Critique the below 3 each with appropriate research articles at least 3 with IF- at least 3.

1. The traditional Inuit (Eskimo) and Maasai diets contain very minimal amounts of phytochemicals (I tried some of their foods traveling in Kamchatcka/Chukotka and Kenia). What health issues, if any, would you expect to find in people consuming these diets? If possible, provide mechanistic explanations linking to phytochemicals.

2. It is interesting to me to see the progression of this research. The first three studies all used cells from the human breast carcinoma line, MCF-7, and all had a duration of 6 days. In 2004 Sergeev et al. found that in vitro genistein is associated with activation of calcium-dependent proteases which induce apoptosis in breast cancer cells. (1) Unlike B-estradiol which "triggers a transient Ca2+ response", the cells treated with genistein had a sustained increase in Ca2+.

In 2006 Sergeev et al. found that like genestein (and vitamin D), polymethoxylated flavones (PMFs) from orange peel were also associated with a sustained increase in intracellular Ca2+, which in turn activated the proteases calpain and calpain-dependent caspase-12,which induced apoptosis of the MCF-7 cells. (2, 3)

Building on knowledge from the previous studies, in 2007 Sergeev et al. demonstrated that hydroxylated PMF were more effective in both antiproliferative and proapoptotic effects in the MCF-7 cells. Interestingly, at day 6 there was no significant difference between apoptosis and cell proliferation between the hydroxylated PMF and the PMF. This shows that hydroxylation is likely necessary for enhancing PMF response in the MCF-7 cells. The hydroxylated PMF's were especially effective in inhibiting cell proliferation. The authors cite both increases in calcium influx across the cell membrane and mobilization of intracellular calcium stores as mechanisms for the sustained increase in intracellular calcium.

These three studies all support the hypothesis that increased intracellular Ca+ is associated with induction of apoptosis, therefore I do believe that animal studies are warranted. In vitro studies should also continue to more clearly define how PMF's cause a sustained increase in intracellular calcium of the breast cancer cells.

3. In addition to the quote identified above, the author of the article is bold enough to state, "the evidence also has implications for research. Antioxidants, folic acid, and B vitamins are harmful or ineffective for chronic disease prevention, and further large prevention trials are no longer justified."

The Fortmann study addressed changes in all-cause mortality, but did not address changes in morbidity. (2) For example, while, supplementation with B12 did not reduce mortality among healthy individuals, did it reduce the occurrence and/or delay the onset of cardiovascular disease? Additionally, the study did found little consistent evidence to support or refute a health effect on all-cause mortality with supplementation with vitamins A, C, or D, folic acid, selenium or calcium. The lack of available evidence makes errors more likely and dismisses the author's statement that there is sufficient evidence to advise against routine supplementation. It should also be noted that there are few fair or good quality studies available with the exception of vitamin E and beta-carotene. While there is a mechanistic basis for

micronutrient supplementation, it is possible that supplementation with only one or two components is not sufficient to affect the complex physiological system. Additionally, a multi-vitamin was defined as three or more ingredients and a number of the studies evaluated only included five ingredients. Thus it could be concluded that this was not an appropriate representation of a true multi-vitamin.

The Grodstein study utilizes information from the Physician's Health Study II, a double-blind, placebocontrolled, 2x2x2x2 factorial trial assessing beta-carotene, vitamin E, ascorbic acid and a multivitamin's role in prevention of chronic disease in male physicians (aged >50 years) (3). Despite a well-designed study, the information provided can only be generalized to a small population (males over the age of 50 with an MD). In general, this population is more likely to have a greater standard of living overall including access to healthcare, recreational programs, and high quality food choices; all of which impact the risk of chronic disease. The study does not adjust for these confounding variables.

The final study cited in the paper, includes only individuals with dementia. Lin et al. found only one study that demonstrated a decline in cognition with multi-vitamin supplementation (4). Additionally, there were only four studies that were of good quality the remaining were of fair quality and had various risks of bias. The instruments used in the study, such as the MMSE, have limited reproducibility in primary care.