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35. Sellmayer A, Witzgall H, Lorenz RL, Weber PC. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol 1995;76:974 36. De Lorgeril M, Renaud S. Mediterranean alpha-linolenic acid-rich diet on secondary prevention of coronary heart disease. Lancet 1994;343:1454 37. Daviglus M, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336:1046 38. Kang JX, Leaf A. Prevention and termination of the beta-adrenergic agonistinduced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes. Biochem Biophys Res Commun 1995;208:629 39. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res 1989;30:785 40. Nestel PJ. Effects of n-3 fatty acids on lipids metabolism. Annu Rev Nutr 1990;10:149 41. Nestel PJ. Fish oil and cardiovascular disease: lipids and arterial function. Am J Clin Nutr 2000; 71(suppl): 228S 42. Griffin BA, Packard CJ. Metabolism of VLDL and LDL subclasses. Curr Opin Lipidol 1994;5:200 43. Roche HM, Gibney M. Effect of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism. Am J Clin Nutr 2000; 71(suppl);232S 44. Nestel PJ, Connor WE, Reardon MR, et al. Suppression by diets rich in fish oil of very low-density lipoproteins production in man. J Clin Invest 1984;74:72 45. Masserei K, Stanton G, Dunbar D. Dietary fish oil increase serum lipids in insulin-dependent diabetics compared with healthy controls. Metabolism 1989; 38:404 46. De Caterina R, Liao J, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000; 71(suppl):213S 47. Dyerberg J, Bang HO, Stofferson E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978;ii:117

Nutrition Volume 16, Numbers 7/8, 2000 48. Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet 1979;2:433 49. Storlein LH, Pan DA, Kriketos AD. Skeletal muscle membrane lipids and insulin resistance. Lipids 1996;31:S261 50. Greens I. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347:1070 51. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 1996;37:907 52. Shalev A, Siegrist-Kaiser C, Yen P, et al. The peroxisome proliferator-activated receptor ␣ is a phosphoprotein: regulation by insulin. Endocrinology 1996;137: 4499 53. Vidal-Puig A, Considine R, Jimenez-Lin˜an M, et al. Peroxisome proliferatoractivated receptor gene expression in human tissues. J Clin Invest 1997;99:2416 54. Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn R. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998;339:953 55. Yu K, Bayona W, Kallen CB, et al. Differential activation of peroxisome proliferator-activated receptor by eicosanoids. J Biol Chem 1995;270:23975 56. Hertz R, Magenheim J, Berman I, Bar-Tana J. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4 ␣. Nature 1998;392:512 57. Amri E, Bertrand B, Ailhaud G, Grimaldi P. Regulation of adipose tissue differentiation. I. Fatty acids are inducers of ␣P2 gene expression. J Lipid Res 1991;32:1449 58. Okuno M, Kajiwara K, Imai S, et al. Perilla oil prevents the excessive growth of visceral adipose tissue in rats by down regulating adipocyte differentiation. J Nutr 1997;127:1752 59. Martinez M. Docosahexaenoic acid therapy in docosahexaenoic acid-deficient patients with disorders of peroxisomal biogenesis. Lipids 1996;31:S145

Cranberry Juice and Urinary-Tract Health: Science Supports Folklore Y. Steven Henig, PhD, and Margaret M. Leahy, PhD From the Ocean Spray Cranberries, Inc., Lakeville, Massachusetts, USA FOLKLORE’S VALUE IN ESTABLISHING THE MEDICAL BENEFITS OF PLANTS AND FOODS Through the ages, folklore has established the value of certain foods in contributing to maintaining health in humans. The 20th century has seen a high degree of interest in establishing or refuting the folklore through sound science. Scientific studies now support much of the folk wisdom. For example, epidemiologic evidence strongly supports the adage “An apple a day keeps the doctor away.” Diets rich in fruits and vegetables are protective against cancer, heart disease, and stroke.1–3 We now know that the role of carrots in helping to maintain vision may be attributed to its high content of ␤-carotene, a pro–vitamin A. As the population ages, there is growing interest in “letting your food be your medicine,” as recommended by Hippocrates. Interest in the role of the American cranberry, Vaccinium macrocarpon, in maintaining health has been documented since colonial days. Cranberries, a fruit native to New England, belong to the Vaccinium family, which also includes Vaccinium oxycoccus (European cranberry or mooseberry, English mossberry, bogberry) and Vaccinium vitis-idaea (preiseberry, whortleberry, lingonberry). These latter varieties are generally not accepted as being

Correspondence to: Y. Steven Henig, PhD, Ocean Spray Cranberries, Inc., One Ocean Spray Drive, Lakeville, MA 02349, USA. E-mail: yshenig@ oceanspray.com

the same as the North American cranberry because of size and compositional differences. The Amerindians of New England used cranberries extensively in their diet, medicine, and commerce according to Native American legends and subsequent accounts by European explorers.4 The Indians ate the wild berries raw or sweetened with maple sugar. Berries were also ground into a damp meal containing meat or fish and sun dried to make pemmican, the chewy dried meat that sustained travelers and hunters.5 Although the identification of cranberries as the antiscorbutic components of fruits and vegetables was not made until much later, cranberries were used by American sailors to prevent scurvy, much as the British made use of limes and other citrus fruits. Medically, the Indians used cranberries in poultices for treating wounds and blood poisoning. The plant leaves were used for urinary disorders, diarrhea, and diabetes.6 Use of cranberries in sauces, relishes, and jellies quickly became popular among colonial Americans. The oldest surviving cranberry-juice recipe dates back to 1683.7 The most common form of cranberry consumption today is in the form of cranberryjuice cocktail (CJC), a sweetened beverage of approximately 27% cranberry juice. The single-strength juice is highly acidic, (⬎2.0% total titratable acidity, w/v), pH 2.5, and quite astringent. These properties make the fruit juice unpalatable at full strength. The most popular cranberry beverage today is a CJC, which is a mixture of single-strength cranberry juice (at least 25% by volume), sweetener, water, and vitamin C.

Nutrition Volume 16, Numbers 7/8, 2000 In the 20th century, the health benefit most often attributed to the cranberry is its role in maintaining urinary-tract health. A 1998 study by the International Food Information Council (personal communication) indicated that 47% of consumers surveyed were aware of a link between cranberry juice and urinary-tract health.

URINARY-TRACT HEALTH ISSUES Urinary-Tract Infections (UTIs) Kuzminski8 recently summarized information with regard to urinary-tract health. Urine in the bladder is normally sterile, and the term urinary-tract infection refers to the presence of microorganisms in the urinary tract, including the bladder, prostate, collecting system, and kidneys.9 Escherichia coli predominates as the most common urinary pathogen, accounting for 85% of community-acquired UTIs.10 Other pathogenic bacteria (Enterococcus, Staphylococcus, Proteus, and Klebsiella) may also be responsible. UTIs are more prevalent among women than among men,11 and it has been estimated that approximately 25% of women have had at least one UTI in their lifetime and many will have several.12 Commonly occurring symptoms of a UTI include frequent and urgent need to urinate, painful urination, cloudy urine, and lower-back pain.13 UTIs present a greater problem for some population segments. These segments include pre- and postmenopausal women, catheterized patients, and pregnant women. In women, the likelihood of bacteriuria increases with advancing age and is highest among institutionalized older women in whom bacteriuria approaches 50% at any given time.14 The risk and severity of UTI dramatically increases with the presence and prolonged use of a urogenital medical device, such as a catheter or ureteral stent.15 UTIs are frequently encountered during pregnancy. The majority of infections in pregnancy are asymptomatic, but these infections place the mother at risk for low-birth-weight infant and preterm birth. Also, pyelonephritis can result in significant maternal and fetal morbidity and mortality.16 Data from the Centers for Disease Control and Prevention indicate that, in 1996, 6.665 million doctors visits involved UTIs17 and 1.551 million hospital discharges involved a UTI diagnosis.18 Cost of diagnostic work-up and treatment has been estimated at $100 per visit.14 Prevention of UTIs Because healthy urine is sterile, bacterial entry and proliferation in the urinary tract is necessary for disease to occur.8 Once within the urinary tract, bacteria will not cause disease unless they proliferate. Proliferation appears to occur through attachment or adhesion to the urinary-tract mucosal surfaces, with subsequent bacterial multiplication and infection of host tissue.19 Bacterial-surface structures such as fimbriae or pili adhere to host-receptor sites.10 Protective mechanisms that interfere with bacterial adhesion in the urinary tract have not been completely elucidated. It has been proposed that ingestion of an adhesion-interfering substance may impair bacterial infection capability.20,21

SCIENTIFIC EVIDENCE VALIDATING A BENEFICIAL EFFECT OF CRANBERRIES ON URINARY-TRACT HEALTH In a discussion of scientific criteria for establishing health claims for functional foods, Clydesdale22 noted that a convincing scientific relation between food and health could be established by using any or all types of scientific data. Clydesdale noted that, often in research, epidemiology leads to mechanistic studies that in turn

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lead to clinical trials and that evidence in each of these areas should be considered. The Keystone National Policy Dialogue on Food, Nutrition and Health23 reviewed the Food and Drug Administration’s procedure for several of the first 10 proposed health claims and noted that the evidence could be classified into three general types: 1. epidemiology: clinical data derived from observational epidemiologic studies assessing associations between food substances and disease 2. biologic mechanisms: data derived from chemical, cellular, or animal models investigating plausible mechanisms of action of food substances 3. intervention trials: controlled assessment of clinical foodsubstance interventions in the human population This classification system is also useful in evaluating the evidence for a beneficial effect of cranberry juice in maintaining urinarytract health. Evidence in each of these areas is reviewed.

Intervention Trials Several intervention trials concerning cranberry juice and urinarytract health have been reported in the literature. Many of these suffer from major experimental-design limitations, including lack of untreated controls, unblinded, no use of placebo, and small number of subjects. The earliest studies can be viewed as providing anecdotal support due to experimental-design issues but do signify the growing degree of interest in substantiating a beneficial effect of cranberry juice on urinary-tract health. Seven intervention trials are reviewed here. Five studies focused on cranberry juice or cocktail, one focused on a solid dietary supplement derived from cranberry juice, and one used cranberry-juice concentrate. Three of these studies were randomized, double-blinded, and placebo-controlled; the others had design limitations. Six of these studies supported a beneficial effect of cranberry juice on urinary-tract health, and one did not. The most robustly designed study (randomized, double blinded, placebo controlled) was conducted by Avorn et al.24 A nursinghome population of 153 elderly women with a mean age of 78.5 y was used in a 6-mo trial. Subjects consumed 300 mL of either a low-calorie CJC or a specially prepared placebo drink that contained no cranberry, on a daily basis. Outcomes measured included bacteriuria (defined as ⬎105 organisms/mL of urine) and the presence of white blood cells. They found that bacteriuria with pyuria can be reduced by nearly 50% with consumption of CJC. In addition, analysis of the probabilities of transition indicated that women in the test group with a positive urine in a given month had only 27% the likelihood of the control group to have their urine remain positive in the following month. Walker et al.25 conducted an intervention trial using a solidcranberry dietary supplement prepared from spray-dried cranberry juice. A 6-mo randomized double-blinded placebo-controlled cross-over study in a population of 19 sexually active women between the ages of 18 and 45 y (median age ⫽ 37 y) was conducted. Subjects consumed two 400-mg capsules of cranberry solids or dicalcium phosphate placebo capsules daily for 3 mo, with opposite treatment for the next 3 mo. The outcome measured was symptomatic UTIs with positive confirmation by urine culture. A statistically significant reduction in risk for UTIs when taking the cranberry supplement was found with the 10 subjects who completed the study. Four other studies on cranberry juice suffered from design limitations, yielding anecdotal findings supporting a beneficial effect of cranberry juice on urinary-tract health. In these cases, cranberry juice was found to be beneficial for urinary-tract health in a mixed-gender study with 60 adults,26 a mixed-gender nursinghome study with 538 patients,27 a case study of an elderly woman,28 and a study of 16 children with neurogenic bladders.29 One study found lack of an effect of cranberry concentrate on

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incidence of bacteriuria. Schlager et al.30 conducted a trial investigating the effect of cranberry prophylaxis on rates of bacteriuria and symptomatic UTIs in 15 children with neurogenic bladders receiving clean intermittent catheterization. The design was a double-blinded, placebo-controlled, cross-over study, with children receiving cranberry concentate for 3 mo and a placebo concentrate the other 3 mo. Urine samples were taken weekly; bacteriuria was confirmed if cultures contained ⬎104 colony-forming units of pathogens per milliliter. The frequency of bacteriuria in patients with neurogenic bladder receiving intermittent catheterization observed in this study was 70%, with cranberry concentrate showing no effect in this population. Escherichia coli remained the most common pathogen in cultures from both placebo and cranberry treatments. The investigators speculated on reasons for seeing lack of an effect. They noted that voiding dysfunction inherent to the neurogenic bladder may have overridden any clinical effect in this population highly prone to UTIs or that the volume of cranberry concentrate ingested may have been too low.

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Epidemiologic Studies One relevant epidemiologic study has been conducted, reporting on the relation between sexual and health behaviors of women and first-time UTIs.31 The study used a population of women using a university health service, with 86 subjects experiencing first-time UTIs and 288 control subjects. After adjusting for frequency of vaginal intercourse, regular drinking of cranberry juice was found to be protective against UTI. Mechanistic Studies Substantiation of the health benefits attributed to foods or herbs through folklore most often rely on clinical or epidemiologic evidence. Arguably, the strongest body of scientific evidence supporting the potential benefits of cranberry juice on urinary-tract health relates to the studies of plausible biological mechanisms. Two primary mechanisms have been investigated. Early work focused on the potential of the cranberry for urine acidification, with resulting bacteriostasis; current research focuses on the inhibitory effect of the cranberry on bacteria to adhere to mucosal surfaces. Several early studies focused on the effect of the cranberry on acidification of the urine as the possible mechanism for its antibacterial effect in the urinary tract,32–36 but studies did not substantiate this mechanism.24,30,37,38 Current theory supports the hypothesis that cranberry juice acts to promote urinary-tract health by inhibiting bacterial adherence to mucosal surfaces.21,40 – 47 Bacterial adherence to mucosal surfaces is generally considered to be an important prerequisite for colonization and infection.19 Avorn et al.24 found no evidence that urinary acidification was responsible for the bacteriostatic effect of cranberry juice: the median pH of urine samples from the cranberry subjects (6.0) was actually higher from that of the placebo group (5.5). Results from mechanistic studies measuring inhibition of bacterial adherence conducted by several researchers have led to the following conclusions.21,40 – 47 ● Mode of action of CJC is associated with interference of adherence and in particular a surface component of E. coli and other gram-negative bacteria to at least a few types of epithelial cells, including uroepithelial cells.21,40 ● In vitro studies have found that the strongest antiadherence activity occurred when the bacteria was preincubated with cranberry juice. In vivo studies have found that urine collected from both mice and humans after drinking CJC significantly inhibited adherence when compared with control urine.21,40 ● It appears that CJC contains two types of different inhibitors. One is fructose, common to many fruit juices. The second inhibitor appears to inhibit certain adhesins (P-fimbriae) of

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some pathogenic strains of E. coli. In one study, activity was a function of the concentration and the time of preincubation of the bacteria with CJC. The P-fimbriae–inhibitory activity of the cranberry juice was dependent on the concentration and the time of preincubation of the bacteria with the cocktail. Evidence that the bacteria adsorb the inhibitor was supported by the finding that inhibition occurred even when bacteria that had been preincubated in CJC were extensively washed with phosphate.41 Whereas orange juice, pineapple juice, and CJC exhibited antiadhesion activity against type-1 fimbriated E. coli containing a mannose-sensitive (type 1) adhesin, only those juices from the Vaccinium genus tested (cranberry and blueberry) contained the mannose-resistant (P-fimbriated) adhesin inhibitor.42,43 Howell et al. identified condensed tannins (proanthocyanidins) as the compounds in cranberries that are responsible for preventing uropathogenic phenotypes of P-fimbriated E. coli from adhering to the urinary tract.44 Purified proanthocyanidin extracts prepared from cranberries with activity confirmed by bioassays measured the ability to inhibit the adherence of uropathogenic strains of P-fimbriated to isolated uroepithelial cells. Purity and identity of the proanthocyanidin fraction was accomplished using 13C-nuclear magnetic resonance imaging, ultraviolet spectroscopy, and chemicalreagent tests. Nuclear magnetic resonance characterization of the proanthocyanidin fraction showed a mixture of epicatechin oligomers of different molecular weights.45 This finding supports the theory of Schmidt and Sobota21 who believed that the antiadherence factor is of low molecular weight (⬍1000) and could conceivably move from the blood into the urine with little difficulty. There may be an additional P-fimbriated adhesin inhibitor in the cranberry. Ofek et al.42,43 believed this inhibitor to be a non-dialyzable high-molecular-weight compound (⬎15 000) that is heat stable and resistant to trypsin. Recent work by Ahuja et al.,46 using transmission electron microscopy, confirmed growth in the control populations of E. coli and the presence of P-fimbriae; growth of bacteria on a media containing cranberry juice was inhibited. Those grown on the cranberry-containing media also demonstrated a 95% reduction in their expression of fimbriae and exhibited extreme cellular elongation. A recent study was conducted ex vivo to determine whether vitamin C and cranberry supplements could help fight UTIs in catheterized patients.47 Urine from healthy subjects was collected after ingestion of vitamin C, a cranberry dietary supplement, or water. The urine was then tested for its ability to act as a substrate for bacterial of silicone rubber, a common component of urinary medical devices. Intake of cranberry tablets (three times daily at 400 mg) reduced the risk of E. coli colonization.

CONCLUSION The totality of the results from the intervention, epidemiologic, and mechanistic studies supports a beneficial effect of cranberry juice in helping to maintain urinary-tract health. Clinical and epidemiologic evidence suggests that regular consumption of cranberry juice reduces the risk of UTIs 24 –31 and is beneficial in moving individuals out of an infected state.24 Normally, urine in the bladder is sterile. Bacterial entry and proliferation in the urinary tract is necessary for disease to occur. Bacterial adherence to mucosal surfaces is generally considered to be an important prerequisite for colonization and infection.19 Data support a mechanism of inhibition by cranberry juice of bacterial adherence to mucosal surfaces.21,39 – 47 CJC appears to contain at least two factors that have antiad-

Nutrition Volume 16, Numbers 7/8, 2000 herence activity to epithelial cells for gram-negative bacteria,26 –29 with most work focused on E. coli strains, which are responsible for more than 80% of UTIs.10 One factor is fructose, which exhibits an antiadherence activity for type-1 fimbriae.26 The other factor, with activity presently found only in cranberry and blueberry juices, appears to inhibit P-fimbriae adherence41– 43 and reduce their expression.46 Cranberry proanthocyanidins have been definitively identified in vitro as the compounds responsible for this antiadhesive effect.44,45 Further research is recommended to better understand cranberry’s beneficial effect on urinary-tract health. An in vivo feeding study with cranberry proanthocyanidins is desired to definitively establish that these compounds are able to cross into the blood and urine to provide the antiadherence effect on P-fimbriated E. coli to uroepithelial cells. Further clinical trials are desired to build the base of evidence in different populations. There is a need for better understanding of dose–response and temporal effects. Important variables for consideration in developing additional trials includes having a test of significant power, achieving a realistic placebo, ensuring compliance, and culturing and identifying resultant uropathogens. Characterization of the strains of E. coli may be helpful, given that in vitro work supports a unique cranberry antiadhesion effect of P-fimbriated versus type-1 E. coli. In addition, the bacterial antiadhesion mechanism of the cranberry may provide other potential benefits for human health. A recent study has found that a cranberry fraction inhibits some bacteria from adhering to each other and from producing dental plaque, which is a major cause of periodontal and gum diseases.48 The bacterial antiadherence property of the cranberry may offer an alternative avenue to antibiotics in prevention or adjunctive treatment of many types of bacterial infections. Given the increasing prevalence of bacterial antibiotic resistance, research in this area may have great significance to human health.

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17. NCHS, CDC, HHS. Ambulatory Care Visits to Physician Offices, Hospital Outpatient Departments, and Emergency Departments. United States, 1996. Washington, DC: US Government Printing Office, 1998 18. NCHS, CDC, HHS. Detailed Diagnoses and Procedures. National Hospital Discharge Survey, 1996. Washington, DC: US Government Printing Office, 1998 19. Harber M, Asscher A. Virulence of urinary pathogens. Kidney Int 1985;28:717 20. Eden CS, Hausson JU, Lidin-Janson G, et al. Host-parasite interaction in the urinary tract. J Infect Dis 1988;157:421 21. Schmidt DR, Sobota A. An examination of the anti-adherence activity of cranberry juice on urinary and non-urinary bacterial isolates. Microbios 1988;55:173 22. Clydesdale FM. A proposal for the establishment of scientific criteria for health claims for functional foods. Nutr Rev 1997;55(12):413 23. Keystone Center. The Final Report of the Keystone National Policy Dialogue on Food, Nutrition and Health. Washington, DC: Keystone Center, 1996 24. Avorn J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyruria after ingestion of cranberry juice. JAMA 1994;271:751 25. Walker EB, Barney DP, Mickelsen JN, Walton RJ, Mickelsen RA Jr. Cranberry concentrate: UTI prophylaxis. J Fam Pract 1997;45:167 26. Papas PN, Brusch CA, Ceresia GC. Cranberry juice in the treatment of urinary tract infections. Southwest Med 1966;47:17 27. Dignam R, Ahmed M, Denman S, et al. The effect of cranberry juice on UTI rates in a long term care facility. J Am Geriatr Soc 1997;45(9):S53 28. Moen DV. Observations on the effectiveness of cranberry juice in urinary infections. Wisc Med J 1962;61:282 29. Rogers J. Pass the cranberry juice. Nurs Times 1991;87(48):36 30. Schlager TA, Anderson S, Trudell J, Hendley JO. Effect of cranberry juice on bactericiria in children with neurogenic bladder receiving intermittent catheterization. J Pedriatr 1999;135:698 31. Foxman B, Geiger AM, Palin K, Gillespie B, Koopman JS. First-time urinary tract infection and sexual behavior. Epidemiology 1995;6:162 32. Blatherwick N. The specific role of foods in relation to the composition of urine. Arch Intern Med 1914;14:409 33. Blatherwick NR, Long ML. Studies on urinary acidity. The increased acidity produced by eating prunes and cranberries. J Biol Chem 1923;57:815 34. Fellers CR, Redmon BC, Parrott EM. Effect of cranberries on urinary acidity and blood alkali reserve. J Nutr 1933;6:455 35. Nickey K. Urine pH: effect of prescribed regimens of cranberry juice and ascorbic acid. Arch Phys Med Rehab 1975;56;556 36. Kinney A, Blount M. Effect of cranberry juice on urinary pH. Nursing Res 1979;28:287 37. Bodel PT, Cotran R, Kass EH. Cranberry juice and the antibacterial action of hippuric acid. J Lab Clin Med 1959;54:881 38. Kahn HD, Panariello VA, Saeli J, Sampson JR, Schwartz E. Effect of cranberry juice on urine. J Am Diet Assoc 1967;51:251 39. Foxman B, Geiger AM, Palin K, Gillespie B, Koopman JS. First-time urinary tract infection and sexual behavior. Epidemiology 1995;6:162 40. Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol 1984;131:1013 41. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of cranberry juice on adherence of Type 1 and P fimbriated Escherichia coli to eukaryotic cells. Antimicrob Agents Chemother 1989;33:92 42. Ofek I, Goldhar J, Zafriri D, et al. Anti-Escherichia adhesin activity of cranberry and blueberry juices. N Engl J Med 1991;324:1599 43. Ofek I, Zafiri D, Goldhar J, et al. Effect of various juices on activity of adhesins expressed by urinary and nonurinary isolates of Escheria coli. In: Tillotson JE, ed. America’s Foods: Health Messages and Claims. Baton Rouge: CRC Press, 1993:193 44. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med 1998;339:1085 45. Foo YP, Lu Y, Howell AB, Vorsa N. Characterization of cranberry proanthocyanidins that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. Phytochemistry 2000;54:173 46. Ahuja SK, Kaak B, Roberts JA. Loss of fimbrial adhesion with the addition of Vaccinium macrocarpon to the growth media of P-fimbriated E. coli. J Urol 1998;159:559 47. Habash MB, Van der Mei HC, Busscher HJ, Reid G. The effect of water, ascorbic acid and cranberry derived supplementation on human urine and uropathogen adhesion to silicone rubber. Can J Microbiol 1999;45:691 48. Weis EI, Lev-Dor R, Kashamn Y, et al. Inhibiting interspecies coaggregation of plaque bacteria. J Am Dental Assoc 1999;129:1719