Medical hypotheses
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Comment Letter
Consideration of medical research vs. scientific research.
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Large-scale randomised trials influence the clinical management of millions of patients throughout the world and are believed to be the most reliable source of evidence on which to base therapeutic decisions. But do they really deserve the accolades bestowed upon them? The decision to perform these studies implies that the treatment difference is expected to be small and, thus, that large numbers of patients are required to achieve statistical significance. This small treatment difference is a direct consequence of limited knowledge of the subject matter which precludes the formation of homogeneous classes of patients with respect to the outcome. ⋯ Large-scale randomised trials continue to be regarded as the gold standard of clinical research. This, of course, merely reflects the ability of powerful vested interests--in particular the pharmaceutical industry--to defy the sound arguments which demonstrate that the methodology of these studies is deeply flawed. Sooner or later, though, common sense must prevail.
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A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins contributes to the aging of proteins and to pathological complications of diabetes. Under hyperglycemic conditions in diabetes, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversible crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). ⋯ Since RAGE is a signal-transducing receptor for AGEs and subsequently evokes inflammatory responses in various types of cells, thus eliciting angiogenesis and thrombogenesis, we hypothesize here that blockade of RAGE expression by nifedipine may have therapeutic potentials in treatment of patients with various AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment reduce the development and progression of diabetic vascular complications? If the answer is yes, is this beneficial effect of nifedipine superior than that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease the incidence of melanoma and/or prolong the survival of patients with this devastating disorder? These prospective studies will provide further valuable information whether blockade by nifedipine of the AGE-RAGE signaling could be clinically relevant.
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Colorectal cancer is a major public health problem, being the second most common cause of cancer in developed countries. Several epidemiological studies have reported moderately increased risks of colorectal cancer in diabetic patients compared with general population. However, the underlying molecular link between diabetes and colorectal cancer remains to be elucidated. ⋯ These observations let us to hypothesize that AGEs could explain the molecular link between diabetes and colorectal cancer. In this paper, we would like to propose the possible ways of testing our hypotheses. Is elevation of serum AGE levels a risk factor for colorectal cancer in patients with diabetes? Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the risk for colorecetal cancer 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, reduce the risk for colorectal cancer as well? Furthermore, are increased levels of AGEs and RAGE in colorectal cancer associated with poor prognosis in patients with diabetes? These clinical studies could clarify whether the AGEs-RAGE interactions serve as a causal link between diabetes and colorectal cancer.