins. This suggests that protein components of the outer segments are probably the major precursors of RPE lipofuscin. The modifications undergone by these proteins that are responsible for their accumulation in the RPE and for lipofuscin fluorescence remain to be determined.
Animals↗
Failure of vitamin E to protect the retina against damage resulting from bright cyclic light exposure.
Cumulative light-mediated damage to the retina over a long time period may be involved in the development of age-related retinopathies. Light is thought to produce retinal damage by initiating autoxidative reactions among the molecular components of the retina. Experiments were therefore conducted (1) to confirm that long-term differences in cyclic light intensity affect the rate of age-related photoreceptor cell loss from the retina; and (2) to determine whether the antioxidant, vitamin E, is an effective inhibitor of damage to the retina by bright cyclic light. Albino rats were fed a basal diet either supplemented with or deficient in vitamin E. Each dietary group was divided into two light-treatment groups which were exposed to 12 hr cyclic light of either 15 lux or 750 lux. After 10 and 17 weeks of treatment, retinal photoreceptor cell densities were determined for animals in each group. Vitamin E deficiency resulted in moderate decreases in photoreceptor cell densities in the dim-light groups after both 10 and 17 weeks. Rats exposed to the bright-light condition suffered a pronounced loss of photoreceptor cells by 10 weeks, and an even greater cell loss by 17 weeks. Vitamin E deficiency did not enhance the effect of bright cyclic light in reducing photoreceptor cell densities. Thus, it appears unlikely that retinal damage by cyclic light occurs via an autoxidative mechanism.
Animals↗
Retinal light damage reduces autofluorescent pigment deposition in the retinal pigment epithelium.
Lipofuscin in the retinal pigment epithelium (RPE) is thought to be derived from phagocytosed photoreceptor outer segment disc membranes. Based on this hypothesis, one would predict that the rate of lipofuscin deposition in the RPE would be proportional to the density of photoreceptor cells in the retina. In previous studies it was demonstrated that specific loss of photoreceptor cells due to a genetic defect resulted in a substantial decrease in the rate of age-related lipofuscin accumulation in the RPE. In order to confirm that this decreased RPE lipofuscin deposition was directly related to reduced photoreceptor cell density, experiments were conducted to determine whether light-induced photoreceptor cell destruction affected RPE lipofuscin content. The effects of retinal light damage on RPE autofluorescent pigment accumulation resulting from both normal aging and vitamin E deficiency were examined. Starting immediately after weaning, albino Fisher 344 rats were fed diets either containing or lacking vitamin E. All animals were maintained on a 12 hr/12 hr light/dark cycle. During the light phases of the cycles, the cage illuminance for one-half the animals in each dietary group was 750 lux, while the remaining rats were exposed to a light level of 15 lux. Illumination was provided by 40 watt cool-white fluorescent lamps. After 17 weeks, rats in both dietary groups that were maintained under the higher light intensity had substantially reduced photoreceptor cell densities relative to animals in the same dietary group maintained under dim light conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Characterization of disease-specific brain fluorophores in ceroid-lipofuscinosis.
By isolating and identifying the molecular components of the storage material in the ceroid-lipofuscinoses, it should be possible to elucidate the metabolic basis for these diseases. Using brains of English setter dogs afflicted with a form of this disorder, the autofluorescent storage granules have been isolated and subjected to extraction with chloroform-methanol. A significant amount of autofluorescent material was solubilized by this procedure. Spectral analysis of the extracts indicated that the disease-specific fluorophores have corrected fluorescence excitation maxima at 335-340 nm and emission maxima at 530 nm. Analysis of the extracts with thin layer chromatography showed the presence of several disease-related fluorophores. In addition, the amounts of several nonfluorescent lipids appeared to be enhanced as a result of ceroid-lipofuscinosis. A cerebral cortex sample from a human subject who died with the late infantile form of ceroid-lipofuscinosis was subjected to the same analytical procedures. The chloroform-methanol extract from the human brain had a fluorescence spectrum very similar to the extracts from the brains of affected dogs. TLC analysis showed a single fluorophore from the human brain sample. This fluorophore had the same retention time as the most prominent fluorophore present in the samples from affected dogs. These findings are consistent with the possibility that the defects underlying the human and canine ceroid-lipofuscinoses are similar. The analytical procedures established in these experiments are useful in evaluating the various models of ceroid-lipofuscinosis and may ultimately serve as the basis for distinguishing among different forms of these disorders.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Fluorophores of the human retinal pigment epithelium: separation and spectral characterization.
Ten fluorescent fractions originating from the chloroform extracts of retinal pigment epithelial (RPE) cells of human donor eyes (ages 52-98 yr) have been separated and characterized by UV-vis absorbance and corrected fluorescence spectroscopy. The semipurified fluorophores fall into four categories based upon their spectral properties: green-emitting fluorophores, a golden yellow-emitting fluorophore, yellow-green-emitting fluorophores and orange-red-emitting fluorophores. All share common absorbance peaks around 280- and 330 nm, and the orange-red-emitting fluorophores also exhibit a strong absorbance peak at 420 nm. No significant visible-emitting fluorophores were detected in the methanol-water phase of these extracts. While these fluorophores are abundant in extracts from adult-derived RPE, most of the fluorophores occur in much lower amounts in RPE extracts from human donors under 10 yr of age. Eyes from child human donors also have much less RPE lipofuscin than those from adult donors, suggesting that most of the fluorophores are lipofuscin derived. This interpretation is supported by the previous finding that all of the fluorophores from whole RPE are also present in extracts of purified lipofuscin granules. Characterization of the chromatographic and spectral properties of the chloroform-soluble fluorescent components from the human RPE provides an important tool for determining the mechanism of RPE lipofuscin fluorophore formation. The absorbance properties defined here are of significance to investigations into the photobiology of the RPE and to those using laser therapy in treatment of age-related retinal diseases.
Adolescent↗
The comparative value of noninvasive testing for diagnosis and surveillance of deep vein thrombosis.
This is a prospective analysis of 351 patients in two distinct groups undergoing ascending phlebography, impedance plethysmography (IPG), and/or phleborheography (PRG) within the same 24-hour period. One hundred twenty patients also had a 125I-fibrinogen uptake test (RFUT). The two patient groups consisted of the following: those patients evaluated because of suspicion of deep vein thrombosis (DVT) (diagnostic) and those patients at high risk for postoperative DVT (total joint replacement) who had routine noninvasive testing and ascending phlebography (surveillance). The overall sensitivities for IPG and PRG were significantly better in the diagnosis group (71% [69 of 97 patients] and 78% [82 of 105], respectively) compared with the surveillance group (20% [14 of 71] and 27% [17 of 63], respectively) (p less than 0.0001). The sensitivities for IPG and PRG detecting proximal (A/K) thrombi was 83% (68 of 82 patients) and 92% (79 of 86) in the diagnosis group compared with 32% (11 of 34) and 33% (9 of 27) in the surveillance group (p less than 0.0001). Although there was no difference in overall incidence of DVT between the diagnosis group (56%, 118 of 212 patients) and the surveillance group (55%, 76 of 139), the results can be explained by the difference in A/K thrombi (84% [99 of 118] and 47% [36 of 76]) (p less than 0.001) and occlusive A/K thrombi (84% [58 of 69] and 23% [7 of 31]) (p less than 0.0001), respectively. Of the patients with A/K thrombi, 97% (67 of 69) in the diagnosis group had hemodynamically detectable thrombi compared with only 48% (12 of 25) in the surveillance group (p less than 0.001). Combining the RFUT with the noninvasive studies for surveillance significantly improved the sensitivity for both A/K and distal thrombi. Patient selection also appears to have a significant influence on the results of the combination of IPG and RFUT when the current surveillance group is compared with similarly performed studies in a previously reported diagnosis group. The location and magnitude of thrombi in any patient population can be skewed depending on indications and timing of testing, thereby significantly affecting the sensitivity of noninvasive tests. IPG and PRG are reliable for evaluating patients with suspected DVT. However, patients with postoperative DVT have a high incidence of nonocclusive thrombi. Because noninvasive hemodynamic tests cannot identify accurately postoperative DVT, they cannot be used to generate epidemiologic data or as end points for studies evaluating efficacy of prophylaxis in patients undergoing total joint replacement, and anatomic studies of the deep venous system continue to be required.
Fibrinogen↗
Autoxidative damage to the retina: potential role in retinopathy of prematurity.
Oxygen can participate in a number of reactions that are potentially damaging to cells and tissues. Reactive forms of oxygen are generated during normal metabolic processes, and a variety of biologic mechanisms have evolved to protect organisms from damage by these compounds. Apparently these protective mechanisms are not fully developed in the fetus, which exists in a hypoxic environment in utero. Premature birth exposes the infant to a sudden increase in environmental oxygen content, for which it is not physiologically prepared. It is likely that this premature exposure to atmospheric oxygen triggers an elevation in the rate of autoxidative reactions in tissues and that the termination of normal retinal vascularization seen in ROP is the result of an attempt to minimize such reactions. This interpretation is supported by the finding that vitamin E, an antioxidant in vivo, reduces the severity of ROP when given at an early enough stage.
Biomechanical Phenomena↗
Dietary vitamins A and E influence retinyl ester composition and content of the retinal pigment epithelium.
Experiments were conducted to determine the influence of dietary levels of vitamin A and alpha-tocopherol on the amounts and composition of retinyl esters in the retinal pigment epithelium of light-adapted albino rats. Groups of rats were fed diets containing alpha-tocopherol and either no retinyl palmitate, adequate retinyl palmitate, or excessive retinyl palmitate. Other groups of rats received diets lacking alpha-tocopherol and containing the same three levels of retinyl palmitate. Retinoic acid was added to diets lacking retinyl palmitate. After 27 weeks, the animals were light-adapted to achieve essentially total visual pigment bleaches, and the neural retinas and retinal pigment epithelium-eyecups were then dissected from each eye for vitamin A ester determinations. Almost all of the retinyl esters were found in the retinal pigment epithelium-eyecup portions of the eyes, mainly as retinyl palmitate and retinyl stearate. Maintaining rats on a vitamin A-deficient, retinoic acid-containing diet led to significant reductions in retinal pigment epithelial retinyl ester levels in rats fed both the vitamin E-supplemented and vitamin E-deficient diets; contrary to expectations, the effect of dietary vitamin A deficiency was more pronounced in the vitamin E-supplemented rats. Vitamin A deficiency in retinoic acid-maintained animals also led to significant reductions in retinyl palmitate-to-stearate ester ratios in the retinal pigment epithelia of both vitamin E-supplemented and vitamin E-deficient rats. Excessive dietary intake of vitamin A had little, if any, effect on retinal pigment epithelial retinyl ester content or composition. Vitamin E deficiency resulted in significant increases in retinal pigment epithelial retinyl palmitate content and in palmitate-to-stearate ester ratios in rats fed all three levels of vitamin A, but had little effect on retinal pigment epithelial retinyl stearate content. In other tissues, vitamin E deficiency has been shown to lower vitamin A levels, and it is widely accepted that this effect is due to autoxidative destruction of vitamin A. The increase in retinal pigment epithelial vitamin A ester levels in response to vitamin E deficiency indicates that vitamin E does not regulate vitamin A levels in this tissue primarily by acting as an antioxidant, but rather may act as an inhibitor of vitamin A uptake and/or storage. The effect of vitamin E on pigment epithelial vitamin A levels may be mediated by the vitamin E-induced change in retinyl palmitate-to-stearate ratios.
Animals↗
Light and aging effects on vitamin E in the retina and retinal pigment epithelium.
Experiments were performed to determine the effects of senescence and light adaptation on vitamin E levels in the neural retina and RPE-choroid-sclera of pigmented rats. Aging resulted in significant increases in alpha-tocopherol levels in both tissues, the effect being most pronounced in the RPE-choroid-sclera. The state of light adaptation had no influence on alpha-tocopherol levels in the neural retina at any of the ages examined, whereas in the RPE-choroid-sclera, alpha-tocopherol levels were substantially higher in light-adapted than in dark-adapted animals at all three ages (12, 22, and 32 months) at which they were measured. The effect of light adaptation on RPE-choroid-scleral alpha-tocopherol levels was most pronounced in the oldest age group.
Adaptation, Ocular↗
Lipofuscin autofluorescence: evidence for vitamin A involvement in the retina.
A lipofuscin-like autofluorescence develops in the degenerating photoreceptor cells of the RCS rat, a strain with inherited retinal dystrophy. In animals with normal retinas, age-related lipofuscin accumulation in the eye is restricted to the retinal pigment epithelium (RPE). Previous investigations have established that RPE lipofuscin accumulation in the normal rat retina can be reduced by dietary vitamin A deficiency. In order to determine whether the photoreceptor-derived fluorescence in the RCS rat retina is related to RPE lipofuscin fluorescence, the influence of dietary vitamin A on the fluorophore content of the RCS rat retina was studied. Vitamin A deficiency substantially reduced the autofluorescence associated with degenerating photoreceptor cells of the RCS rat retina. A specific vitamin A-dependent fluorophore was isolated from these retinas using thin-layer chromatography (TLC). The mobility of this fluorophore on TLC differs from that of the major age-dependent fluorophore isolated from the RPE of normal rats. Thus, if the vitamin A-dependent fluorophores of the photoreceptors and RPE are related, it appears that the fluorophore generated in the photoreceptor cells must undergo chemical modification once it has been taken up by the RPE. The fact that both the RPE- and photoreceptor-associated fluorophores are vitamin A-dependent suggests that such a relationship between them is likely. These experiments indicate that the RPE is somewhat different from other lipofuscin-accumulating tissues in that a major precursor of RPE lipofuscin fluorophores originates in another cell type and enters the RPE via phagocytosis.
Animals↗