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EDUCATION AND DEBATE: Andrew G Renehan, Catherine Booth, and Christopher S Potten What is apoptosis, and why is it important? BMJ 2001; 322: 1536-1538 [Full text]

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Apoptosis

Ravi Goyal   (23 June 2001)

Apoptosis is crucial in atherosclerosis

James H F Rudd   (2 July 2001)

Fluoride and Apoptosis: Trading Dental Caries for Cellular Death?

Joseph Mercola, Cory A Mermer   (20 July 2001)

Apoptosis 23 June 2001
Ravi Goyal, SHO Orthopaedics Wythenshawe, Manchester Send response to journal: Re: Apoptosis	As well as giving a cellular basis for patholgical disease,the mechanism of apoptosis is a commonly asked question in the viva of the MRCS!!
Apoptosis is crucial in atherosclerosis 2 July 2001
James H F Rudd, BHF Clinical Research Fellow Addenbrookes hospital, Cambridge Send response to journal: Re: Apoptosis is crucial in atherosclerosis	The article by Renehan et al highlights the role of apoptosis in many human diseases. However, it also has a central role to play in the pathogenesis of atherosclerosis. The lipid core of advanced atherosclerotic plaques is made up of macrophage foam cells. These cells have a high rate of apoptosis, and once dead, contribute to plaque enlargement by releasing their lipid stores and thus increasing core volume. Additionally, vascular smooth muscle cells, vital to the structural integrity of the fibrous cap, are senescent and are prone to apoptosis(1,2). The rate of apoptosis is increased further by plaque inflammation, mediated especially by macrophages, in which the release of inflammatory mediators have direct and indirect pro-apoptotic effects on the smooth muscle cells, promoting plaque rupture and clinical events. Plaque rupture can therefore be thought of as occuring as a direct consequence of high levels of apoptosis in macrophages and smooth muscle cells within the plaque. Future therapies directed at reducing clinical events may work by reducing apoptosis in these cells. References 1. Bennett MR, Macdonald K, Chan SW, Boyle JJ, Weissberg PL. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res 1998; 82(6):704-712 2. Bennett MR, Littlewood TD, Schwartz SM, Weissberg PL. Increased sensitivity of human vascular smooth muscle cells from atherosclerotic plaques to p53-mediated apoptosis. Circ Res 1997; 81(4):591-599.
Fluoride and Apoptosis: Trading Dental Caries for Cellular Death? 20 July 2001
Joseph Mercola, Medical Director, Medical Researcher Optimal Wellness Center, Schaumburg, Illinois, USA, Cory A Mermer Send response to journal: Re: Fluoride and Apoptosis: Trading Dental Caries for Cellular Death?	When apoptosis or "programmed cell death" was first identified as a cellular function in 1972, water fluoridation in the United States had already been around for over two decades. Several years ago, fluoride (F) was found to induce apoptosis (1), joining a list of other apoptosis inducing substances, such as radiation, mercury and anti-cancer drugs. The mechanism of action is likely through activation of the enzyme caspase-3 (2). Although these discoveries may be important in the development of pharmacological agents to treat cancer or other diseases, it should cause a great deal of concern regarding current levels of F exposure. While F has long been known to be highly toxic, we find it most disturbing that it acts through apoptosis rather than necrosis, since the former requires genetic interference. As researchers stated last year "Even though fluoride toxicity is increasingly being considered to be important, very little information is available on the mechanism of action of fluoride." (2) Since apoptosis is potentially implicated in the development of neurological disorders such as autism, Alzheimer's, and schizophrenia (3, 4), this lack of understanding is concerning. A logical question would be if pregnant women consuming large amounts of F be increasing their unborn child's risk of autism? While this is unproven, it is biologically possible, especially considering the vital role of apoptosis in embryogenesis. This is especially relevant when one considers the fact that any benefit of water fluoridation in the reduction of dental caries is miniscule at best. In 1990, researchers from the National Institute of Dental Research in the US performed an epidemiological study and declared "The results suggest that water fluoridation has played a dominant role in the decline in caries and must continue to be a major prevention methodology." (5) However, a closer look at the study shows that the conclusion is not supported by the actual data. The difference in tooth decay was actually found to be 0.6 DMFS (Decayed, Missing, or Filled Surfaces). In other words, the tremendous benefit of fluoridation amounted to about one half of a single tooth surface, out of a total number of tooth surfaces of 128 (less than 0.5% difference). In addition, it is doubtful whether such a small difference is even statistically significant. The medical community really needs to ask itself exactly what their priorities should be. Considering the fact that apoptosis "sculpts the developing brain", as a review in Nature describes it (6), it needs to determined if we are willing to continue to recommend that children be subjected to the potential risk of water fluoridation for the meager benefits, if any, described above. How can we assure the public that it is perfectly safe, when the biological effects of fluoride are still in the process of being unraveled, even today? Cory Mermer Medical Researcher Joseph Mercola, DO Medical Director Optimal Wellness Center Schaumburg, IL References: 1. Hirano S, Ando M. Apoptotic cell death following exposure to fluoride in rat alveolar macrophages. Arch Toxicol 1996;70(3-4):249-51. 2. Anuradha CD, Kanno S, Hirano S. Fluoride induces apoptosis by caspase-3 activation in human leukemia HL-60 cells. Arch Toxicol 2000 Jul;74(4-5):226-30 3. Margolis RL, Chuang DM, Post RM. Programmed cell death: implications for neuropsychiatric disorders. Biol Psychiatry 1994 Jun 15;35(12):946-56. 4. Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000 Jun;108 Suppl 3:511-33 5. Brunelle JA, Carlos JP. Recent trends in dental caries in U.S. children and the effect of water fluoridation. J Dent Res 1990 Feb;69 Spec No:723-7. 6. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000; 407: 802-809.