[Antioxidants for prophylaxis of eye diseases]
Klin Oczna (Poland) Feb 1996, 98 (2) p141-3
The contemporary literature has widely described the role of free oxygen radicals and their antioxidants in pathogenesis of some eye diseases, mainly cataract, age-related macular degeneration, retinopathy of prematurity and cystic macular oedema. This paper presents publications which stress the importance of antioxidants use in prophylaxis of cataract and age-related macular degeneration. Positive antioxidants role was proved both in experimental research and in clinical observations. (29 Refs.)
Antioxidants and angiogenetic factor associated with age-related macular degeneration (exudative type)
Ishihara N, Yuzawa M, Tamakoshi A
Department of Ophthalmology, Nihon University School of Medicine, Tokyo, Japan.
Nippon Ganka Gakkai Zasshi 1997 Mar;101(3):248-51
To confirm the hypothesis that antioxidants and angiogenetic factors may be associated with the development of age-related macular degeneration (exudative type), we compared serum levels of vitamins A, C, and E and carotinoid, zinc, selenium and b-FGF (basic-fibroblast growth factor) in 35 patients with age-related macular degeneration (exudative type) with the levels in 66 controls. The average serum zinc level was significantly lower in the patient group than in the control group. Serum vitamin E-alpha levels also tended to be lower. Most serum b-FGF levels were below the standard value in each group. Based on the above results, we conclude that subnormal levels of zinc and vitamin E may be associated with the development of age- related macular degeneration.
Retinal tubulin binds macular carotenoids.
Bernstein PS, Balashov NA, Tsong ED, Rando RR
John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City 84132, USA.
Invest Ophthalmol Vis Sci (United States) Jan 1997, 38 (1) p167-75
PURPOSE: To investigate the biochemical mechanisms responsible for the specific uptake, concentration, and stabilization of the carotenoids lutein and zeaxanthin in the macula.
METHODS: Soluble extracts of bovine retina mixed with radioactive carotenoids were purified by hydrophobic interaction, ion exchange, and gel filtration chromatography. Carotenoid-associated proteins in these purified preparations were identified through photoaffinity labeling and protein microsequencing. Similar purifications on human macular tissue without the addition of exogenous carotenoids also were performed.
RESULTS: Experiments on bovine retinal tissue demonstrated that tubulin is the major soluble carotenoid-binding protein. When soluble extracts of human macular protein were examined, the endogenous carotenoids lutein and zeaxanthin were found to copurify with tubulin.
CONCLUSIONS: Tubulin is found in abundance in the receptor axon layer of the fovea, where it can serve as a locus for the deposition of the high concentrations of macular carotenoids found there. The binding interaction of carotenoids and tubulin in the Henle's fiber layer could play an important role in the photoprotective effects of the macular carotenoids against the progression of age-related macular degeneration. The association of carotenoids with tubulin, a protein that can form highly ordered linear arrays, may provide an explanation for the dichroic phenomenon of Haidinger's brushes.
Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration.
Hammond BR Jr, Wooten BR, Snodderly DM
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston MA 02114, USA.
Vision Res (England) Sep 1996, 36 (18) p3003-9
The foveal region of the retina has a yellow pigmentation composed primarily of the carotenoids lutein and zeaxanthin. Past studies have shown that cigarette smoking depresses carotenoid concentrations in the blood. This is the first report on the effects of cigarette smoking on carotenoids in the retina. Macular pigment optical density (MP) was measured psychophysically by comparing foveal and parafoveal sensitivities to light of 460 and 550 nm. General dietary patterns, smoking frequency (cigaretts/day) and personal data were collected by questionnaire. Thirty-four smokers and 34 nonsmokers were compared. Subjects were matched with respect to age, sex, dietary patterns and overall pigmentation (i.e., eye, skin and hair color). The smoking group had a mean MP of 0.16 (SD = 0.12) compared to a mean MP of 0.34 (SD = 0.15) for nonsmokers (P < 0.0001). MP density and smoking frequency were inversely related (r = -0.498 P < 0.001) in a dose-response relationship. A variety of evidence suggests that MP protects the macula from actinic damage both passively (by screening potentially harmful short-wave light) and actively as an antioxidant (e.g., by quenching reactive oxygen species). If smoking causes a reduction in MP density, then smokers may be at risk. Epidemiologic data identifying smoking as a risk factor for the neovascular form of age-related macular degeneration are consistent with this hypothesis.
Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns.
Hammond BR Jr, Curran-Celentano J, Judd S, Fuld K, Krinsky NI, Wooten BR, Snodderly DM
Schepens Eye Research Institute, Boston, MA 02114, USA.
Vision Res (England) Jul 1996, 36 (13) p2001-12
Sex differences in macular pigment (MP) optical density (measured psychophysically) were examined. Concentrations of lutein and zeaxanthin (L and Z) (non-separated) and beta-carotene (BC) in the blood were determined using reverse phase high-performance liquid chromatography. Dietary intake of L and Z, BC, fat, and iron were estimated by questionnaire. Males had 38% higher MP density than females (P < 0.001) despite similar plasma carotenoid concentrations and similar dietary intake (except for fat). Dietary intake of carotenoids, fat and iron, as well as plasma concentrations of L and Z were positively related to MP density in males. Conversely, only plasma L and Z was related to MP density for females, and dietary fat was negatively related to MP density. Sex differences in protection of the retina by MP and in the relationship between the retina, blood and diet could be a factor in the incidence of retinal diseases, especially age-related macular degeneration.
Retinol (Vitamin A) supplements in the elderly
Centre for the Study of Host Resistance, Montreal General Hospital, Quebec, Canada
Drugs and Aging (New Zealand), 1996, 9/1 (48-59)
Aging is associated with many changes in epithelial tissues, immune function and haematopoiesis-myelopoiesis. There is increasing evidence that retinoids can significantly influence some of these changes. Retinoids may also have anticancer effects and protect against age-associated conditions such as macular degeneration. However, retinol (vitamin A) can be toxic when taken in excess and the elderly may be at particular risk for hypervitaminosis A. Evaluation of elderly people ingesting significantly more or less than the recommended daily intake of retinol requires an understanding of the biology of retinoids and consideration of the relative risks and benefits of supplementation.
Studies on the mechanism of early onset macular degeneration in cynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress
Nicolas MG, Fujiki K, Murayama K, Suzuki MT, Shindo N, Hotta Y, Iwata F, Fujimura T, Yoshikawa Y, Cho F, Kanai A
Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan.
Experimental Eye Research (United Kingdom), 1996, 62/4 (399-408)
Initial investigations done in this laboratory detected increased albumin and decreased glyceraldehyde 3-phosphate dehydrogenase concentrations in the retina of an animal model manifesting early onset macular degeneration. Both glyceraldehyde 3-phosphate dehydrogenase and albumin are markers of oxidative stress in cells. In this study, we used the same animal model to study further biochemical and physiological processes which may be involved in the pathogenesis of early onset macular degeneration in monkeys. We detected 60% lower catalase and glutathione peroxidase activities in the affected retinas suggesting lower antioxidant activities and oxidative stress. One of the consequences of oxidative stress is the production of metallothionein, a low molecular weight protein also induced by high concentrations of heavy metals such as zinc. Metallothionein was detected by RT-PCR in these monkey retinas. However initial quantitative PCR studies on this protein showed that the synthesis of metallothionein in affected retinas appears to be less than in normal controls. The affected retinas also showed a fourfold lower zinc concentration compared with the normal controls. No significant difference, however, could be detected in the zinc concentrations in plasma samples. Since induction of metallothionein synthesis is mediated by transcription factors which require heavy metals such as zinc for binding to specific sites in the DNA, the lowered zinc concentration may, thus, correlate with the lowered metallothionein expression. And since metallothionein is suggested to function as a free radical scavenger, the lowered metallothionein synthesis may consequently contribute to increased peroxidation reactions in the affected retinas. It appears therefore, that oxidative stress and the decreased metallothionein synthesis may be involved in the pathogenesis of early onset macular degeneration in this animal model.
Association of zinc and antioxidant nutrients with age-related maculopathy.
Mares-Perlman JA, Klein R, Klein BE, Greger JL, Brady WE, Palta M, Ritter LL
Department of Ophthalmology, University of Wisconsin, Madison, USA.
Arch Ophthalmol (United States) Aug 1996, 114 (8) p991-7
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.
Oral zinc and the second eye in age-related macular degeneration.
Stur M, Tittl M, Reitner A, Meisinger V
Klinik fur Augenheilkunde, Abteilung A, Allgemeines Krankenhaus der Stadt Wien, Austria.
Invest Ophthalmol Vis Sci (United States) Jun 1996, 37 (7) p1225-35
PURPOSE. To investigate the short-term effect of oral zinc substitution on the development of age-related macular degeneration in the second eye of patients with an exudative form of the disease in the first eye.
METHODS. A 2-year, double-masked, randomized, placebo-controlled study including 112 white patients with age-related macular degeneration and exudative lesions (choroidal neovascularization, pigment epithelial detachment, or both) in one eye and a visual acuity of better than 20/40 and macular degeneration without any exudative lesion in the second eye was performed. Patients received either 200 mg of oral zinc sulfate or placebo once daily for 24 months. The main outcome parameters were visual acuity, contrast sensitivity, color discrimination, and retinal grating acuity, as well as serum levels of zinc and copper, red blood cell count, hemoglobin, and morphologic changes detected by grading of monochrome fundus photographs and fluorescein angiograms.
RESULTS. In the treatment group, the mean zinc serum level increased significantly (P < 0.0001) from 79 +/- 10 micrograms/dl to 108 +/- 26 micrograms/dl compared to no change (82 +/- 16 micrograms/dl to 85 +/- 10 micrograms/dl) in the placebo group. Serum levels of copper, hemoglobin, and red blood cell count did not change significantly in either group. A choroidal neovascular membrane (CNV) was detected in 14 patients during the treatment period (nine in the treatment group, five in the placebo group). Seven additional patients (three in the treatment group, four in the placebo group) experienced visual loss caused by CNV, and in two patients (one in each group), serous pigment epithelial detachment developed without angiographic evidence of CNV after the end of treatment, during a mean additional follow-up time of 20.8 +/- 8.2 months. In eyes in which exudative lesions did not develop, there was no significant change in any of the functional parameters during the 24-month treatment period, but there was a significant increase in the nonexudative alterations (drusen size, drusen confluence, hyperpigmentation, and focal degeneration of the retinal pigment epithelium) in both groups.
CONCLUSIONS. Oral zinc substitution has no short-term effect on the course of age-related macular degeneration in patients who have an exudative form of the disease in one eye.
Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group
Seddon JM; Ajani UA; Sperduto RD; Hiller R; Blair N; Burton TC; Farber MD; Gragoudas ES; Haller J; Miller DT; et al
JAMA 1994 Nov 9;272(18):1413-20
Published erratum appears in JAMA 1995 Feb 22;273(8):622
OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults.
DESIGN--The multicenter Eye Disease Case-Control Study.
SETTING--Five ophthalmology centers in the United States.
PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex.
MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses.
RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of Vitamin-C, particularly from foods.
CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.
Evidence by in vivo and in vitro studies that binding of pycnogenols to elastin affects its rate of degradation by elastases
Tixier J.M.; Godeau G.; Robert A.M.; Hornebeck W.
Biochem Pharmacol 1984 Dec 15;33(24):3933-9
Procyanidol oligomers and (+) catechin bound to insoluble elastin markedly affect its rate of degradation by elastases. Insoluble elastin pretreated with procyanidol oligomers (PCO) was resistant to the hydrolysis induced by both porcine pancreatic and human leukocyte elastases. The quantitative adsorption of pancreatic elastase was similar on either untreated or PCO-treated elastin suggesting that the binding of this compound to elastin increases the non-productive catalytic sites of elastase molecules. (+) Catecholin-insoluble elastin complexes were partially resistant to the degradation induced by human leukocyte elastase but were not hydrolysed at the same rate as untreated samples by a constant amount of pancreatic elastase. In addition, the coacervation profile of kappa-elastin peptides as a function of temperature is greatly modified in presence of these flavonoids. We conclusively evidenced that PCOs bind to skin elastic fibres when injected intradermally into young rabbits. As a result, these elastic fibres were found more resistant to the hydrolytic action of porcine pancreatic elastase when injected to the same site. These in vivo studies emphasized the potential effect of these compounds in preventing elastin degradation by elastase(s) as occurred in inflammatory processes.
Antioxidant enzymes of the human retina: Effect of age on enzyme activity of macula and periphery
De La Paz M.A.; Zhang J.; Fridovich I.
Duke University Eye Center, DUMC, Box 3802, Durham, NC 27710 USA
Current Eye Research (United Kingdom), 1996, 15/3 (273-278)
The purpose of this research was to evaluate the effect of age on protective antioxidant enzyme activity of normal fresh cadaver human retina of the macula and periphery. Antioxidant enzymes were assayed in tissue extracts generated from 5 mm trephined punches of retina obtained centered over the macula and the superior midperiphery of normal fresh human cadaver retina. Cadaver tissue was obtained from donors of a wide age range (age 7 to 85 years). The assays were performed within 6 h of enucleation and within 24 h of donor death. Antioxidant enzymes assayed included superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Hexokinase and glucose-6-phosphate dehydrogenase, enzymes not directly involved in protection against oxidative damage, were assayed for comparison. Enzyme specific activities were calculated for the macula and periphery using protein concentration of the extract as the denominator. Using linear regression analysis, over the age range of 25 to 75 years, superoxide dismutase activity of the periphery but not the macula tended to decline with age (p = 0.04, R2 = 0.21). Interindividual variability was high, and variability increased with age. The difference between the macular and peripheral enzyme activities for glutathione peroxidase tended to decline with increasing donor age (p = 0.025, R2 = 0.33). There was no effect of age on the specific activities of catalase, glucose-6-phosphate dehydrogenase, and glutathione reductase. The specific activity of hexokinase from the macula declined with increasing donor age (p = 0.022, R2 = 0.43). Time from death to enucleation or beginning of experiment was not a significant factor. In summary, age does not have an effect on the activity of major antioxidant enzymes of the macula in normal human retina. There is a tendency for an effect of age on peripheral superoxide dismutase activity and the difference between macular and peripheral glutathione peroxidase activity. High interindividual variability of antioxidant enzyme activity exists in humans.
Low glutathione reductase and peroxidase activity in age-related macular degeneration
Cohen S.M.; Olin K.L.; Feuer W.J.; Hjelmeland L.; Keen C.L.; Morse L.S.
Department of Ophthalmology, UC Davis, 1603 Alhambra Boulevard, Sacramento, CA 95816 USA
Br. J. Ophthalmol. (United Kingdom), 1994, 78/10 (791-794)
Age-related macular degeneration (ARMD) may result from events initiated by reactive oxygen species. Blood samples from 18 patients with ARMD and 18 similarly aged controls were analysed for activities of important antioxidants. Blood glutathione reductase activity was lower in patients with ARMD compared with controls (p = 0.035). The activities of glutathione peroxidase (p = 0.18) and erythrocyte superoxide dismutase (p = 0.29) were similar between the two groups by a Student's two sample t test. Logistic regression was used to determine which enzyme activities were associated with ARMD after adjusting for possible confounding variables: smoking history, age, multivitamin use, and cardiovascular disease. Glutathione reductase activity (p = 0.05) and glutathione peroxidase activity (p = 0.065) were significantly associated with ARMD by this analysis. The relation of glutathione reductase and glutathione peroxidase activity to ARMD merits further study.
Antioxidant enzymes in RBCs as a biological index of age related macular degeneration
Prashar S.; Pandav S.S.; Gupta A.; Nath R.
Department of Biochemistry, PGIMER, Chandigarh 160012 India
Acta Ophthalmol. (Denmark), 1993, 71/2 (214-218)
The present study was undertaken to assess the levels of antioxidant enzymes in red blood cells of subjects with age-related macular degeneration and age-matched controls. The results obtained show a significant decrease in activities of superoxide dismutase (p < 0.001) and glutathione peroxidase (p < 0.001) as compared to the controls. A good correlation (r =O.99) was also observed between age and decreased activity of antioxidant enzymes in controls, and also correlated well with age related macular degeneration. In conclusion, oxidative stress as assessed by antioxidant enzymes is more pronounced in subjects with age-related macular degeneration as compared to age-matched controls.
Oxidative effects of laser photocoagulation
Jennings P.E.; MacEwen C.J.; Fallon T.J.; Scott N.; Haining W.M.; Belch J.J.F.
Department of Medicine, Ninewells Hospital and Medical School, Dundee, DD19SY United Kingdom
Free Radic. Biol. Med. (USA), 1991, 11/3 (327-330)
Diabetic proliferative retinopathy is a common and sight-threatening condition. Oxidative stress is an integral and possibly causative part of the pathogenesis. Although laser photocoagulation is usually a beneficial treatment it remains unclear how it works. The possibility that it induces a sudden, temporary increase in free radical activity either by direct thermal damage or by oxygen reperfusion is explored in this clinical study by measuring the oxidative status in the peripheral blood of 13 patients undergoing panretinal photocoagulation. There were significant increases at one hour in malondialdehyde-like material (MDA-LM), 8.1 (6.9-9.6) nmol/mL, to 9.1 (7.6-9.8) nmol/mL, (< 0.005); plasma thiols (PSH), 423 (352-457) microm/L, to 444 (382-478) microm/L, (p < 0.005) and red cell reduced glutathione (GSH), 1357 (1295-1655) microm/L, to 1480 (1305-1760) microm/L, (p < 0.01). Diene conjugates rose over the first hour 0.55 (0.36-0.79) od/mL, to 0.58 (0.34-0.85) od/mL falling to 0.56 (0.36-0.79) od/mL at 2 h but these changes were not significant. At 2 h, MDA-LM 8.4 (6.7-9.6) nmol/mL and PSH 404 (379-462) microm/L had returned to baseline but GSH remained significantly elevated 1500 (1325-1675) microm/L, (p < 0.005 compared to baseline). This is a new observation and in some circumstances such generation of free radicals could explain the mechanism behind the complications of photocoagulation by direct or indirect damage to vascular endothelium leading to increased vascular permeability manifest as macular oedema or choroidal effusions.
Antioxidant status and neovascular age-related macular degeneration
Yannuzzi L.A.; Sorenson J.A.; Sobel R.S.; Daly J.R.; DeRosa J.T.; Seddon J.M.; Gragoudas E.S.; Puliafito C.A.; Gelles E.; Gonet R.; Burton T.C.; Culver J.; Metzger K.; Kalbfleisch N.; Zarling D.; Farber M.D.; Blair N.; Stelmack T.; Sperduto R.D.; et al.
Biometry and Epidemiology Program, National Eye Institute, Bldg 31, 9000 Rockville Pike, Bethesda, MD 20892 USA
Arch. Ophthalmol. (USA), 1993, 111/1 (104-109)
We evaluated the hypothesis that higher serum levels of micronutrients with antioxidant capabilities may be associated with a decreased risk of neovascular age-related macular degeneration by comparing serum levels of carotenoids, vitamins C and E, and selenium in 421 patients with neovascular age-related macular degeneration and 615 controls. Subjects were classified by blood level of the micronutrient (low, medium, and high). Persons with carotenoid levels in the medium and high groups, compared with those in the low group, had markedly reduced risks of neovascular age-related macular degeneration, with levels of risk reduced to one half and one third, respectively. Although no statistically significant protective effect was found for Vitamin-C or E or selenium individually, an antioxidant index that combined all four micronutrient measurements showed statistically significant reductions of risk with increasing levels of the index. Although these results suggest that higher blood levels of micronutrients with antioxidant potential, in particular, carotenoids, may be associated with a decreased risk of the most visually disabling form of age-related macular degeneration, it would be premature to translate these findings into nutritional recommendations.
Nutrition in the elderly
Morley J.E.; Mooradian A.D.; Silver A.J.; Heber D.; Alfin-Slater R.B. BR> Department of Medicine, University of California School of Medicine, Los Angeles, CA 90024 USA
Ann. Intern. Med. (USA), 1988, 109/11 (890-904)
Nutritional modulation is one approach to successful aging. In animals, dietary restriction increases life span. Alterations in the macronutrient and micronutrient constituent of the diet can modulate gene expression. Anorexia is common in elderly persons. The results of studies in animals suggest that aging is associated with a decrease in the opioid feeding drive and an increase in the satiating effect of cholecystokinin. Unrecognized depression is a common, treatable cause of anorexia and weight loss in elderly persons. Protein synthesis decreases in elderly persons; nevertheless, nitrogen balance can be maintained in patients with fairly low intakes of protein. Carbohydrate intolerance is common and may be modulated by nutritional intervention and physical activity. The role of cholesterol in the development of heart disease in very old persons is controversial. Homebound and institutionalized elderly persons often do not expose their skin to sunlight; because the skin of older persons has a decreased ability to form vitamin D, the vitamin D status in these persons is precarious and they are at risk for osteopenia. Vitamins are often abused by elderly persons. Drug administration alters the vitamin requirements of persons. Borderline zinc state has been associated with deteriorating immune function, especially in persons who have diabetes mellitus or who abuse alcohol. Zinc administration appears to protect against the deteriorating vision associated with age-related macular degeneration. Selenium deficiency seems to be associated with an increased prevalence of cancer.