Role of Nd3+ and Pb2+ on the RNA Cleavage Reaction by a Small Ribozyme. :

Author : Ohmichi T; Sugimoto N
Address : Department of Chemistry, Faculty of Science, Konan University, Higashinada-ku, Kobe, Japan.
Journal : Biochemistry, 36(12):3514-21 1997 Mar 25
Abstract : Leadzyme is a ribozyme that requires Pb2+. We have previously shown that the addition of Nd3+ in the presence of Pb2+ increased significantly the yield of the RNA cleavage reaction by a leadzyme, although other rare earth ions or divalent ions except Pb2+ did not promote the reaction [Sugimoto, N., & Ohmichi, T. (1996) FEBS Lett. 393, 97-100]. To investigate the combined effects of Nd3+ and Pb2+ on the binding and cleavage steps of a leadzyme, CUGGGAGUCC, with a substrate, GGACCGAGCCAG, kinetics for the leadzyme reaction have been measured at various concentration ratios of Nd3+ and Pb2+. At low concentration ratios of Nd3+ under a constant total concentration of metal ions, Nd3+ increased the stability of the complex between the leadzyme and the substrate. In contrast, at high concentration ratios of Nd3+, the addition of Nd3+ decreased the stability of the complex. The rate constant of the cleavage step was maximized when the ratio of Nd3+ to Pb2+ was 1:1. These results suggest that the complex between the leadzyme and the substrate has binding sites for Nd3+ ion that influence complex stability and catalyze directly the cleavage reaction. On the basis of the results, we propose a two-metal-ion mechanism in which Pb2+ and Nd3+ play the roles of base and acid catalyst, respectively.

Site-Specific Cleavage Reaction Catalyzed by Leadzyme is Enhanced by Combined Effect of Lead and Rare Earth Ions.

Author : Sugimoto N; Ohmichi T.
Address : Department of Chemistry, Faculty of Science, Konan University, Kobe, Japan.
              sugimoto@konan-u.ac.jp
Journal : FEBS Lett, 393(1):97-100 1996 Sep 9
Abstract : Lead-dependent ribozyme (leadzyme) is a ribozyme working with Pb2+. In this paper, we have investigated the combined effect of metal ions, especially rare earth ions, on the cleavage reaction by the leadzyme. As a result, it was observed that although only a rare earth ion or another divalent ion except Pb2+ did not play a role as the catalyst, the addition of a rare earth ion in the presence of Pb2+ increased significantly the yield of the cleavage reaction. The result suggests that the complex between the leadzyme and the substrate should have two classes of metal ion binding sites.

Is There a Prevention and Treatment Strategy for Macular Degeneration?

Author : Richer SP.
Origin : VA Medical Center, N. Chicago, IL 60064.
Journal : Journal of the American Optometric Association, 1993 Dec, 64(12):838-50.
Abstract :

BACKGROUND : Reduced antioxidant defense of the retina secondary to poor nutrition and smoking combined with increased life expectancy and exposure to solar radiation can provide a triple assault on the aging retina. If left untreated, without prophylactic measures, 7.5 million American adults will suffer vision loss from ARM by the year 2020.

METHODS : Better known pathobiologic interrelationships between ARM, nutritional/antioxidant status and UV/blue visible solar exposure risk based on animal research and recent epidemiologic studies is presented, along with an overview of ocular free radical biochemistry.

RESULTS : Because ARM begins parafoveally, and confounding ocular lens changes often occur, there have been practical clinical/research difficulties in early diagnosis, and assessing improvement/loss from nutritional intervention. Threshold Amsler grid testing, contrast sensitivity and more recently red foveal flicker fusion frequency testing are presented as promising tests, for discerning subtle pathologic and functional changes in vision.

CONCLUSIONS : A conservative prevention/treatment strategy is presented involving identification of at-risk patients, solar radiation protection, nutritional counseling based on the new USDA Food Pyramid concept and vitamin/mineral supplementation if necessary for non-compliant high risk patients. Excessive vitamin intake of particular micronutrients has some drawbacks, and the optometrist should be aware of the implications of self-prescribed OTC ocular formulations, the difference between UV risk vs. "blue light hazard" and ongoing clinical trials.

Free radicals and Antioxidant Supplementation: A Review of Their Roles in Age-Related Macular Degeneration.

Author : van der Hagen AM; Yolton DP; Kaminski MS; Yolton RL.
Origin : Pacific University, College of Optometry, Forest Grove, OR 97116.
Journal : Journal of the American Optometric Association, 1993 Dec, 64(12):871-8.
Abstract :

BACKGROUND: Age-related macular degeneration (ARMD) is a major cause. of blindness in the elderly. Unfortunately, no proven form of treatment is currently available for the dry, atrophic form of ARMD seen in more than 90 percent of patients with this condition.

METHODS: A recent theory suggests that ARMD is associated with damage to the retina caused by free radicals. If this is correct, it is possible that the damage could be prevented or moderated by supplementing the diet with specific antioxidant vitamins and minerals that enhance the body's natural defenses against free radicals.

RESULTS AND CONCLUSION: This paper reviews the literature regarding the pathogenesis of ARMD and presents a rationale for its management or prevention by the use of supplemental vitamins and minerals.

Antioxidants and Eye Disease.

Author : Christen WG Jr.
Origin : Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Journal : American Journal of Medicine, 1994 Sep 26, 97(3A):14S-17S; discussion 22S-28S.
Abstract : Oxidative mechanisms are believed to play an important role in the pathogenesis of age-related eye disease, in particular, cataract and macular degeneration, the two most important causes of visual impairment in older adults. For this reason, there is considerable interest in determining whether vitamins and trace minerals with antioxidant properties can be of benefit in preventing the onset or progression of disabling eye disease. Basic research studies have shown that antioxidants can protect against the cumulative effects of oxidative stress in animal models of cataract and macular degeneration. Data from observational epidemiologic studies in humans, however, are inconclusive. While results from several studies, primarily cross-sectional and case-control, are compatible with a possible protective role for micronutrients in cataract and macular degeneration, data for specific nutrients or specific disease types have often been inconsistent. Further, these observational studies are limited because of the inherent imprecision of dietary exposure data and the likely effects of uncontrolled confounding. Thus, reliable data regarding a potentially important benefit of vitamin supplementation in eye disease will emerge mainly from well-designed, large-scale, randomized trials. Such data are already being collected in the National Eye Institute-sponsored Age Related Eye Disease Study, as well as in the Physicians' Health Study and Women's Health Study.

Are antioxidants or Supplements Protective For Age-Related Macular Degeneration?

Author : West S; Vitale S; Hallfrisch J; Munoz B; Muller D; Bressler S; Bressler NM.
Origin : Dana Center for Preventive Ophthalmology, Johns Hopkins Hospital, Baltimore, Md.
Journal : Archives of Ophthalmology, 1994 Feb, 112(2):222-7.
Abstract :

OBJECTIVES : The relationships between fasting plasma levels of retinol, ascorbic acid, alpha-tochopherol, and beta-carotene and age-related macular degeneration (AMD) were studied in a population enrolled in the Baltimore Longitudinal Study of Aging (BLSA), in which most of the data were collected 2 or more years before assessment of macular status.

DESIGN : A total of 976 participants in the study were scheduled for a biennial examination from January 1988 through January 1, 1990, which included taking lens and macular photographs. A total of 827 (85%) of the participants had fundus photographs taken, and most plasma data were available for 82% of those subjects with fundus photographs. Age-related macular degeneration was defined as neovascular changes, geographic and nongeographic atrophy, large or confluent drusen, or hyperpigmentation. A total of 226 cases of AMD were available for analysis.

RESULTS : Logistic regression analyses suggested that alpha-tocopherol was associated with a protective effect for AMD, adjusted for age, sex, and nuclear opacity. An antioxidant index, including ascorbic acid, alpha-tocopherol, and beta-carotene, was also protective for AMD. Our conclusions must be tempered with the knowledge that the population under study was basically well nourished, and few individuals had any clinically deficient status. The study cannot exclude the possibility that quite low levels of micronutrients, lower than those observed in this study, might be risk factors for AMD.

CONCLUSIONS : The data suggest a protective effect for AMD of high plasma values of alpha-tocopherol. An antioxidant index, composed of plasma ascorbic acid, alpha-tocopherol, and beta-carotene, was also protective. The use of vitamin supplements to prevent AMD is not supported by these data, which showed no protective effect of vitamin use.

Preventative Ophthalmology. Age-related Macular Degeneration.

Author : Bressler NM; Bressler SB.
Journal : Ophthalmology, 1995; Aug, 102(8):1206-11.
Abstract :

PURPOSE : This report was designed to review the current knowledge degeneration (AMD) and visual loss associated with this entity in practical terms for the comprehensive ophthalmologist.

METHODS : Animal studies, epidemiologic studies, and clinical trials identified through the use of MEDLINE, a reference list of articles reviewed, and personal contact with experts in this area provided information reviewed for this report.

RESULTS : Reports concerning ultraviolet and visible light provide limited, inconsistent, and conflicting data to support the theory that light exposure leads to AMD. Micronutrient supplementation is a provocative but largely unproven hypothesis. Positive associations of cigarette smoking and cardiovascular disease or certain risk factors for cardiovascular disease with AMD provide potential clues as to the underlying pathogenesis of AMD and are yet another reason to treat these health problems. Drusen may disappear after laser to the macula; however, this intervention will require careful, randomized, prospective trials to determine if this therapy can reduce the risk of choroidal neovascularization and visual loss developing in patients with AMD.

CONCLUSIONS : It is reasonable to have individuals wear sunglasses for comfort and possible protection from ultraviolet light exposure to all ocular structures (especially the lens) at little or no risk to the patient. Physicians probably should be reluctant to prescribe micronutrients or suggest other interventions (such as laser to drusen) until their health claims have been substantiated and their long-term safety soundly established.

Nutritional Supplement Use and Age-Related Macular Degeneration.

Author : Chew EY.
Origin : National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Journal : Curr Opin Ophthalmol, 1995 Jun, 6(3):19-24.
Abstract : Age-related macular degeneration is one of the leading causes of visual loss among people aged 65 years or older. The causes and factors associated with the progression of age-related macular degeneration are unknown presently. Basic research and epidemiologic data support the hypotheses that higher levels of antioxidant vitamins and minerals may protect the eye from the development of age-related macular degeneration. For this reason and also because of the lack of effective treatment for most cases of age-related macular degeneration, nutritional supplements with antioxidants have emerged as possible therapy for age-related macular degeneration. Nutritional supplements are not proven therapy for age-related macular degeneration. The potential beneficial effects and adverse side effects of the nutritional supplements have not yet been fully evaluated in carefully conducted clinical trials. Several randomized placebo-controlled clinical trials are presently underway. Results of these studies will provide important data to clarify the potential beneficial and adverse effects of such treatment. Until these results are available, it would be premature to make recommendations in favor of vitamin or mineral supplements.

Are Antioxidants or Other Supplements Protective for Age-Related Macular Degeneration?

Author : Fekrat S; Bressler SB.
Origin : Retinal Vascular Center, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Journal : Curr Opin Ophthalmol, 1996 Jun, 7(3):65-7
Abstract : As the number of individuals with age-related macular degeneration increases, the economic and social consequences of this blinding disease rise. No proven preventive measures exist to halt development or progression of this disease. The specific insults that trigger and perpetuate age-related macular degeneration are unknown; however, it may be the result of repetitive oxidative injuries. Several studies suggest a possible protective role for antioxidant micronutrients and other trace minerals, but data for specific antioxidants have been inconsistent between studies. Although promising, the preliminary evidence is limited. Reliable data on whether antioxidant vitamins or trace minerals decrease the development or progression of age-related macular degeneration will emerge from several ongoing large-scale randomized clinical trials. Based on the currently available information, it is not possible to recommend antioxidant micronutrient supplementation to protect against development or retard progression of age-related macular degeneration.

Antioxidants and Age-Related Eye Disease. Current and Future Perspectives.

Author : Christen WG.Christen WG; Glynn RJ; Hennekens CH.
Origin : Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Journal : Annals of Epidemiology, 1996 Jan, 6(1):60-6
Abstract : Oxidative mechanisms may play an important role in the pathogenesis of age-related eye disease, in particular cataract and macular degeneration, the two most important causes of visual impairment in older adults. For this reason, there is considerable interest in determining whether vitamins and trace minerals with antioxidant properties can be of benefit in preventing the onset or progression of disabling eye disease. Basic research studies have shown that antioxidants can protect against the cumulative effects of oxidative stress in animal models of cataract and macular degeneration. Data from observational epidemiological studies in humans, however, are inconclusive. While results from several studies, primarily cross-sectional and case-control, are compatible with a possible protective role for micronutrients in disease development, data for specific nutrients or specific disease types have often been inconsistent. Further, these observational studies are limited because of the inherent imprecision of dietary exposure data and the likely effects of uncontrolled confounding. Thus, reliable data regarding a potentially important benefit of vitamin supplementation in eye disease will emerge mainly from well-designed, large-scale, randomized trials.

Evidence for Protection Against Age-Related Macular Degeneration by Carotenoids and Antioxidant Vitamins.

Author : Snodderly DM.
Origin : Schepens Eye Research Institute, Macular Disease Research Center Boston, MA 02114, USA.
Journal : American Journal of Clinical Nutrition, 1995 Dec, 62(6)
Abstract : Epidemiologic data indicate that individuals with low plasma concentrations of carotenoids and antioxidant vitamins and those who smoke cigarettes are at increased risk for age-related macular degeneration (AMD). Laboratory data show that carotenoids and antioxidant vitamins help to protect the retina from oxidative damage initiated in part by absorption of light. Primate retinas accumulate two carotenoids, lutein and zeaxanthin, as the macular pigment, which is most dense at the center of the fovea and declines rapidly in more peripheral regions. The retina also distributes alpha-tocopherol (vitamin E) in a nonuniform spatial pattern. The region of monkey retinas where carotenoids and vitamin E are both low corresponds with a locus where early signs of AMD often appear in humans. The combination of evidence suggests that carotenoids and antioxidant vitamins may help to retard some of the destructive processes in the retina and the retinal pigment epithelium that lead to age-related degeneration of the macula.

Association of Zinc and Antioxidant Nutrients with Age-Related Maculopathy.

Author : Mares-Perlman JA; Klein R; Klein BE; Greger JL; Brady WE; PaltaM; Ritter LL.
Origin : Department of Ophthalmology, University of Wisconsin, Madison, USA.
Journal : Archives of Ophthalmology, 1996 Aug, 114(8):991-7.
Abstract :

OBJECTIVE : To quantify relationships between dietary intake of zinc and antioxidant nutrients and early and late age-related maculopathy (ARM).

DESIGN : A retrospective longitudinal cohort design using data pertaining to diets in the past (1978-1980), which were assessed retrospectively using a food frequency questionnaire.

SETTING : Beaver Dam, Wis.

PATIENTS : A 50% random sample of free-living Beaver Dam Eye Study participants, 43 to 86 years of age (N = 1968).

MAIN OUTCOME MEASURE : The presence of early and late ARM determined from fundus photography.

RESULTS : People in the highest vs lowest quintiles for intake of zinc from foods had lower risk for early, ARM (odds ratio = 0.6, 95% confidence interval, 0.4-1.0, P for trend .05). This relationship appeared to be stronger for some types of early ARM (increased retinal pigment) than for others. Zinc intake was unrelated to late ARM. However, small numbers (n = 30) of people with this condition limit the ability to draw conclusions about this later stage. Levels of carotenoids were unrelated to early or late ARM. Odds for early ARM were lower in people in the highest vs lowest quintiles for the intake of vitamins C or E. However, these associations were not statistically significant.

CONCLUSIONS : The data are weakly supportive of a protective effect of zinc on the development of some forms of early ARM. Prospective studies are needed to further evaluate the potential influence of these and other nutritional factors on different types and stages of age-related macular degeneration.

Multicenter Ophthalmic and Nutritional Age-Related Macular Degeneration Study: Part 1: Design, Subjects and Procedures.

Author : Richer S.
Origin : Eye Clinic 112e, DVA Medical Center, North Chicago, IL 60064, USA.
Journal : Journal of the American Optometric Association, 1996 Jan, 67(1):12-29.
Abstract :

BACKGROUND : A prospective 18 month, double-blind case-controlled study was designed to determine whether a specific over-the-counter multivitamin/mineral/antioxidant nutrient capsule taken twice daily prevents the progression of, or improves the outcome of non-exudative ARMD. Two randomly assigned experimental ARMD groups are compared to each other, to age matched ARMD-free case controls and to 1994 NHANES III nutritional data.

METHODS : Thirty-two dry ARMD patients assigned to group one (placebo) and 39 dry ARMD patients were assigned to group two (Ocuguard, a broad spectrum antioxidant capsule). A third age and sex matched ARMD-free case control group of 13 patients who met the same entrance criteria were also selected. All participants underwent thorough visual and nutritional evaluation prior to initiation of the study. Both ophthalmic tests and dietetic assessments were also performed at 6, 12 and 18 months following a 2-week initiation period.

RESULTS : In comparison to NHANES-III age stratified population data and the Recommended Daily Allowance (but not case controls), the ARMD population manifested decreased intake of nutrients vital to cardiovascular health: vitamin E, magnesium, zinc, vitamin B6 and folic acid. The two randomly assigned experimental groups were well matched, with little difference in baseline demographic, ocular, hematologic and pre-intervention symptoms. There were differences in nutritional intake between the two groups, due primarily to significantly higher percent ideal body weight in group two.

Dietary modification of human macular pigment density.

Author : Hammond BR Jr; Johnson EJ; Russell RM; Krinsky NI; Yeum KJ; Edwards RB; Snodderly DM.
Origin : Department of Social and Behavioral Sciences, College of Arts and Sciences, Arizona State University West, Phoenix 85069-7100, USA.
Journal : Investigative Ophthalmology and Visual Science, 1997 Aug, 38(9):1795-801.
Abstract :

PURPOSE : The retinal carotenoids lutein (L) and zeaxanthin (Z) that form the macular pigment (MP) may help to prevent neovascular age-related macular degeneration. The purpose of this study was to determine whether MP density in the retina could be raised by increasing dietary intake of L and Z from foods.

METHODS : Macular pigment was measured psychophysically for 13 subjects. Serum concentrations of L, Z, and beta-carotene were measured by high-performance liquid chromatography. Eleven subjects modified their usual daily diets by adding 60 g of spinach (10.8 mg L, 0.3 mg Z, 5 mg beta-carotene) and ten also added 150 g of corn (0.3 mg Z, 0.4 mg L); two other subjects were given only corn. Dietary modification lasted up to 15 weeks.

RESULTS : For the subjects fed spinach or spinach and corn, three types of responses to dietary modification were identified: Eight "retinal responders" had increases in serum L (mean, 33%; SD, 22%) and in MP density (mean, 19%; SD, 11%); two "retinal nonresponders" showed substantial increases in serum L (mean, 31%) but not in MP density (mean, -11%); one "serum and retinal nonresponder" showed no changes in serum L, Z, or beta-carotene and no change in MP density. For the two subjects given only corn, serum L changed little (+11%, -6%), but in one subject serum Z increased (70%) and MP density increased (25%).

CONCLUSIONS : Increases in MP density were obtained within 4 weeks of dietary modification for most, but not all, subjects. When MP density increased with dietary modification, it remained elevated for at least several months after resuming an unmodified diet. Augmentation of MP for both experimental and clinical investigation appears to be feasible for many persons.

Moderate wine consumption is associated with decreased odds of developing age-related macular degeneration in NHANES-1.

Author : Obisesan TO; Hirsch R; Kosoko O; Carlson L; Parrott M.
Origin : Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA.
Journal : Journal of the American Geriatrics Society, 1998 Jan,; 46(1):1-7.
Abstract :

OBJECTIVE : To determine the association between alcohol intake and the risk of developing age-related macular degeneration (AMD).

DESIGN : Case control study.

PARTICIPANTS : The sample consisted of 3072 adults 45 to 74 years of age with macular changes indicative of AMD who participated in a nationally representative sample of the first National Health Nutrition and Examination Survey (NHANES-1) between 1971 and 1975: (a) the ophthalmology data set and (b) the medical history questionnaire.

MAIN OUTCOME MEASURES : Alcohol intake and the risk of developing AMD were measured. AMD was determined by staff at the National Eye Institute by fundoscopy examination using standardized protocol.

RESULTS : Overall, 184 individuals (6%) had AMD. We observed a statistically significant but negative association between AMD and the type of alcohol consumed in a bivariate model (OR 0.86; 95% CI 0.73, 0.99). In the same model, age maintained a consistently strong association with AMD (OR 1.08; 95% CI 1.06-1.11; P < .001). Among the different types of alcohol consumed in NHANES-1 (beer, wine, and liquor), the effect of wine, either alone (OR 0.66; 95% CI 0.55-0.79) or in combination with beer (OR 0.66; 95% CI 0.55-0.79) or liquor (OR 0.74; 95% CI 0.63-0.86), dominated the negative association observed between AMD and alcohol type. Additionally, a statistically significant and negative association between wine and AMD was noted after adjusting for the effect of age, gender, income, history of congestive heart failure, and hypertension (OR 0.81; 95% CI 0.67-0.99).

CONCLUSION : Moderate wine consumption is associated with decreased odds of developing AMD. Health promotion and disease prevention activities directed at cardiovascular disease may help reduce the rate of AMD-associated blindness among older people.

Aluminum exposure and metabolism

Author : Greger JL. Sutherland JE.
Origin : Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA.
Journal : Critical Reviews in Clinical Laboratory Sciences, 1997 Oct, 34(5):439-74.
Abstract : Aluminum (Al) is a nonessential, toxic metal to which humans are frequently exposed. Oral exposure to aluminum occurs through ingestion of aluminum-containing pharmaceuticals and to a lesser extent foods and water. Parenteral exposure to aluminum can occur via contaminated total parenteral nutrition (TPN), intravenous (i.v.) solutions, or contaminated dialysates. Inhalation exposure may be important in some occupational settings. The gut is the most effective organ in preventing tissue aluminum accumulation after oral exposure. Typically .i.Al:gastrointestinal absorption; of aluminum from diets is < 1%. Although the mechanisms of aluminum absorption have not been elucidated, both passive and active transcellular processes and paracellular transport are believed to occur. Aluminum and .i.Al:calcium; may share some absorptive pathways. Aluminum absorption is also affected by the speciation of aluminum and a variety of other substances, including citrate, in the gut milieu. Not all absorbed or parenterally delivered aluminum is excreted in urine. Low .i.Al:glomerular filtration; of aluminum reflects that most aluminum in plasma is nonfiltrable because of complexation to proteins, predominantly .i.Al:transferrin;. The importance of .i.Al:biliary secretion; of aluminum is debatable and the mechanism(s) is poorly understood and appears to be saturable by fairly low oral doses of aluminum.

Intestinal malabsorption, celiac disease and associated lymphoma: from symptoms to diagnosis Gasbarrini G

Author : Gasbarrini G; Corazza GR; Biagi F; Brusco G; Andreani ML; Malservisi S; Greco AV.
Origin : Istituto di Medicina Interna, Universitˆ Cattolica Sacro Cuore, Roma.
Journal : Riv Eur Sci Med Farmacol, 16 Suppl 1:39-68, 1994 Sep-Dec
Abstract : The clinical consequences of intestinal malabsorption are extremely variable and a dissociation between malabsorption, malabsorption syndrome and enteropathy is often noted. Enteropathy does not always results in malabsorption and in an alteration of the tests exploring the absorptive function. The following have particular relevance in clinical practice: coeliac disease, malabsorption induced by microbiologic agent (including Whipple's disease), post-surgical malabsorption and selective carbohydrate malabsorption. In particular, coeliac disease has been analyzed in its various aspects, from studies with organ cultures to immunological hypotheses, from the classical variety to subclinical forms and to serious complications, such as enteropathy-associated T cell lymphoma. Malabsorption syndromes are dramatically underdiagnosed: in the typical case of coeliac disease, enteropathy represents a clinical iceberg, and the discovery of the submerged portion, represented by the polymorphous subclinical varieties, has just started. As far as intestinal malabsorption is concerned, the main clinical problem regards the diagnosis.