Medical hypotheses
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Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. ⋯ Since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the impairment of DDAH actions by AGEs could be one possible molecular mechanism of the ADMA elevation in diabetic patients. In this paper, we would like to propose the possible ways of testing our hypotheses. Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the levels of ADMA in diabetic patients? If the answer is yes, is this beneficial effect of metformin superior to that of other anti-diabetic agents with equihypoglycemic properties? Does treatment with pyridoxamine, a post-Amadori inhibitor (so-called Amadorins) of AGE formation, also reduce the levels of ADMA and subsequently improve endothelial dysfunction in diabetic patients? Are the ADMA-lowering effects of these agents associated with an increase of DDAH expression and/or activity in endothelial cells? These clinical studies could clarify whether AGEs are involved in the elevation of ADMA in patients with diabetes via suppression of DDAH expression and/or activity, thus providing a novel molecular mechanism for accelerated atherosclerosis in diabetes.
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Elderly surgical patients constitute a unique surgical group. They require special consideration in order to preempt the long term adverse effects of anesthesia. This paper examines the proposition that general anesthesia causes harm to elderly patients with its impact being felt long after the anesthetic agents are cleared from the body. ⋯ Its' occurrence may herald an increase in morbidity and mortality. Based on both human and animal data, this paper outlines a unitary theoretical framework to explain these phenomena. If this hypothesis proves to be correct, anesthesiologist should consider regional rather than general anesthesia for equivalent surgical procedures to reduce POCD and consequently achieving superior patient outcome.
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Reducing sugars can react non-enzymatically with the amino groups of proteins to form reversible Schiff bases, and then Amadori products. These early glycation products undergo further complex reactions such as rearrangement, dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives termed "advanced glycation end products" (AGEs). The pathological role of the non-enzymatic glycation of proteins has become increasingly evident in various types of disorders such as diabetic vascular complications, neurodegenerative diseases, and melanoma growth and metastasis. ⋯ Further, we have shown that atorvastain blocks the AGE-signaling to C-reactive protein (CRP) expression in human hepatoma cells in vitro via anti-oxidative properties. These observations led us to speculate that atorvastatin could be a promising remedy for treating patients with AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypotheses. (1) Does atorvastatin treatment reduce the development and progression of diabetic vascular complications with normocholesterolemic patients? If the answer is yes, is this beneficial effect of atorvastatin superior to that of other cholesterol-lowering agents with equihypolipidemic properties? (2) Are these beneficial effects of atorvastain attributed to its AGE-lowing properties? Does the blockade by atorvastain of the AGE signaling pathway, in other words, the suppression of 8-hydroxydeoxyguanosine and CRP levels by atorvastatin treatment, contribute to its cardioprotective properties? (3) Does the treatment with atorvastatin decrease the incidence of neurodegenerative disorders such as Alzheimer's disease and/or prolong the survival of these patients? (4) How about the effects of atorvastatin on the incidence of malignant melanoma? These prospective studies will provide further valuable information whether the blockade by atorvastatin of the AGE formation or the AGE-downstream signaling could be clinically relevant.
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Critically ill patients are at high risk of developing serious neurological dysfunctions including delirium and long-term neurocognitive impairment. Here a novel mechanism is proposed for this highly deleterious condition. A growing body of evidence has shown that critical illness and its treatment can lead to de novo cerebral atrophy including white and grey matter abnormalities, delirium, and neurocognitive decline. ⋯ In combination with exposure to other ICU related threats to neurocognitive function, prolonged decoupling of this circuit may lead to deleterious neurodegenerative consequences such as excitotoxicity. Over time this has the potential to result in apoptosis and long-term cognitive impairment. Delirium appears to be a good candidate for the causal mechanism of ICU related cognitive decline and may be a critical point of intervention.
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Editorial Historical Article
Measuring revolutionary biomedical science 1992-2006 using Nobel prizes, Lasker (clinical medicine) awards and Gairdner awards (NLG metric).
The Nobel prize for medicine or physiology, the Lasker award for clinical medicine, and the Gairdner international award are given to individuals for their role in developing theories, technologies and discoveries which have changed the direction of biomedical science. These distinctions have been used to develop an NLG metric to measure research performance and trends in 'revolutionary' biomedical science with the aim of identifying the premier revolutionary science research institutions and nations from 1992-2006. I have previously argued that the number of Nobel laureates in the biomedical field should be expanded to about nine per year and the NLG metric attempts to predict the possible results of such an expansion. ⋯ The University of Oxford, UK, was the only institution outside of the USA which featured as a significant centre of revolutionary biomedical science. Long-term success at the highest level of revolutionary biomedical science (and probably other sciences) probably requires a sufficiently large number of individually-successful large institutions in open competition with one another--as in the USA. If this model cannot be replicated within smaller nations, then it implies that such arrangements need to be encouraged and facilitated in multi-national units.