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From the Townsend Letter
July 2009

Literature Review & Commentary
by Alan R. Gaby, MD

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Topical Manuka Honey for MRSA Infection
In case reports, three hospice patients with ulcers contaminated with methicillin-resistant Staphylococcus aureus (MRSA) improved after receiving daily topical applications of manuka honey.

Comment: Antibiotic-resistant infections have become a major public health problem in recent years, in part as a result of widespread use of antiseptics in hospitals and antibiotics both in and out of hospitals. According to some estimates, MRSA infections are responsible for more deaths each year in the US than the AIDS virus. Manuka honey has demonstrated broad-spectrum antibacterial activity, largely because of the production of hydrogen peroxide by the enzyme glucose oxidase. Catalase removes the hydrogen peroxide and eliminates the antibacterial properties of most honeys, but manuka honey retains its antibacterial properties for reasons that are not clear. Garlic extracts have also demonstrated activity against various strains of S. aureus in vitro. Both of these natural substances deserve further study as treatments for MRSA, particularly since treatment with honey and garlic does not appear to lead to the emergence of resistant bacterial strains.
Chambers J. Topical manuka honey for MRSA-contaminated skin ulcers. Palliat Med. 2006;20:557.

Nutritional Support for Tuberculosis Patients
Four hundred seventy-one HIV-infected and 416 HIV-negative adults in Tanzania who had pulmonary tuberculosis were randomly assigned to receive, in double-blind fashion, a combination of micronutrients or placebo, beginning at the time antituberculosis medication was begun. The daily micronutrient regimen consisted of 5,000 IU of vitamin A, 20 mg of thiamine, 20 mg of riboflavin, 25 mg of vitamin B6, 100 mg of niacin, 50 µg of vitamin B12, 500 mg of vitamin C, 200 IU of vitamin E, 0.8 mg of folic acid, and 100 µg of selenium. Compared with placebo, active treatment reduced the risk of tuberculosis recurrence by 45% overall (p = 0.02) and by 63% in HIV-infected patients (p = 0.02). There was no significant difference in mortality rate between groups. However, in HIV-negative patients, the death rate was nonsignificantly lower by 64% in the active-treatment group than in the placebo group (p = 0.08). Supplementation increased CD3+ and CD4+ cell counts and decreased the incidence of extrapulmonary tuberculosis and genital ulcers in HIV-negative patients. Micronutrient supplementation also reduced the incidence of peripheral neuropathy by 57% (p < 0.001), irrespective of HIV status.

Comment: Malnutrition is a serious problem among the general population in Tanzania. However, even in Western counties, both HIV infection and tuberculosis are frequently associated with poor nutritional status, which adversely affects the capacity of the immune system to fight infections. The results of this study indicate that providing even a modest amount of nutritional support to patients with tuberculosis improves the outcome of conventional therapy and possibly decreases the death rate.
Villamor E et al. A trial of the effect of micronutrient supplementation on treatment outcome, T cell counts, morbidity, and mortality in adults with pulmonary tuberculosis. J Infect Dis. 2008;197:1499–1505.

Vitamin D Prevents Infections
Some 5,292 elderly British individuals (mean age, 77 years) participating in a study on fracture prevention were randomly assigned to receive 800 IU per day of vitamin D, 1,000 mg per day of calcium, both supplements, or placebo for 24 to 62 months. About two-thirds of the participants responded to a questionnaire at a median of 18 months after randomization. Among the 55% of questionnaire respondents who were still taking their treatment, the incidence of infections was 20% lower in those assigned to receive vitamin D than in those assigned not to receive vitamin D (p = 0.06).

Comment: Vitamin D enhances immune function, and vitamin D deficiency increases the risk of developing infections. Although the results of the present study were only of borderline statistical significance, they suggest that vitamin D supplementation can prevent infections among the general population of elderly individuals. In a previous study conducted among black women in the US, the incidence of cold or influenza symptoms was significantly lower among those who received vitamin D than among those who received a placebo. A dose of 800 IU per day of vitamin D appears to be the minimum amount that improves various clinical outcomes in elderly people.
Avenell A et al. Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing. 2007;36:574–577.

Probiotic for Ulcerative Colitis
Twenty-nine children (mean age, 9.8 years; range, 2–16 years) with newly diagnosed ulcerative colitis were randomly assigned to receive, in double-blind fashion, a probiotic preparation (VSL#3; 1,800 billion bacteria per day) or placebo for one year. VSL#3 consists of four strains of lactobacilli, three strains of bifidobacteria, and one strain of Streptococcus salivarius subsp. thermophilus. All patients received glucocorticoids and mesalazine until remission occurred, and then continued to receive mesalazine as maintenance therapy. The proportion of patients who achieved remission was significantly greater in the VSL#3 group than in the placebo group (93% vs. 36%; p < 0.001). After one year, the relapse rate was significantly lower in the VSL#3 group than in the placebo group (21% vs. 73%; p = 0.014). No adverse effects of VSL#3 were seen.

Comment: It has been suggested that chronic infection plays a role in the pathogenesis of ulcerative colitis. In one study, facultatively enteropathogenic organisms such as Klebsiella spp. or Pseudomonas aeruginosa were found in colonic biopsy samples of nearly one-half of patients with ulcerative colitis. The possible role of bacterial infection in this disease is supported by a study in which colonic infusion (by retention enema) of fecal flora from healthy donors resulted in an apparent cure in six of six patients with severe ulcerative colitis. The beneficial effect of probiotic treatment in the present study is presumably due to changes in the intestinal flora.
Miele E et al. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104:437–443.

Don't Forget the B12 When Using Folic Acid
Data from the 1999–2002 National Health and Nutrition Examination Survey were used to evaluate the interaction between high serum folate and low vitamin B12 status (plasma vitamin B12 < 148 pmol/L or methylmalonic acid > 210 nmol/L) with respect to anemia and cognitive impairment. In the face of marginally low vitamin B12 status, higher serum folate levels (as compared with normal folate levels) were associated with a higher prevalence of anemia and cognitive impairment and were also associated with higher levels of homocysteine and methylmalonic acid. The opposite trends regarding the relationship between folate, homocysteine, and methylmalonic acid levels were seen in people who had vitamin B12 levels of 148 pmol/L or greater.

Comment: It is well known that supplementing with folic acid can mask the laboratory diagnosis of vitamin B12 deficiency. It is less well known that folic acid supplementation may actually cause vitamin B12 deficiency. The results of the present study raise the possibility that folic acid supplementation could promote the development of anemia and cognitive decline in people with marginal vitamin B12 status, presumably by decreasing the activity of two vitamin B12-dependent enzymes, methionine synthase and methylmalonic acid-coenzyme A mutase. Early studies in patients with pernicious anemia suggested that high folic acid intake adversely influenced the natural history of vitamin B12 deficiency. Case reports mentioned rapid neurological deterioration after improvement of anemia. One report stated that "some patients who had not previously shown signs of nervous system disturbances developed such signs, often very acutely, after being treated with folic acid for variable periods." Based on these observations, it would be prudent to administer a vitamin B12 supplement to patients who are receiving folic acid. Now that folic acid is being added to refined flour, it might be a good idea to throw in some vitamin B12 as well.
Selhub J et al. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009;89(Suppl):702S–706S.

Vitamin D Levels Are Declining
Serum 25-hydroxyvitamin D (25[OH]D) levels were measured in 18,158 participants in National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and 20,289 participants in NHANES 2000–2004. Age-adjusted mean serum 25(OH)D concentrations were 5–20 nmol/L lower in NHANES 2000–2004 than in NHANES III. After adjustment for changes in assay procedures, age-adjusted means in NHANES 2000–2004 remained significantly lower (by 5–9 nmol/L) in most males, but not in most females. In a study subsample, adjustment for the confounding effects of assay differences changed mean serum 25(OH)D concentrations by approximately 10 nmol/L, and adjustment for changes in factors likely related to real changes in vitamin D status (body mass index, milk intake, and sun protection) changed mean serum 25(OH)D concentrations by 1–1.6 nmol/L.

Comment: Studies published over the past 5 to 10 years have concluded that the prevalence of low vitamin D status is remarkably high among otherwise healthy people. The results of the current study suggest that this high frequency of low vitamin D status is due in part to changes in the way 25-OH(D) levels are measured. However, part of the decline is real, and is attributable to a reduction in sun exposure, a decrease in intake of vitamin D-fortified milk, and an increase in the number of people who are overweight or obese (the skin of overweight people is relatively inefficient at synthesizing vitamin D from sunlight). Low vitamin D status may contribute to bone loss, falls, some autoimmune diseases, increased susceptibility to infection and cancer, and diabetes. Supplementing with vitamin D and/or increasing sun exposure by a modest amount could provide substantial health benefits for many people.
Looker AC et al. Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. Am J Clin Nutr. 2008;88:1519–1527.

Calcium During Pregnancy and Fetal Lead Exposure
Six hundred-seventy women in their first trimester of pregnancy were randomly assigned to receive, in double-blind fashion, 1,200 mg per day of supplemental calcium or placebo. After adjustment for baseline lead levels, age, trimester of pregnancy, and dietary energy and calcium intake, calcium supplementation was associated with an 11% reduction in the mean blood lead level relative to placebo (p = 0.004). This reduction was more evident in the second trimester (−14%; p < 0.001) than in the third trimester (−8%; p < 0.11). The effect of calcium supplementation was strongest in women who consumed at least 75% of the pills (−24%, p < 0.001) and in those who had a baseline blood lead greater than 5 µg/dl (−17%; p < 0.01).

Comment: Prenatal lead exposure is associated with deficits in fetal growth and neurological development. Calcium supplementation may decrease fetal lead exposure by two separate mechanisms. First, it may inhibit the absorption of lead ingested from food and water. Second, calcium supplementation may decrease the amount of lead mobilized from maternal bone by decreasing the amount of maternal bone breakdown needed to meet fetal calcium requirements. Other benefits of high calcium intake during pregnancy include prevention of maternal bone loss and a reduction in the incidence of preeclampsia.
Ettinger AS et al. Effect of calcium supplementation on blood lead levels in pregnancy: a randomized placebo-controlled trial. Environ Health Perspect. 2009;117:26–31.

Vitamin A Eye Drops for Dry Eyes
One hundred-fifty patients with dry eye syndrome were randomly assigned to receive vitamin A eye drops (Viva Drops; Vision Pharmaceuticals) 4 times per day, 0.05% cyclosporine A eye drops twice a day, or no treatment (control group) for three months. All patients used artificial tears four times per day. After three months, both active-treatment groups showed significant improvements com­pared with the control group with respect to blurred vision, tear film breakup time, Schirmer tear test results, and goblet cell density. Some of these improvements were also significant after two months. There was no significant difference in any of these parameters between vitamin A and cyclosporine A.

Comment: Severe vitamin A deficiency, which occurs frequently in some developing countries, can cause dryness of the eyes and other, more serious ocular pathologies. The dryness results in part from a loss of goblet cells, which reappear after vitamin A deficiency is corrected. In Western societies, vitamin A deficiency severe enough to cause eye disease is uncommon, except among people with chronic liver disease. However, it is possible that a localized vitamin A deficiency can develop on the surface of eyes that are stressed by a harsh environment, chronic inflammation, or use of contact lenses; and that such a deficiency contributes to or exacerbates dry eye syndrome. The results of the present study indicate that vitamin A eye drops are an effective treatment for dry eyes.
Kim EC et al. A comparison of vitamin A and cyclosporine A 0.05% eye drops for treatment of dry eye syndrome. Am J Ophthalmol. 2009;147:206–213.e3.

Alan R. Gaby, MD


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