Dr. Ron’s Research Review – January 26, 2011

This week’s research review contains information on activated charcoal, iron, and urinalysis.

Combination of oral activated charcoal plus low protein diet as a new alternative for handling in the old end-stage renal disease patients

         (Musso, Michelangelo et al. 2010)

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

         (Kell 2009)

Poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology, etc.

         (Kell 2010)

Urinalysis in Western culture: a brief history

         (Armstrong 2007)

Dr. Ron


Articles

Urinalysis in Western culture: a brief history

            (Armstrong 2007) Download

Today physicians use urine to diagnose selective conditions but from ancient times until the Victorian era, urine was used as the primary diagnostic tool. Laboratory medicine began with the analysis of human urine, which was called uroscopy and today is termed urinalysis. Uroscopy was the mirror of medicine for thousands of years. From a liquid window through which physicians felt they could view the body's inner workings. Numerous, somewhat accurate, physiologic theories arose from uroscopy. Then the importance of urinary diagnosis became exaggerated, and increasingly complex, until physicians required only the presence of urine, not patients, to diagnose disease. Uroscopy then escaped medical control, becoming first a home health aid and then a tool of uneducated practitioners. Thomas Brian led a medical rebellion against all uses of uroscopy and published the Pisse Prophet, a book that devastated uroscopy.

Combination of oral activated charcoal plus low protein diet as a new alternative for handling in the old end-stage renal disease patients

            (Musso, Michelangelo et al. 2010) Download

Chronic dialysis is a valid therapeutic option in very elderly ESRD patients, even though the decision to dialyze or not has little impact on survival. Additionally, very old patients usually do not agree with starting chronic dialysis. Even though, activated charcoal is a cheap treatment for working as adsorbent for nitrogenous products its utility is very limited. We studied the combination of a low protein diet and oral activated charcoal to reduce serum urea and creatinine levels in very old ESRD patients who had refused to start chronic dialysis. Nine lucid, very old > 80 years, ESRD patients who had refused to start dialysis were prescribed a treatment based on a combination of a very low protein diet and oral activated charcoal (30 gram/day). None of the patients had anuria, oliguria, edema, significant metabolic acidosis or hyperkalemia. None of them had significant gastrointestinal symptoms. After one week and ten months of charcoal use significant decrease in blood urea and creatinine levels was observed and none of them required emergency dialysis during this time. In conclusion, in patients more than 80 years of age low protein diet and oral activated charcoal may control the uremic symptoms effectively.


Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

            (Kell 2009) Download

BACKGROUND: The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. REVIEW: We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation).The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible.This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here. CONCLUSION: Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples

         (Kell 2010) Download

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-kappaB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.
References

Armstrong, J. A. (2007). "Urinalysis in Western culture: a brief history." Kidney Int 71(5): 384-7.

Kell, D. B. (2009). "Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases." BMC Med Genomics 2: 2.

Kell, D. B. (2010). "Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples." Arch Toxicol 84(11): 825-89.

Musso, C. G., H. Michelangelo, et al. (2010). "Combination of oral activated charcoal plus low protein diet as a new alternative for handling in the old end-stage renal disease patients." Saudi J Kidney Dis Transpl 21(1): 102-4.