Sixteen women with idiopathic melasma were randomly assigned to apply 5% ascorbic acid cream on one side of the face and 4% hydroquinone cream on the other side, each night for 16 weeks. Sunscreen was applied daily throughout the study. The best subjective improvement was reported on the hydroquinone side, with 93% good and excellent results, compared with 62.5% on the ascorbic acid side (p < 0.05). However, colorimetric measures showed no significant difference between treatments. Side effects (mainly skin irritation) occurred in 68.7% of patients on the side where hydroquinone was applied and in 6.2% of cases on the side treated with ascorbic acid.

Comment: Melasma is a dark pigmentation of the skin that occurs on sun-exposed areas of the face. It is particularly common in pregnant women and in women taking oral contraceptives or hormone-replacement therapy during menopause. Hydroquinone is a bleaching agent that is effective in some cases. Tretinoin cream, and in some cases topical steroids or chemical peels, are also used. The results of the present study suggest that topical ascorbic acid cream is a safe and effective alternative to conventional treatments. Although ascorbic acid cream was somewhat less effective than hydroquinone, it was better tolerated, and may therefore be considered as a first line therapy for patients wishing to try the safest treatments first.

Espinal-Perez LE, et al. A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol 2004;43:604-607.

Huang HY, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum 2005;52:1843-1847.

One hundred eighty-four nonsmoking volunteers (mean age, 58 years) were randomly assigned to receive, in double-blind fashion, one of the following for two months: 1) vitamin C 500 (mg/day), 2) vitamin E (RRR-alpha-tocopheryl acetate, 400 IU/day), 3) both supplements, or 4) placebo. The mean fasting serum uric acid concentration decreased (-0.5 mg/dl) in the vitamin C groups and increased (+0.09 mg/dl) in the no-vitamin-C groups (p < 0.0001 for the difference in the change between groups). Among the 21 participants with hyperuricemia (serum uric acid level greater than 7 mg/dl) at baseline who received vitamin C, the mean serum uric acid concentration decreased by 1.5 mg/dl (p = 0.0008). Vitamin E had no effect on serum uric acid concentrations.

Comment: Lowering serum uric acid levels is useful for the prevention and management of gout. As hyperuricemia is also an independent cardiovascular disease risk factor, reducing serum uric acid levels may be one of the many mechanisms whereby vitamin C enhances heart health. The results of the present study indicate that supplementation with 500 mg/day of vitamin C for two months produced a modest reduction in serum uric acid levels. Previous research suggested that this effect is due to an increase in urinary excretion of uric acid.

The uric acid-lowering effect of vitamin C was reported as early as 1976, but doses of 8 g/day were used and the supplementation period lasted only one week. The new study indicates that considerably smaller doses, when taken over a longer period of time, can also lower uric acid levels.

Twenty-nine kidney stone formers (mean age, 49.8 years) and 19 non-stone formers (mean age, 50.8 years) received 1,000 of ascorbic acid twice a day (with the morning and evening meals) for six days, and no ascorbic acid (control period) for another six days, in random order. A low-oxalate diet was consumed throughout the study. On day six of each treatment period, the subjects received 136 mg of oxalate two hours before breakfast. Of the 48 participants, 19 (12 stone formers, 7 non-stone formers) were identified as responders, defined by an increase in 24-hour total oxalate excretion of greater than 10% after ascorbic acid treatment than after the control period. Responders had a greater 24-hour Tiselius Risk Index (a measure of calcium oxalate saturation) after ascorbic acid supplementation than after the control period (mean, 1.10 vs. 0.76), because of a 31% increase in the percentage of oxalate absorbed (10.5% vs. 8.0%) and a 39% increase in endogenous oxalate synthesis. The authors concluded that supplementation with 1,000 mg of ascorbic acid twice a day increased urinary oxalate excretion and the Tiselius risk index for calcium oxalate kidney stones in 40% of participants, both stone formers and non-stone formers.

Comment: Opponents of nutritional therapy have long claimed that vitamin C supplementation can cause kidney stones, even though there is virtually no evidence supporting that belief (see Arch Intern Med 1998;158:2187-2191). In fact, a large epidemiological study showed that the risk of kidney stone formation was 22% lower in men who consumed 1,500 mg/day or more of vitamin C, compared with the risk in men who consumed less than 250 mg/day. Although high-dose vitamin C may induce a small increase in urinary uric acid excretion in some people, and a larger increase in a very small proportion of the population, other effects of the vitamin might be expected to help prevent kidney stones. For example, increasing urinary ascorbic acid excretion may cause a small increase in urine acidity, which could reduce calcium oxalate precipitation. Vitamin C in the urine also binds calcium, thereby reducing the formation of calcium oxalate crystals.

While the new study appears to demonstrate that vitamin C increases kidney stone risk, its experimental design does not mimic real-life conditions. The participants in this study were given a fairly large amount of oxalate on an empty stomach, two hours before breakfast. Under normal circumstances, oxalate is a constituent of a meal, and the calcium present in that meal would bind a proportion of ingested oxalate and prevent it from being absorbed. Vitamin C may increase urinary oxalate in people dosed with pure oxalate, but it is not at all clear that the same effect would occur when oxalate is ingested as part of a meal.

It is possible that vitamin C supplementation can promote stone formation in rare individuals who have a particular genetic makeup, but for the general population there is no convincing evidence that vitamin C causes kidney stones.

Massey LK, et al. Ascorbate increases human oxaluria and kidney stone risk. J Nutr 2005;135:1673-1677.

Twenty-three patients with 2 to 96 warts (all on the hands except for two cases with plantar warts) and 9 patients with 1 to 2 corns on the feet applied a lipid extract of garlic twice a day until full or best recovery was seen. Complete recovery was seen in all cases with warts after 1 to 2 weeks of treatment. Seven of 9 patients with corns showed complete recovery after 10 to 20 days and the other 2 patients showed marked improvement, with no further improvement on continuation of treatment. In a control group of patients treated with the vehicle (chloroform:methanol (2:1) solution), no improvement in warts was seen. In patients who had numerous warts, when only 1 or 2 large warts were treated, the other small warts located in the same area disappeared, too. Side effects included blistering, redness, burning, and hyperpigmentation of the skin around the application area, which usually disappeared completely in 1 to 2 weeks. Zinc oxide ointment was applied to the surrounding normal skin in all cases in an attempt to prevent side effects.

Comment: Although there is often a large placebo effect when warts are treated, the 100% cure rate within 2 weeks that was observed in this study seems far greater than one would expect from a placebo. The results with corns are also impressive. In an earlier study of 5 children with warts on the hands, nightly application of half a clove of garlic (with the cut side touching the skin) resulted in complete clearing of the lesions within 9 weeks. The results of the new study suggest that a lipid-soluble extract of garlic is more effective than either whole garlic or an aqueous extract. Because this treatment can cause blistering contact dermatitis, care should be taken to avoid applying the extract to normal skin. Covering the affected area with Band-Aids or waterproof tape after application of garlic, and washing the area each morning, may help prevent the garlic from migrating to the surrounding skin.

Dehghani F, et al. Healing effect of garlic extract on warts and corns. Int J Dermatol 2005;44:612-615.

Twenty-eight women (mean age, 50.2 years) with hypoadrenalism due to Addison's disease (71%) or bilateral adrenalectomy for Cushing's disease (29%) were randomly assigned to receive, in double-blind fashion, 50 mg/day of DHEA or placebo for 12 weeks. Compared with placebo, DHEA significantly increased insulin sensitivity, as determined using a hyperinsulinemic-euglycemic clamp (p < 0.05), and significantly decreased the mean fasting plasma insulin concentration (p = 0.005).

Comment: These results indicate that supplementation with 50 mg/day of DHEA for 12 weeks significantly increased insulin sensitivity in women with adrenal insufficiency. In an earlier study, administration of 50 mg/day of DHEA reduced abdominal fat and insulin resistance in elderly men and women (JAMA 2004;292:2243-2248). Observational studies have shown that the normal age-related decline in DHEA levels may play a role in the development of age-related insulin resistance. Taken together, these studies suggest that supplementation with physiological doses of DHEA would improve glucose metabolism in people with sub-optimal DHEA levels. However, DHEA treatment may not be advisable for everyone with insulin resistance, only those with evidence of DHEA deficiency. For example, many women with polycystic ovary syndrome have both insulin resistance and elevated blood levels of DHEA. I have found that the serum concentration of DHEA-sulfate is a reasonably good indicator of a person's DHEA status. Serum DHEA may be even more reliable, but DHEA is present in such small concentrations in the blood that the laboratory measurement may be prone to error.

Dhatariya K, et al. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 2005;54:765-769.

Cerebral folate deficiency can be defined as any neuropsychiatric condition associated with low cerebrospinal fluid (CSF) levels of 5-methyltetrahydrofolate (5MTHF), the active folate metabolite in the CSF, in association with normal folate metabolism outside the central nervous system, as reflected by normal hematologic values, normal serum homocysteine levels, and normal folate levels in serum and erythrocytes. Infantile-onset cerebral folate deficiency develops 4-6 months after birth. It is characterized by marked irritability, slow head growth, psychomotor retardation, cerebellar ataxia, pyramidal tract signs in the legs, dyskinesias, and in some cases seizures. After the age of 3 years, optic atrophy and blindness may develop.

Serum specimens were examined in 28 children (median age, 7.1 years; range, 2.5-19.3 years), with cerebral folate deficiency, 5 of their mothers, 28 age-matched controls, and 41 patients with an unrelated neurological disorder. Serum from 25 of the 28 patients and 0 of 28 controls contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus. These antibodies are capable of preventing folate from binding to the receptors on the epithelial cells of the choroid plexus.

Folinic acid at a pharmacological dose can bypass autoantibody-blocked folate receptors and enter the CSF by way of the reduced folate carrier. Oral folinic acid (0.5 to 1.0 mg/kg of body weight/day in 2 divided doses) normalized 5MTHF levels in the CSF and led to clinical improvement, which included improvement in autistic behavior and complete control of seizures. Two autistic children who were treated at a younger age (2 and 3 years, respectively) showed improvements in communication skills and neurological abnormalities, whereas two other autistic children who were treated at ages 5 and 12 years, respectively, remained autistic. Of the three patients who did not have autoantibodies, all improved after treatment with oral folic acid or folinic acid. One of these three patients had four of the clinical criteria of the cerebral folate deficiency syndrome and frank autistic behavior, and recovered completely after receiving 400 mcg/day of folic acid.

No autoantibodies against folate receptors were found in serum from 41 patients with central nervous system disease unrelated to cerebral folate deficiency or in the 5 mothers of patients with cerebral folate deficiency. The authors concluded that cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the CSF. Treatment with folinic acid can bypass this block and produce clinical improvement.

Comment: This study demonstrates that some neuropsychiatric disorders are caused by cerebral folate deficiency, resulting from impaired transport of folate into the CSF. Cerebral folate deficiency cannot be detected by standard laboratory tests for folate status. Oral folinic acid produces clinical improvement, especially if treatment is begun early in life. While the manifestations of cerebral folate deficiency described in this report are fairly specific, it is possible that milder forms of cerebral folate deficiency also exist and include only some of these manifestations. Measurement of CSF folate concentrations might, therefore, be considered for patients who have some or all of these neurological symptoms. In cases where it is not feasible to perform a lumbar puncture to obtain CSF, a therapeutic trial with folinic acid may be considered.

It is possible that folate-blocking antibodies are cross-reacting antibodies that are produced in response to ingestion of allergenic foods. Food sensitivity is said to be very common in autistic children. Additional research might focus on whether exclusion of common allergens (such as gluten grains and dairy products) from the diet would cause these antibodies to disappear.

Ramaekers VT, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005;352:1985-1991.

Sixteen non-overweight children (aged 12-16years) were studied during three separate three-week periods: 1) baseline, 2) increasing targeted sedentary behaviors by 25-50% (increase phase), and 3) decreasing targeted sedentary behaviors by 25-50% (decrease phase). Sedentary behavior was defined as activities such as watching television or videotapes, playing video games, and recreational computer use. Compared with baseline, targeted sedentary behaviors increased by 81.5 minutes/day (45.8%) during the increase phase and decreased by 109.8 minutes/day (-61.2%) during the decrease phase. Mean energy intake decreased by 463 kcal/day (p < 0.01) during the decrease phase. No significant changes in energy intake were observed during the increase phase. Decreasing sedentary behaviors also resulted in a mean increase of energy expenditure of 113 kcal/day.

Comment: These findings indicate that a decrease in sedentary behaviors is accompanied both by a decrease energy intake and an increase in energy expenditure in non-overweight adolescents. Reducing the amount of time involved in watching television and playing on the computer would therefore be expected to help prevent the development of obesity.

Epstein LH, et al. Influence of changes in sedentary behavior on energy and macronutrient intake in youth. Am J Clin Nutr 2005;81:361-366.

Ten male and 10 female patients (mean age, 43.7 years) with untreated essential hypertension were randomly assigned to receive 100 g/day of flavanol-rich dark chocolate (DC; containing 88 mg of flavanols) or 90 g per day of flavanol-free white chocolate (WC) for 15 days. After a 7-day washout period, each person consumed the other type of chocolate for an additional 15 days. The diet was made isocaloric compared with baseline by reducing the intake of other foods that were similar in energy and macronutrient composition to chocolate. After DC consumption, mean 24-hour systolic blood pressure decreased by 11.9 mm Hg (p < 0.0001 comparing DC with baseline and with WC). After DC, mean diastolic blood pressure decreased by 8.5 mm Hg (p < 0.0001 comparing DC with baseline and with WC). DC but not WC significantly decreased insulin resistance (p < 0.0001), as determined by homeostasis model assessment, and significantly improved flow-mediated dilatation of the brachial artery. The mean LDL-cholesterol concentration decreased from 3.4 mmol/L to 3.0 mmol/L after DC (p < 0.05 comparing DC with baseline and with WC).

Comment: In this study, consumption of 100 g/day of dark chocolate for 15 days decreased blood pressure and serum LDL cholesterol levels, improved flow-mediated dilatation of the brachial artery (which may reduce the risk of atherosclerosis), and decreased insulin resistance in patients with essential hypertension. The results suggest that eating dark chocolate is useful for treating hypertension and might help prevent atherosclerosis and diabetes. However, the study lasted only 15 days, and it is not known whether these benefits would persist with continued use. In addition, 100 g of dark chocolate contains 531 calories, and long-term consumption of this amount of chocolate could cause obesity. While the participants in this study kept their total energy intake the same by eliminating other foods from their diet, it is likely that most people who consume that much chocolate would increase their total calorie intake.

Furthermore, chocolate contains a number of psychoactive chemicals, including phenylethylamine (an amphetamine-like compound) and anandamide (a substance that binds to the "marijuana receptor" in the brain). For many people, chocolate is not only addictive, but also causes various adverse reactions such as migraines or mood changes. Nevertheless, persons who are able to include a controlled amount dark chocolate as part of a healthful, weight-maintaining diet might benefit from such an addition. It should be noted the positive effects attributed to chocolate occur only with dark chocolate, not with white chocolate (which has only small amounts of flavonoids) or milk chocolate (milk strongly inhibits the absorption of the beneficial flavonoids).

Grassi D, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 2005;46:398-405.