Medical hypotheses
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B-type natriuretic peptide (BNP) is released from cardiac ventricles in response to increased wall tension in patients with heart failure. It has been used as a biochemical marker for the diagnosis of congestive heart failure. BNP is also increased in patients with acute myocardial infarction, and is associated with an increased risk of cardiovascular mortality in those with impaired left ventricular function after myocardial infarction. We hypothesized that an increase in BNP soon after acute myocardial infarction is an independent predictor for long-term prognosis in patients with no clinical signs of left ventricular function.
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In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development and progression of diabetic retinopathy. Bisphosphonates are potent inhibitors of bone resorption and are widely used drugs for the treatment of osteoporosis and osteolytic bone metastasis. ⋯ NADPH oxidase-derived reactive oxygen species (ROS) generation is required for the AGE-RAGE signaling in vascular wall cells, and small G protein Rac is a critical component of vascular NADPH oxidase complex. These observations let us to speculate that minodronate, a newly developed nitrogen-containing bisphosphonate, might be a promising remedy for treating patients with diabetic retinopathy by inhibiting the AGE-RAGE signaling pathways through suppression of ROS generation via inhibition of Rac prenylation. In this paper, we like to propose the possible ways of testing our hypotheses: (1) Does treatment with minodronate decrease the risk for the development and progression of diabetic retinopathy in osteoporotic patients? (2) If the answer is yes, is this beneficial effect of minodronate superior to that of other nitrogen-noncontaining bisphosphonates with equihypolipidemic properties? (3) Does minodronate treatment suppress NADPH oxidase-mediated ROS generation in retinas of diabetic animals? (4) Does treatment with pyridoxamine, a post-Amadori inhibitor of AGE formation, attenuate these beneficial effects of minodronate on diabetic retinopathy? These clinical and animal studies could clarify whether the use of minodronate is of benefit in patients with AGE-RAGE-related disorders such as diabetic retinopathy, even in the absence of osteoporosis.
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Brain neuronal dysfunction has been implicated in pathogenesis of migraine but direct evidence is lacking. Scintillating scotoma of migraine is generally believed to originate at the visual cortex. While cortical spreading depression is a relatively late physiological alteration in migraine, its protective role in neuronal ischaemia is increasingly being recognized. ⋯ Headache of migraine possibly arises from a similar mechanical deformation of the anterior eye segment followed by antidromic discharge in the trigeminovascular system. Lateralizing negative deficits such as homonymous hemianopia probably reflect vasospastic complications of migraine. A rational explanation for the most characteristic clinical features of migraine and a new template to elucidate the pharmacological basis of anti-migraine drugs is offered.