The enzyme 5-lipoxygenase catalyzes the conversion of arachidonic acid to leukotrienes, which are involved in the inflammatory process. Chronic inflammation is believed to play an important role in the development of atherosclerosis. In the present study, 5-lipoxygenase genotypes, carotid-artery intima-media thickness (a measure of the severity of atherosclerosis), and markers of inflammation were determined in 470 healthy men and women (aged 40-60 years) participating in the Los Angeles Atherosclerosis Study. Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6% of the participants, whereas 94% had at least one copy of the common allele. The mean carotid-artery intima-media thickness was 12% greater (p < 0.001) among carriers of two variant alleles than among carriers of the common allele. The increase in intima-media thickness associated with the genetic variant was similar in this cohort to that associated with diabetes. Increased dietary intake of arachidonic acid significantly increased the atherogenic effect of the variant genotype, whereas increased intake of marine omega-3 fatty acids blunted the effect. In contrast, neither of these dietary factors was associated with intima-media thickness in subjects carrying the common allele. The plasma level of C-reactive protein (a marker of inflammation) was two-fold higher (2.6 vs. 1.3 mg/L; p = 0.007) among carriers of two variant alleles than among carriers of the common allele.

Comment: Atherosclerosis is considered a polygenic disease, in that numerous different genetic influences are involved in its development. Some genetic variations interact with specific environmental factors. For example, people who carry a gene for iron overload might be able to reduce their risk of atherosclerosis by avoiding excessive intake of iron. Those with the common genetic variant of the methylenetetrahydrofolate reductase enzyme have a higher-than-normal requirement for folic acid, and may be able to reduce their risk of atherosclerosis by increasing their intake of folic acid. Some people who develop premature atherosclerosis have elevated homocysteine levels due to a defect in the vitamin B6-dependent enzyme cystathionine synthase; in those people homocysteine levels can be reduced by supplementing with vitamin B6.

The results of the present study indicate that about 1 in 16 people have a genetic variant of an enzyme that influences fatty acid metabolism. People with this variant are more susceptible to the potential adverse effects of eating meat (which is high in arachidonic acid), and more likely to be protected by eating fish, than are people with the more common variant. Genetic factors may explain why some people can abuse their bodies and not develop chronic illness, while others seem to suffer the consequences of even minimal dietary and lifestyle indiscretions.

Dwyer JH, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004;350:29-37.

In the Heart Outcomes Prevention Evaluation (HOPE) study, 9,541 patients with cardiovascular disease or diabetes, plus one other cardiovascular risk factor, were randomly assigned to receive, in double-blind fashion, 400 IU/day of vitamin E (RRR-alpha-tocopheryl acetate) or placebo, and either an angiotensin-converting-enzyme inhibitor (ramipril) or placebo, for a mean of 4.5 years. Results of the study showed that ramipril was beneficial, but vitamin E was not.

At the end of the study, 6,786 patients agreed to enter a continuation phase, in which all patients received ramipril, and 3,994 patients were randomly assigned to receive 400 IU/day of vitamin E or placebo for an additional 2.6 years, producing a total study duration of 7.1 years. At the end of the first part of the study, the incidences of heart failure events and hospitalizations for heart failure were higher in the vitamin E group than in the placebo group, but the differences were of only borderline statistical significance. The results from the continuation phase, when combined with the original results, did achieve statistical significance: heart failure events occurred in 14.7% of those using vitamin, compared with 12.6% of those using placebo (16.7% increase) and hospitalizations for heart failure occurred in 5.8% and 4.2% of patients, respectively (38.1% increase).

Comment: Vitamin E has a long and controversial history as a potential treatment for heart disease. While some large-scale clinical trials have found vitamin E to be beneficial, the majority of studies have found little or no effect of vitamin E. The HOPE trial is the first to suggest that vitamin E actually increases the risk of certain types of heart disease.

All of the studies of vitamin E supplementation for heart-disease prevention have used alpha-tocopherol, whereas the vitamin E in food contains four different isomers: alpha-, beta-, gamma-, and delta-tocopherol. An increasing body of evidence indicates that gamma-tocopherol has a strong cardioprotective effect. Moreover, supplementing with large doses of alpha-tocopherol results in a decline in serum concentrations of gamma-tocopherol. It is possible, therefore, that the positive effects of alpha-tocopherol are negated by a reduction in gamma-tocopherol levels. That possibility is supported by epidemiological studies indicating that vitamin E from food protects against heart disease, whereas vitamin E from supplements (e.g., alpha-tocopherol alone) does not. Future vitamin E studies should use “mixed tocopherols” that contain the four vitamin E isomers in proportions that are similar to those found in the diet.

Zoler ML. Supplemental vitamin E linked to heart failure. Fam Pract News 2003(October 1):28.

Two recent studies have shown that vitamin D deficiency may be a contributing factor in some cases of diabetes and/or metabolic syndrome (insulin resistance). In a study of 126 healthy volunteers (mean age 26 years) with normal glucose tolerance, there was a significant positive correlation (p < 0.0001) between the serum 25-hydroxyvitamin D concentration (a measure of vitamin D nutritional status) insulin sensitivity, and a significant negative correlation between serum 25-hydroxyvitamin D and measures of pancreatic beta-cell function. People with subnormal concentrations of 25-hydroxyvitamin D had a greater prevalence of components of the metabolic syndrome than did those with normal levels (30% vs. 11%; p < 0.01). In the other study, 7 of 10 women with type 2 diabetes had low serum concentrations of 25-hydroxyvitamin D. After supplementation with 1,332 IU/day of vitamin D for one month, a significant 34% increase was seen in insulin secretion, although it still remained significantly lower than that in nondiabetic controls. Insulin resistance also decreased by a mean of 21%, although that change was not statistically significant.

Comment: The results of these and other studies indicate that vitamin D plays a role in the secretion, and possibly the action, of insulin. Moreover, vitamin D deficiency appears to be common among people with type 2 diabetes, and may also be a risk factor for the metabolic syndrome. Preventing these common disorders, therefore, requires more than just turning off the television and getting some exercise; we need to do some of that exercise outdoors, under the vitamin D-producing sun.

Chiu KC, et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-825.

Borissova AM, et al. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 2003;57:258-261.

Fifty-four patients with metastatic prostate cancer (M1b or D2) were randomly assigned to receive orchiectomy alone (control group) or orchiectomy plus lycopene, 2 mg twice a day. After six months the mean prostate-specific antigen (PSA) level was 65% lower in the lycopene group than in the control group (9.1 vs. 26.4 ng/ml; difference not significant). After two years the respective PSA levels were 3.0 and 9.0 ng/ml (p < 0.001 for difference between groups). Eleven patients in control group (40%) and 21 in the lycopene group (78%) had a complete PSA response (p < 0.05), with progression in 7 (25%) and 2 (7%), respectively (p < 0.05). Bone scans showed a complete response in four patients in the control group (15%), compared with eight (30%) in the lycopene group (p < 0.02). The mortality rate was 22% in the control group and 13% in the lycopene group (p < 0.001).

Comment: These results indicate that adding lycopene to orchiectomy produced a greater decrease in serum PSA levels, a higher rate of complete responses, and higher survival rates, compared with orchiectomy alone, in men with advanced prostate cancer. Other preliminary studies have suggested that lycopene given by itself has anti-cancer activity in men in the earlier stages of prostate cancer. In addition, epidemiological studies have shown that consumption of tomato products (the main dietary source of lycopene) is associated with a reduced risk of developing prostate cancer. Lycopene is commercially available both as a synthetic product and as an extract from tomatoes. The latter preparation contains, in addition to lycopene, other carotenoids and phytochemicals that may have beneficial effects. Supplementing with tomato extracts or eating tomato products may, therefore, be more effective than taking synthetic lycopene, although direct comparisons have not yet been made.

Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int 2003;92:375-378.

Nine hundred twenty-one children (aged 3-6 years) attending daycare centers in Finland were randomly assigned to receive xylitol chewing gum (one piece, three times a day, each chewed for 5-10 minutes, for a total of 2.5 g/day of xylitol) or to brush their teeth after lunch. The respective treatments were continued for periods of one to three years, with one to four months off during the summers. At age nine years, the proportion of children who were caries-free was 57% in the xylitol group, compared with 49% in the brushing group (p < 0.05). No significant difference between groups was seen at ages three or seven years.

Comment: These results indicate that regular chewing of xylitol-containing gum is at least as effective as tooth brushing for the prevention of dental caries in children aged 3-6 years. Xylitol is a non-nutritive sweetener that has been demonstrated in several studies to help prevent the development of dental caries. The anti-caries effect of xylitol is presumably related to its capacity to inhibit the growth of Streptococcus mutans, a component of mouth flora that has been implicated in the pathogenesis of caries. The beneficial effect of xylitol chewing gum appears to be most pronounced for teeth that erupt after the commencement of gum chewing, as opposed to teeth that are already present when the child starts using the gum. One study has demonstrated that mothers can prevent the development of dental caries in their children by chewing xylitol gum, beginning three months after the birth of the baby until the child is two years old.

Kovari H, et al. Use of xylitol chewing gum in daycare centers: a follow-up study in Savonlinna, Finland. Acta Odontol Scand 2003;61:367-370.

In a study of 375 males and 492 females who completed seven-day diet diaries, the proportion of the daily energy ingested in the morning was negatively correlated with total daily energy intake (r = -0.13; p < 0.01), whereas the proportion ingested late in the evening was positively correlated with total daily energy intake (r = 0.14; p < 0.01).

Comment: Folk wisdom holds that, to promote good health, one should begin the day with a large breakfast and consume progressively smaller amounts with each successive meal. The results of the present study support that concept and suggest that such a pattern of eating might help prevent obesity. People who ate a larger proportion of their total daily caloric intake in the morning tended to eat fewer calories per day, whereas people who ate more at night tended to consume more total calories each day. Previous studies have suggested that the satiation of value of food eaten earlier in the day is greater than that of food eaten later on. Some people have observed that an effective method of losing weight is to avoid eating after 8 p.m.

De Castro JM. The time of day of food intake influences overall intake in humans. J Nutr 2004;134:104-111.

Fifty-nine women (aged 19-41 years) with pelvic pain and a history of endometriosis and/or infertility received either a placebo (n = 13) or a combination of vitamin E (1,200 IU/day) and vitamin C (1,000 mg/day) (n = 46) for two months. It was not specified whether the treatment allocation was randomized or blinded. At the end of the treatment period, levels of inflammatory markers in peritoneal fluid, which was collected by laparoscopy, were significantly lower in the supplemented group than in the placebo group. Forty-three percent of the women in the supplemented group reported an improvement in everyday pain, compared with none of the women in the placebo group. Twenty-four percent of the women in the supplemented group reported an improvement in dyspareunia, compared with none of those in the placebo group.

Comment: These results suggest that supplementation with vitamins E and vitamin C can relieve pain and improve dyspareunia in women with endometriosis. Although it is not clear how these vitamins work, they are known to reduce oxidative stress, which is often increased in women with endometriosis. Prior to this study, there had been very little research on the use of natural substances for the treatment of endometriosis. Other antioxidants, such as selenium, zinc, carotenoids, vitamin A, and flavonoids, should also be investigated as potential treatments for this common and painful condition.

Johnson K. Antioxidant therapy quickly improves endometriosis pain. Fam Pract News 2004(March 15):75.

The effect of vitamin K1 prophylaxis was assessed in 507,850 babies born in Denmark from November 1992 to June 2000. Of these, 78% (about 396,000) received oral and 22% received intramuscular (IM) prophylaxis. The oral regimen used was 2 mg given at birth, followed by 1 mg once a week until age 3 months, as long as the babies were more than 50% breast-fed. Those given IM prophylaxis also received weekly oral vitamin K, as described above. Compliance was good, with 94% of the infants completing the course of treatment. No case of vitamin K-deficiency bleeding (VKDB) occurred in either group.

Comment: Oral vitamin K prophylaxis given once at birth was used in many European countries during the past two decades, but was abandoned because of unsatisfactory protection from late VKDB. In Denmark, weekly oral prophylaxis was practiced from November 1992 to June 2000, at which time Roche withdrew the only licensed vitamin K1 preparation (Konakion®) from the market, without any explanation. The current retrospective study demonstrates that weekly oral vitamin K supplementation during the first three months of life is an effective method of preventing hemorrhagic disease during infancy. In contrast, during the time when oral vitamin K prophylaxis consisted of a single dose at birth, the incidence of late VKDB in Denmark was 4.5 per 100,000.

Giving IM injections to neonates can cause pain and also carries a small risk of infection, hematoma, and neuronal damage. Moreover, IM administration of vitamin K1 is unphysiologic, resulting in transient plasma vitamin K levels 1,000 times greater than the normal adult values. Consequently, oral vitamin K prophylaxis is preferable in cases where it is expected to be effective. IM prophylaxis may be preferable for high-risk infants; i.e., those with gestational age less than 33 weeks, a history of difficult delivery or asphyxia requiring resuscitation, or a mother who is using anticonvulsant medication. Vitamin K-enriched formulas (usually containing 50 mcg of vitamin K per liter) provide good protection against late VKDB, since the disease is seen almost exclusively in breast-fed infants.

Hansen KN, et al. Weekly oral vitamin K prophylaxis in Denmark. Acta Paediatr 2003;92:802-805.