I am appalled that this paper managed to get past peer review and reach publication. The authors define 'breastfed' as 'partially or completely breastfeeding at time of death or interview'. This implies there were babies entered into the breastfed group who were receiving formula in quantities that are unknown. What exactly is partially breastfed? Is this one, two, three bottles of formula per day? One breastfeed per day? I cannot seem to find any more data about the feeding. They seem to have grouped partial and fully breastfeeding together, so one cannot extrapolate this data to exclusively breastfed infants.

The authors do not have data on maternal alcohol/ drug consumption in the previous 24 hours in three out of five of the studies. They have instead used imputed data to make up for this. How one goes about imputing values from studies conducted across the world with different cultural habits is beyond me!

I am struggling to understand why they looked at 'mothers who took 2 units or more of alcohol in the previous 24 hours'. This implies that there were mothers in the control group who had alcohol on board who co- slept with their babies which is clearly against advice regarding sleeping safely with your baby. Recalling units is also extremely difficult, given that most people (in my professional experience as a GP) cannot accurately estimate how many units they are drinking.

We also have no information on the partners' alcohol and drug consumption. Surely this must be an important variable to include in a study looking at all the hazards of bed-sharing?

If only the authors asked the right question (i.e. what is the risk of SIDS in babies who are exclusively breastfed who co-sleep with parents who do not drink alcohol, smoke or take drugs?), then we may actually have some useful answers.

Oh yes, I also object to being compared to a sow! The authors use the analogy of a sow crushing her piglets to meet the Bradford-Hill criteria. This is really scraping the barrel. If we [breastfeeding mothers] are now to be compared with animals, at least have the decency to compare us to animals of the same order who live in their natural environment and are not intensively farmed!

This study has now been splashed around the media as if it is gospel, despite its many flaws. I am deeply concerned about the message this study will send to exclusively breastfeeding mothers who will now be petrified of bed-sharing so will fall asleep on sofas/ breastfeeding chairs instead. In the meantime, mothers will co-sleep anyway without access to information on safe bed-sharing.

The BMJ Open has a duty to filter out the studies which draw conclusions from inadequate data which is subject to all kinds of bias, where the confounding issues have not been appropriately accounted for. I am disappointed BMJ Open - the consequences of publishing such a study could be disastrous!

Conflict of Interest:

Salaried GP, breastfeeding mother

Charlotte K Russell - Research Associate, Department of Anthropology, Durham University

Helen L Ball - Professor of Anthropology, Department of Anthropology, Durham University; Director of the Parent-Infant Sleep Lab

Dear Editor,

This publication analyses SIDS-risks associated with bed-sharing under different circumstances using data from five historical SIDS studies. Unlike previous analyses of these data, this analysis includes data on feeding type. It promises, at last, to enable those of us working with parents and the staff who support them to be able to answer complicated but commonly asked questions about SIDS, and allow parents to make informed decisions about any potential risk associated with their personal and cultural infant care beliefs and behaviours.

Because this analysis is based on old data, however, it can only inform us as to the risks as they existed 15-26 years ago: knowledge both of bed-sharing behaviour and safety issues not considered here have advanced considerably in the intervening period. The authors present analysis of a dataset in which 'safer' bed-sharing is considered as distinct from bed-sharing in conjunction with known hazards (that is, breastfeeding infants bed-sharing in the absence of smoking, alcohol, drugs and sofa-sharing). Babies were categorized as bed-sharing if they were found dead in the parental bed, or woke up in the parental bed in the morning following the 'index night' (deviating from the original analyses which used many different definitions for 'bed-sharing'). This definition under-estimates the number of 'control' babies who bed-shared as some infants bed-share for a portion of the night and are placed in a cot following the last feed, so would not wake up in the parents' bed (and would be classed here as 'room-sharers'), however babies who die would not be returned to the cot. 'Accidental' (and consequently unplanned) bed- sharing is therefore also likely to be overrepresented in the SIDS group (Ball 2012). Both factors would inflate the risk associated with bed- sharing.

The authors predict a SIDS-rate of approximately 1 per 10,000 babies for room-sharers, and 2 per 10,000 babies for bed-sharers. The current rate of SIDS in UK is 1/3000, or 3.4/10,000, which means that both sleep locations for breastfed infants of non-smoking parents in the absence of alcohol experience very few SIDS deaths. It is curious, therefore, that the authors focus attention only to this small difference in predicted SIDS rates for breastfed babies of non-smoking parents who bed-share compared to room-sharing-while ignoring the hugely inflated risks associated with hazardous bed-sharing environments. It appears as though the authors choose to target breastfeeding mothers in this way as they are a sub-group with strong opinions about the benefits of bed-sharing, even though the infants of these mothers contribute negligibly to UK SIDS rates.

The recommendations of the authors that parents are advised to 'simply avoid bedsharing' indicates a worrying lack of cultural awareness or sensitivity to childrearing beliefs of different groups of parents on the part of these SIDS researchers. Such a recommendation does not allow parents, especially those whose infants are at low risk for SIDS (healthy term births, breastfed, not exposed to parental smoking or alcohol consumption), to make an informed choice to bed-share or not. While single message recommendations may have been appropriate and effective in previous campaigns targeting simple infant care practices such as supine vs. prone sleep position, they are inappropriate and ineffective for addressing infant care issues involving relational behaviours and cultural beliefs (Ball and Volpe 2012). Closing down all discussion of the reasons why parents might bed-share with their infant by issuing a dogmatic recommendation inhibits health professionals from raising the topic, causes parents to lie about their behavior, and stifles the provision of information about hazardous sleeping environments and the degrees of risk involved (Fetherston and Leach, 2013).

We argue that SIDS is not the only issue that must be taken into consideration when considering parent-infant bed-sharing, and that risk minimization, involving parent education and facilitating informed choice, is a more logical and ethical approach to the bed-sharing issue, than one focusing on risk elimination.

References:

Ball, H. L. (2012). Sleeping with the baby. IBFAN Breastfeeding Briefs, No. 53, September 2012.

Ball, H. L., & Volpe, L. E. (2013). Sudden Infant Death Syndrome (SIDS) risk reduction and infant sleep location - moving the discussion forward. Social Science & Medicine, 79, 84-91.

Fetherston C.M., & Leach, J.S. (2012) Analysis of the ethical issues in the breastfeeding and bedsharing debate. Breastfeeding Review, 20(3): 7-17.

Conflict of Interest:

Ball and Russell run the Infant Sleep Information Source (ISIS), an online source of infant sleep research information for parents and health professionals (www.isisonline.org.uk). They do so as part of their academic outreach activities and do not receive any income from the project.

In their paper1 Carpenter et al. conclude that bed-sharing of infants under 3 months with their parents even when the latter did not smoke and had no other risk factors the adjusted odds ratio for SIDS was 5.1 (2.3 to 11.4). This risk was greatly increased when the parents smoked, took alcohol or drugs. These findings are not surprising and confirm that co- sleeping is particularly dangerous for babies under three months of age. The main message is that co-sleeping (with or without other risk factors such as alcohol, other drugs or smoking) should never occur, but it is OK to breast feed in the parental bed and then to put the baby to sleep "face up" in its own cot (with clean linen) in the same room as the parent(s). The study pre-supposes that accidental smothering is the reason for these deaths while providing no autopsy evidence to that effect. The paper does not discuss the role of bacterial infection and only briefly alludes to it peripherally in terms of thermal stress (overheating) and the release of lethal toxins. It has been our view, that the theory of respiratory compromise due to smothering may account for only a very small minority of cases. The parental bed or sofa represents a dangerous sleeping surface, as both of these are heavily contaminated with bacteria such as Escherichia coli and Staphylococcus aureus which are equipped with a variety of lethal toxins. A baby sleeping in such a contaminated environment could inhale or ingest shed skin cells covered in these bacteria. A genetically susceptible baby is at risk in the co-sleeping situation. This risk is further increased with every additional risk factor.

Infection has long been recognised as a risk factor for SIDS as shown by symptoms and signs of respiratory and/or gastrointestinal infection in the days preceding SIDS death.2 Infection of normally sterile sites with major bacterial pathogens in SIDS has been independently described by two research groups.3,4 This finding could represent the 'footprint' of a bacteraemic episode prior to death.5,6 Bloodstream infection is a profound inducer of hypoxaemia; the mechanism of which is not fully understood, however, the cytokine storm almost certainly plays a major role7 and the hypoxaemia the storm produces seems to precede the final demise in monitored SIDS cases. In addition, it is plausible that the findings of Vargas et al.8 in relation to Pneumocystis lung colonization/infection, with increased mucus production, could contribute to hypoxaemia.

Not only is infection (via sepsis or toxaemia) an inducer of hypoxaemia, it is also a key thermogenesis inducer and is usually overlooked by SIDS researchers married to linking prone sleep to respiratory physiology. On the other hand, supportive evidence for plausible links between prone sleep position and infection have been proposed based on bacterial colonization and toxin induction with raised nasopharyngeal temperatures prone,9,10 and bacterial contamination of the sleeping surface promoting colonization of the infant's nasopharynx and gut.9-11 From studies in a neonatal ward conducted many years ago, it has long been known that organisms, such as E. coli are shed into the air and onto surrounding furniture by infants and their care-givers and that these bacteria can then colonize other infants and sometimes cause serious infection.12 Furthermore, as skin scales decorated with Staphylococcus aureus, and coliform (e.g. Escherichia coli) bacteria are shed in "dangerous sleeping environments" (parental bed, sofa, etc.) it is not unreasonable to conjecture that prone babies will inhale or ingest these bacteria and thereby provide the first step in a pathway leading to SIDS via the so-called "Common Bacterial Hypothesis of SIDS"13 or via toxigenic effects of these bacteria,5,6,14-24 Hypotheses of pathogenesis fail to adequately link all the known risk factors for SIDS into a holistic, all- encompassing hypothesis. Respiratory and brainstem and cardiac hypotheses compete to explain hypoxemia in the progression to SIDS and therefore do not satisfy a complete pathogenetic mechanism. A microbiological basis needs to be considered as the key for the epidemiological risk factors and the physiological findings provide a plausible explanation for SIDS.

Conflict of Interest: The authors have no conflicts of interest to disclose. Word count: 804 (excluding abstract and references)

Contributors' Statement: Paul N. Goldwater: Professor Goldwater drafted the initial manuscript and approved the manuscript as submitted. Karl A. Bettelheim: Dr Bettelheim conceptualized the article and reviewed and revised the manuscript and approved the manuscript as submitted.

REFERENCES 1. Carpenter R, McGarvey C, Mitchell EA, Tappin DM, Vennemann MM, Smuk M, Carpenter JR Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five major case-control studies. BMJ Open Access Research, May 21, 2013.

2. Hoffman HJ, Damus K, Hillman L, Krongrad E: Risk factors for SIDS. Results of the National Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study. Ann N Y Acad Sci. 1988; 533: 13- 30.

3. Weber MA, Klein NJ, Hartley JC, Lock PE, Malone M, Sebire NJ: Infection and sudden unexpected death in infancy: a systematic retrospective case review. Lancet 2008; 371: 1848-1853.

4. Goldwater PN: Sterile site infection at autopsy in sudden unexpected deaths in infancy. Arch Dis Child. 2009;94(4):303-7. Epub 2008 Sep 15.

5. Goldwater PN. A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence. BMC Medicine 2011;9:64. http://www.biomedcentral.com/1741-7015/9/64.

6. Highet AR, Berry AM, Goldwater PN. Novel hypothesis for unexplained sudden unexpected death in infancy (SUDI) Arch Dis Child 2009; 94:841-843.

7. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. New Engl J Med. 2003; 348(2): 138-150.

8. Vargas SL, Ponce CA, Gallo F, Felipe Astorga J, Bustamante R, Chab? M, Durand-Joly I, Iturra P, Miller RF, Moukthar Aliouat EI, Dei-Cas E. Near universal prevalence of Pneumocystis and associated increase in mucus in the lungs of infants with sudden unexpected death. Clin Infect Dis 2013; 56: 171179.

9. Blackwell CC, Gordon AE, James VS, MacKenzie DA, Mogensen-Buchanan M, El Ahmer OR, Al Madani OM, T?r? K, Csuk?s Z, S?tonyi P, Weir DM, Busuttil A. The role of bacterial toxins in sudden infant death syndrome (SIDS). Int J Med Microbiol 2002; 291:561-570.

10. Molony N, Blackwell CC, Busuttil A. The effect of prone posture on nasal temperature in children in relation to induction of staphylococcal toxins implicated in Sudden Infant Death Syndrome FEMS Immunol. Med. Microbiol. 1999; 25: 109-114.

11. Goldwater PN. Sudden infant death syndrome: A critical review of approaches to research Arch Dis Child 2003, 88:1095-1100

12. O'Farrell SM, Lennox-King SMJ, Bettelheim KA, Shaw EJ, Shooter, RA. Escherichia coli in a maternity ward. Infection 1976, 4:146-152.

13. Morris JA. The common bacterial toxins hypothesis of sudden infant death syndrome. FEMS Immunol Med Microbiol 1999; 25:11-17.

14. Bettelheim KA, Dwyer BW, Smith DL, Goldwater PN, Bourne, AJ. Toxigenic Escherichia coli associated with sudden infant death syndrome. Med J Aust. 1989; 151:538.

15. Bettelheim, KA, Goldwater, PN, Dwyer, BW, Bourne, AJ & Smith, DL. Toxigenic Escherichia coli associated with Sudden Infant Death Syndrome. Scand J Infect Dis.1990; 22:467-476.

16. Bettelheim, KA, Smith, H, Goldwater, PN, Morris, JA, Murrell, TGC, Sweet, C, Weaver, SA. Sleeping position and cot deaths Lancet 1991; 338:192.

17. Bettelheim KA, Chang BJ, Elliott SJ, Gunzburg ST, Pearce, JL. Virulence factors associated with strains of Escherichia coli from cases of sudden infant death syndrome (SIDS). Comp Immunol Microbiol Infect Dis. 1995; 18:179-188.

18. Bettelheim KA, Luke RKJ, Johnston N, Pearce JL, Goldwater, PN. A Possible Murine Model for Investigation of Pathogenesis of Sudden Infant Death Syndrome Curr Microbiol 2012, 64:276-282.

19. Goldwater, PN, Bettelheim, KA. Curliated Escherichia coli, soluble curlin and the sudden infant death syndrome (SIDS): J Med Microbiol 2002; 51:1009-1012.

20. Highet, AR, Goldwater PN. Staphylococcal enterotoxin genes are common in Staphylococcus aureus intestinal flora in Sudden Infant Death Syndrome (SIDS) and live comparison infants. FEMS Immunol Med Microbiol. 2009; 57:151-155.

21. Pearce JL, Luke RKJ, Bettelheim KA. Sudden infant death syndrome: What questions should we ask? FEMS Immunol Med Microbiol 1999; 25:7-10.

22. Pearce JL, Luke RKJ, Bettelheim KA. Extraintestinal Escherichia coli isolations from SIDS cases and other cases of sudden death in Victoria, Australia FEMS Immunol Med Microbiol 1999; 25:137-144.

23. Pearce JL, Luke RKJ, Bettelheim KA. Infection and food: a factor in sudden infant death syndrome? FEMS Immunol Med Microbiol 2004; 42:66- 75.

24. Pearce JL, Bettelheim KA, Luke RKJ, Goldwater, PN. Serotypes of Escherichia coli in Sudden Infant Death Syndrome. J Appl Microbiol 2010; 108:731-735.

Conflict of Interest:

None declared

Response by the authors:

On behalf of the PLP10 study co-authors (1), Ioannis S Patrikios, George N Loukaides and Mario C Pantzaris, I report our opinion and response to the e-letter "Omega-3, omega-6 and vitamin treatment for relapsing-remitting multiple sclerosis" by Oivind Torkildsen. We really appreciate the comments by Dr Oivind Torkildsen (2) and we thank him for giving us the chance to clarify more on the subject. On the other hand we have to acknowledge that even though we respect his approach and course of thinking we keep a totally different bio-reasoning on the evaluation of the PLP10 study results. Moreover, we feel the need to report that all comparisons that follow are only used for statement clarification purposes and for no other reason.

We acknowledge that at the time of preparation of the manuscript we were fully aware of all references mentioned in the e-letter, by Oivind Torkildsen, including the OFAMS study (2), Bates (3) and the published review articles (4, 5); but it was not possible for us to discuss all and everything in this single PLP10 article (1) where the main target was to report a difficult subject, a clinical study, and with limitations on the number of references and words. However, the Farinottis' review paper, the first and major one (Cochrane review, dietary intervention for multiple sclerosis, 2007) (6), is cited in our work. The Farinottis' 2012 paper (5) is an update of the previous one (6). Moreover, we believe that the rational and background information in the introduction, of our paper, is clear and enough (as a non-review article), with all ingredients that have been used, very well discussed / explained and referenced.

It was not our intention and/or our purpose to discuss all previous trials that have been performed testing PUFAs, mainly because we strongly believe that our intervention is not comparable to any of the formulations or PUFA supplements that have been used in those trials but instead totally different; like the quantities/quality/purity of the specific PUFAs used, ratio of the main ingredients, stereochemistry and molecular shape, additives like the specific vitamins and especially gamma- tocopherol. It was our decision to consider as a much more important issue the explanation and discussion, why the PLP10 formulation had the potential to probably be effective, as a result of a possible synergy between the known bio-abilities of each ingredient that has been used; than to try to discuss what has been previously tested and failed, on PUFA formulations and trials. In a way, it is our belief that the formulations are the ones that have been probably failed but not the PUFAs. It is widely known, accepted and well reported by Mehta (8), as well as by Farinotti (5, 6), that those studies are overloaded with crucial methodological limitation such as inappropriate study design, undefined endpoints, mixed multiple sclerosis (MS) type population, inappropriate statistics and many others. This is the actual statement by Mehta: "controlled and noncontrolled trials have produced mixed results regarding the efficacy of PUFAs in MS; however, these trials have several limitations that could partially explain the lack of a treatment effect"; also, "finally, relative uncertainty exists in relation to the optimal dosing of omega-3 and omega-6 PUFAs" (8).

It is well defined (5, 6, 7) that the most probable and major issue of the puzzle is to elucidate the correct formulation between the specific PUFAs to be used for a possible efficacy and for conclusive results on the relation of these specific PUFAs with MS. Mehta reports: "Despite the lack of definitive evidence that PUFAs can be beneficial in MS, the anti- inflammatory potential of these agents is intriguing" (8). Although, we believe that specific antioxidant vitamins have to be co-supplied along with other specific essential molecules of the omega-6 series, among other structured molecules, as in PLP10. The scientific plausibility of these ingredients is recognized out of numerous scientific published reports but the correct formulation is the missing clue.

Moreover, it is obvious that major issues and novelties that are discussed in the PLP10 paper have been gone unnoticed. This could be the reason that someone can fall in the trap and try to compare the PLP10 intervention/formula with other PUFA blends (using different EPA, DHA, GLA formulations) for MS therapy that have been previously clinically tested. For example, we believe that it is not scientifically correct to compare the OFAMS study or any previous PUFA study on MS with the PLP10 study or draw any conclusions as a result of comparing the two studies. Otherwise it is like comparing peaches and apples; except if as a result of someone using EPA, DHA, LA and GLA among others and in different quantity, quality, ratio, etc., are considered all the same anyway. But then we are not discussing Biochemistry or bio-metabolism but something else. In that case let us go years back and remember the Dopamine story. Through research, Dopamine was reported as a potential biomolecule for efficacy on Parkinsons' disease. Many studies have been conducted in order to prove those research findings (of Dopamine as a therapeutic drug on Parkinsons' disease) without conclusive efficacy until one researcher (George Constantin Cotzias, L-Dopa treatment) considerably increased the quantity/dosage of it and the efficacy issue has been resolved.

The OFAMS and PLP10 studies in reality are experimenting on two completely different PUFA "cocktail" formulations and through two completely different study designs. The OFAMS daily dose of the EPA (1350 mg) was almost in double the ratio compared to the DHA (850 mg) (a very low dosage, in our opinion anyway); that means EPA: DHA, 2:1 wt/wt and without any other ingredient in the supplements, but only those two specific omega-3 PUFAs. Moreover, an immediate effect (within the first 6 months on intervention) was expected since the study design included a single endpoint at 6 months, changing then to the addition of interferon; and this six month- period is reported as an evaluation for monotherapy (2). In our opinion this is an extremely short period for an efficacy indication as a result of an orally consumed PUFA formulation. All of these parameters are contradicting to our study philosophy and the therapeutic approach. Our philosophy was primarily focusing on the evaluation of the involved biochemical network of events that are probably simultaneously participating (contributing) in the pathogenesis. The holistic, systems medicine approach, as we have been discussing it. Our formula has been prepared to contain exactly the opposite ratio of those specific ingredients (EPA: DHA, 1: 3 wt/wt) than the ratio of those ingredients in the OFAMS study; 6 times more than the total daily quantity of the EPA + DHA used in the OFAMS study, in 1:1 wt/wt ratio of the total omega-3 to the total omega-6 content within the PLP10 formulation in contrast to the OFAMS study supplements; not to discuss the additional ingredients of the PLP10 formulation (2, 1). All of these specificities concerning the PLP10 formulation have been used for a specific purpose and have been based on a biochemical rational; believing, as explained in the article and in the supplementary data, on the potential manipulative abilities by each one of those ingredients on the involved network of bio- mechanisms and factors in the MS pathology(from the dietary factors, the genes involved, the immunological and pro/anti-inflammatory mediators up to the triggering of the reparatory mechanisms).

It is true that the intervention A which included all PUFAs and other specific fatty acids, as in PLP10 (intervention B), had no any significant efficacy but the same is true for the intervention C that included only gamma-tocopherol but no vitamin E (alpha-tocopherol). The primary evaluation of this specific observation is the reason behind the conclusion that this significant positive efficacy of PLP10, on both the annual relapse rate and disability progression, might be the result of a synergistic effect of all ingredients within the PLP10 "cocktail" formula on the total network of events in the pathophysiology of MS. It is our strong belief that most (if not all) of the previous studies on the PUFAs are associated with several important limitations. Moreover, crucial parameters that are concerning and related to the biochemistry of the essential PUFA supplements that are consumed orally (in relation to the bioavailability, ratio, quantities, quality, purity, chronotherapy, etc) are missing or ignored by the protocols and the designs of the previous studies.

It is a frowned upon for anyone to report conclusively that the EPA, DHA and/or LA and GLA cannot support/affect and or manipulate specific anti-inflammatory /reparative biomechanisms in neurodegenerative type of diseases in general and specifically MS when the data and results were collected out of studies associated with so many important limitations. The "problem" with the OFAMS study, in our opinion, is clearly the formulation [the ingredients used (focused only on omega-3 PUFA), dosage (minimal) and ratio (EPA in excess compared to DHA)]. Furthermore, we believe that the OFAMS study was not properly designed for a nutritional supplement formulation and it was associated with limitations regarding the chronotherapy, endpoint assignment and study length parameters (i.e. specific omega-6 PUFAs were missing as well as antioxidants and the study included an endpoint with an efficacy expectation in a very short time after the first dose of treatment). According to our overview for the pathophysiology of the disease, in relation to the aforementioned ingredients (within the supplements used in the OFAMS study), someone would probably expect increased inflammation activity as a result of such interventions, since increased quantities of free radicals would result from the additionally consumed PUFA without normalization of the antioxidants within the organism; especially in a body that is most probably suffering by significant antioxidant deficiency (8) and mostly within the first six months on treatment where the PUFA content begin to be normalized, thus forcing probably the excess release of arachidonic acid (inflammation initiator) from the cellular membranes.

Considerably high number of in vivo, in vitro and ex vivo published data are reporting strong positive results on all of the individual ingredients within the PLP10 formulation in relation to the biomechanisms involved in MS and the related anti-inflammatory, protective and reparative mechanisms. For example, Calder published several excellent papers (as well as review papers) (9, 10), Van Miteren (8), Lippi (11) and many others like Gallai (12), Endres (13), Gil ? (14) etc. To our knowledge, our intervention is novel and the only one that is containing such a blend of PUFAs and other specific fatty acids along with specific antioxidants, specifically including gamma-tocopherol and in such high dosage.

As a conclusion we strongly believe that the unexpected strong efficacy of PLP10 most probably is due to the synergistic effect of all ingredients within the intervention and not only due to vitamins. Once again, more conclusive results will be available upon completion of the present, phase III, large size, multicenter, double-blind, randomized, placebo-controlled, "MINERAL" clinical study that is in progress and is aiming to answer, hopefully, most of the aforementioned issues.

References 1 Pantzaris MC, Loukaides GN, Ntzani EE, Patrikios IS. A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double- blind, placebo-controlled proof-of-concept clinical trial. BMJ Open. 2013; 3 (4).

2 Omega-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Torkildsen O, Wergeland S, Bakke S, Beiske AG, Bjerve KS, Hovdal H, Midgard R, Lille?s F, Pedersen T, Bj?rnar? B, Dalene F, Kleveland G, Schepel J, Olsen IC, Myhr KM. Arch Neurol. 2012 Aug;69(8):1044-51

3 Bates D, Cartlidge NE, French JM, et al. A double-blind controlled trial of long chain n-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1989; 52 : 18-22.

4 Geldern G, Mowry EM. The influence of nutitional factors on the prognosis of multiple sclerosis. Nature Reviews Neurology. 2012; 8, 678- 689

5 Farinotti M, Vacchi L, Simi S, Di Pietrantonj C, Brait L, Filippini G.Dietary interventions for multiple sclerosis. Cochrane Database Syst Rev. 2012; 12: CD004192.

6 Farinotti M, Simi S, Di Pietrantonj C, et al. Dietary interventions for multiple sclerosis (Review). Cochrane Database Syst Rev 2007(1)CD004192.

7 Mehta LR, Dworkin RH, Schwid SR. Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis. Nat Clin Pract Neurol 2009;5:82-92.

8 Van Meeteren ME, Teunissen CE, Dijkstra CD, et al. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr 2005;59:1347-61.

9 Calder PC. n?3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006;83:S1505-19.

10 Calder P. Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases Mol. Nutr Food Res 2008;52:885-97

11 Riccio P. The molecular basis of nutritional intervention in multiple sclerosis: a narrative review. Complement Ther Med 2011;19:228- 37.

12 Gallai V et al. (1995) Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol 56: 143-153

13 Endres S et al. (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320:265-271

14 Gil A. Polyunsaturated fatty acids and inflammatory diseases. Biomed Pharmacother 2002;56:388-96.

Conflict of Interest:

The author response.