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Doi:10.1016/s0899-9007(03)00026-Nutrition Volume 19, Numbers 11/12, 2003 16. Carpenter KC, Roberts S, Sternberg S. Nutrition and immune function: a 1992 size, the place of residence of the subjects whether living at home or in institutions, and the baseline status of the subjects. In several 17. Sano M, Ernesto C, Thomas RG, et al. A controlled study of selegiline, alpha- studies, single nutrients were used. Zinc supplements corrected the tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 1997; changes in immune system resulting from induced zinc deficiency such as CD4:CD8 ratio and thymulin Vitamin E im- 18. Morris JC. The clinical dementia rating (CDR): current version and scoring rules.
proved delayed hypersensitivity response and antibody level after 19. Chandra RK. Preventive nutrition: Consideration of cost-benefit and cost- Two different commercial combinations of vita- mins and trace minerals increased delayed cutaneous hypersensi-tivity response and other selected parameters of immunity in old Few studies have looked at incidence of infection.
Zinc and selenium supplements reduced the occurrence of infec- tious illness in aged Two clinical studies in which treatedsubjects received the multinutrient supplement used in our trials showed beneficial effects in terms of infection In partic-ular, one was a very large study of 763 nursing home patients inCanada who received the multinutrient or a placebo for 19 mo. The To the Editor: It is surprising that Roberts and Sternberg find no average age of the subjects was 85 y. The mean number of merit at all in our studies; they have no positive comments to episodes of infection was 1.94 in the treated group compared with make, none whatsoever. They “doubt everything in it [the 2.26 in the placebo group (P Ͻ 0.001); the results were considered Nutrition paper]” and extend their paint brush approach to the of great significance for medical management and health care costs Lancet paper. The two papers were reviewed by a number of in long-term facilities for older individuals. A recent study re- referees and statisticians before the journals accepted and pub- ported benefits from multivitamin and mineral supplementation, lished them. Their statements by themselves question the scientific objectivity of Roberts and Sternberg and point to an obvious bias Thus, it is no longer disputed that the weight of evidence, on their part; there may well be a conflict of interest involved.
reported first by and now by supports the concept Aging is associated with a reduction in many physiologic that modest amounts, not mega doses, of vitamins and trace functions. It is now accepted that a proportion of these changes elements enhance immune responses, and where examined and may be the consequence of an inadequate intake of vitamins, trace depending upon the nutrients being supplemented and their elements, minerals, and other Even a “healthful” diet amounts, decrease the incidence of infection.
cannot provide all these elements in amounts that are necessary for A causal connection between nutrient deficiencies and impaired health promotion and prevention of acute and chronic diseases.
cognitive function particularly in the elderly has been postulated Roberts and fault our and cannot believe that by many authors and is supported by considerable In nutrition can make a significant difference to functional outcomes particular, attention has been given to vitamin C and B vitamins.
in the elderly, especially immune responses, incidence of infection, Changes in homocysteine levels brought about by vitamin defi- and some aspects of cognitive function. I point out some of the ciencies may play an important pathogenetic role. Older subjects inaccuracies in their very selective and biased commentary in without clinical dementia as well as those with Alzheimer disease which they cite only those references that suit their views but had higher plasma homocysteine concentrations and lower serum ignore others that go against their views. Therefore, I question the folate and vitamin B12 levels than did age-matched scientific basis of their comments and why the positive commen- Vitamin E supplements improved clinical endpoints in patients dation of my work by other readers and reviewers of our studies with Alzheimer even though there was no difference in the treated and placebo groups on the Cognitive subscale of the The design of our studies and methods of analysis have been Alzheimer Disease Assessment Scale or any other cognitive test commended by many individuals. The first was stated to score. Surprisingly, Roberts and Sternberg deny what this author have provided “hard evidence” based on a “well-designed prospec- stated. Why? In the Nun Study, low serum folate level was tive trial … whose results, when considered in the context of the strongly associated with atrophy of the cerebral Multiple basic and intermediate endpoint clinical data now available, are deficiencies are common in the elderly and can be expected to biologically credible. More prospective trials are needed, and they produce widespread cerebral damage, both structural and must be as meticulously conducted as the first one.Simin Mey- dani, a leader in this field, has referred to this paper as “a landmark There can be differences in methods used to describe results of study.The study plans were discussed with The Lancet office any study; as a reviewer of articles for some of the most presti- and many of the changes in final analyses and presentation were gious medical journals, as a member of some editorial boards, and made as a direct result of the suggestions of the three expert as the Editor-in-Chief of Nutrition Research, I have encountered referees and two statisticians of the journal who also saw the raw many instances of a totally different approach and conclusion by data that they had asked for. An author cannot ignore such rec- two referees and by statisticians invited by a journal. We could ommendations and our publication resulted after the final approval take published papers, including those by Drs. Roberts and Stern- of the journal’s referees, statisticians, and the editorial staff. Were berg, and by the editors of Nutrition, and ask new reviewers to all of them wrong and incompetent? If so, then an author would evaluate them. Such an exercise will invariably result in different generally be quite happy to be a part of that group.
results, statistical numbers, and conclusions. Such an exercise for Several studies have confirmed the beneficial effects of nutrient several papers in the field of nutritional immunology is being supplementation on immune responses in the Not all prepared for publication. Reanalysis of published psychiatry pa- the results can be expected to be identical to those of our trial. The pers in a British journal has sometime led to different strength of the evidence presented in these papers by other authors Differences in statistical approaches and methods of analyses that varies, dependent in part on the variety and amounts of nutrients result in different results and conclusions are common knowledge provided, duration of the trial, outcome variables assessed, sample to authors and editors and have been the subject of less thangenerous sarcasm. The readers would be surprised to see opinionsthat would make one wonder why reputed journals could have Correspondence to: Ranjit Kumar Chandra, OC, MD, FRCPC, MACP, accepted and published such manuscripts. In many instances, two Y-182 Regency Park II, DLF City Phase IV, Gurgaon 122002, India.
reviewers for the same journal provide diametrically opposite recommendations for analysis, description, and discussion. In Nutrition Volume 19, Numbers 11/12, 2003 terms of clinical conclusions and public health application, differ- publication. Their comments about the Lancet paper has already ences in two treatment groups expressed as less than 0.001 or less been responded The statement that there have been any than 0.00000001 are of no practical For practicing problems with replication of the results of our study on immune clinicians, such hair-splitting is no value and a waste of everyone’s responses and infection is false and totally unsubstantiated, as time. Most editors have learnt to ignore such biased diatribe.
discussed extensively above. In fact, the contrary is The I and my colleagues in psychiatry, psychology, nutrition, im- paper they refer to does not appear in their bibliography, so no munology, and statistics do not agree with the comments of Rob- response from me for their unsupported and biased statement, nor erts and Sternberg about the range of numerical scores to be a failure for letters from and to them to reach the addressee, can be expected in modified Mini-Mental State Examination and other tests of cognitive function employed by us. Restrictions on pre- Only time and other trials will attest to the strength of our mium journal space does not always allow authors to describe conclusions. This has already happened with the immune response these. Many editors accept this with or without the additional data. A balanced interpretation of the clinical experience and wording of “data not shown.” Our statistical consultants also have published evidence to date would indicate that supplementation different views about the methods of analysis that do not, in anycase, alter the broad conclusions of our studies. “A difference, to with a combination of vitamins and trace elements in optimum be a difference, must make a difference.“We think of tests of amounts that are based on dose-response curves and tested subse- significance more as methods of reporting than for making deci- quently in a well-designed, randomized, double-blind, placebo- sions because much more must go into making medical policy than controlled prospective trial can be expected to improve immunity, reduce infection, and improve selected cognitive functions.
It is not clear why Drs. Roberts and Sternberg bring in the Can a nutrient supplement improve functional outcome in the question of the patent rights of the micronutrient supplement that elderly? The answer based on the objective evidence so far is an we used in the trial. As opposed to many studies that employed unequivocal yes. I invite Drs. Roberts and Sternberg to try such a commercially available preparations and therefore the authors supplement for a personal confirmation of our findings.
would have obvious or perceived financial associations with com-our studies were not funded by any industry. Moreover, Ranjit Kumar Chandra, OC, MD, FRCPC, MACP
we first determined the optimum amounts of each micronutrient for enhancing immunity in older subjects. This was followed bythe double-blind, randomized, prospective There was nocommercial benefit nor any conflict of interest involved, as perguidelines outlined by various Almost 10 y after theLancet paper was published, the combination of nutrients used in the trial was now made available to the public on a limited scale in 1. Hoffer LJ. Nutritional supplements and health. Ann R Coll Phys Surg Can one province of Canada through the generosity of a small not-for- profit foundation on the stipulation that all proceeds would be 2. Bendich A, Deckelbaum RJ. Preventive nutrition. Totawa, NJ: Humana Press, given toward research in the province by third-party investigators.
Parenthetically, it remains to be explored whether Drs. Roberts 3. Roberts S, Sternberg S. Do nutritional supplements improve cognitive function in and Sternberg have any conflicts of interest and bias, real or perceived, in terms of financial grants from companies that have 4. Chandra RK. Effect of vitamin and trace-element supplementation on immune products for the treatment of dementia or altered cognitive func- responses and infection in elderly subjects. Lancet 1992;340:1124 tions, honoraria, consulting fees, service on advisory boards, own- 5. Chandra RK. Effect of vitamin and trace-element supplementation on cognitive ership of equity or options thereon, fees for expert testimony, and function in elderly subjects. Nutrition 2001;17:709 6. Meydani S. In: Sastre A, Rosenberg IH, eds. Nutrition and aging. Basel: Karger, No disclosure statement has been provided. My attempts to obtain this information directly from Drs Roberts and Sternberg 7. Beisel WL. Nutritional immunology. A profile of Ranjit K. Chandra. J Nutr have elicited no clear response so far.
The improvement in functional outcome reported by us has the 8. Fawzi M. Multivitamins and minerals for infection? Ann Intern Med 2002;138: support of many studies. It is also biologically highly plausible.
Many vitamins and trace elements play an essential role as cofac- 9. Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R. Effect of a tors in hundred of enzymes involved in synthesis of proteins, mutivitamin and mineral supplement on infection and quality of life. Ann Intern polypeptides, DNA, and cytokines. For instance, zinc facilitates the action of more than 200 enzymes including some that promote 10. Chandra RK. Nutrition, immunity and infection. Proc Natl Acad Sci USA cell replication and protein synthesis; it is also an integral compo- nent of thymulin, a T-cell maturational hormone produced by 11. Chandra RK. Graying of the immune system. Can nutrient supplements improve thymic epithelial cells. In their commentary, Roberts and Stern- immunity in the elderly? JAMA 1997;277:1398 berg completely ignore these evidences. Also, they provide two 12. Jeejeebhoy KN. Micronutrients and aging; review of recent evidence. Whitehall- versions of how others, for example, Dr. Carpenter, got to read our 13. Prasad AS, Meftah S, Abdallah J, et al. Serum thymulin in human zinc deficiency.
Shenkin et made useful comments to which we respond- To date, we have not heard from them; thus, we assume that 14. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in they are satisfied with our explanations. On what basis do Roberts vivo immune response in healthy elderly subjects. JAMA 1997;277:1380 15. Bogden JD, Bendich A, Kemp FW. Daily micronutrient supplements enhance and Sternberg believe that our reply to Shenkin et al. was “mis- delayed hypersensitivity skin test response in older people. Am J Clin Nutr leading”? It is most unethical for them to attribute such a statement to others. Are Roberts and Sternerg the spokespersons and inter- 16. Pike J. Effect of vitamin and trace element supplementation on immune indices in healthy elderly. Int J Vit Nutr Res 1995;65:117 It is not appropriate for Roberts and Sternberg to ask me to 17. Girodon F, Lombard M, Galan P, et al. Effect of micronutrient supplementation respond to their comments on a paper by another author, Jain, on infection in institutionalized elderly subjects. Ann Nutr Metab 1997;41:98 published in another journal, Nutrition ResearchI encourage 18. Jain AM. Influence of vitamins and trace-elements on the incidence of respiratory them to write a formal letter to the journal about this paper and I infection in the elderly. Nutr Res 2002;22:85 expect that such a letter, together with the author’s reply if Jain 19. Liu B. Effect of multivitamin and mineral supplementation on infection rates in wishes to respond, will be considered by the journal for possible elderly long-term care residents. Manuscript in preparation, 2003 Nutrition Volume 19, Numbers 11/12, 2003 20. Mitchell B, Ulrich N. Effect of nutrient supplementation on immune responses 27. Swinscow TDV, Campbell MJ. Statistics at square one. London: BMJ Books, 21. Selhoub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and 28. Haines SJ. Six statistical suggestions for surgeons. Neurosurgery 1981;9:414 neurocognitive function in the elderly. Am J Clin Nutr 2000;71(suppl):614S 29. Mosteller F, Gilbert JP, McPeek B. Reporting standards and research strategies 22. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Amer J Clin for controlled trials. Control Clin Trials 1980;1:37 30. Drazen JM, Curfman GD. Financial associations of authors. N Engl J Med 23. Lindeman RD, Romero LJ, Koehler KM, et al. Serum vitamin B12, C and folate concentrations in New Mexico elder health survey; correlations with cognitive 31. Koshland DE, Jr. Conflict of interest policy. Science 1992;257:595 and affective functions. J Am Coll Nutr 2000;19:68 32. Rennie D, Flanagin A, Glass RM. Conflicts of interest in the publication of 24. Sano M, Ernesto C, Thomas RG. A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 1997;336:1216 33. Shenkin SD, Whiteman MC, Pattie A, Deary IJ. Supplementation and the elderly; 25. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesberry WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease; findings from 34. Chandra RK. Response to the comments of Shenkin et al. Nutrition 2002;18:364 the Nun study. Am J Clin Nutr 2000;71:993 35. Chandra RK. Nutrition and immune function. Lancet 2003;361:2247 26. White SJ. Statistical errors in papers in the British Journal of Psychiatry. Br J
Dramatic prostate-specific antigen response with activatedhemicellulose compound in metastatic castration-resistantprostate cancerJeffrey Turnera and Uzair ChaudharybCastration-resistant prostate cancer (CRPC) is anincurable disease with limited treatment options. HerbalKeywords: activated hemicellulose compound, castration-resistant prostatesupplements are unconventional treatments for a vari