Medical hypotheses
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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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It is plausible to assume that in the future science will form the compulsory core element both of school curricula and multi-disciplinary undergraduate degrees. But for this to happen entails a shift in the emphasis and methods of science teaching, away from the traditional concern with educating specialists and professionals. Traditional science teaching was essentially vocational, designed to provide precise and comprehensive scientific knowledge for practical application. ⋯ Specialist vocational science education will progressively be shifted to post-graduate level, in Masters and Doctoral programs. A multi-disciplinary and conceptually-based science core curriculum should provide an appropriate preparation for dealing with the demands of modern societies; their complex and rapidly changing social systems; and the need for individual social and professional mobility. Training in rational conceptual thinking also has potential benefits to human health and happiness, since it allows people to over-ride inappropriate instincts, integrate conflicting desires and pursue long-term goals.
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Editorial
The future of 'pure' medical science: the need for a new specialist professional research system.
Over recent decades, medical research has become mostly an 'applied' science which implicitly aims at steady progress by an accumulation of small improvements, each increment having a high probability of validity. Applied medical science is, therefore, a social system of communications for generating pre-publication peer-reviewed knowledge that is ready for implementation. However, the need for predictability makes modern medical science risk-averse and this is leading to a decline in major therapeutic breakthroughs where new treatments for new diseases are required. ⋯ Pure medical science would work most effectively and efficiently if practiced in many independent and competing institutions in several different countries. The main 'market' for pure medical science would be the applied medical scientists, who need radical strategies to solve problems which are not yielding to established methods. The stimulus to create such elite pure medical science institutions might come from the leadership of academic 'entrepreneurs' (for instance, imaginative patrons in the major funding foundations), or be triggered by a widespread public recognition of the probable exhaustion of existing applied medical science approaches to solving major therapeutic challenges.
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The widespread explanation of patophysiology of tension pneumothorax is that compression to the mediastinum by the progressively accumulating intrapleural air causes torsion at the atrio-caval junction, impaired filling of the right heart and circulatory arrest as potentially life-threatening complication. Some experimental studies on animals put into question such an explanation, suggesting that respiratory arrest due to hypoxia of the respiratory center, not a circulatory arrest, represents dominant life threatening feature. ⋯ respiratory arrest, preceding circulatory arrest, seems to be the principal life threatening condition in patients with progressive tension pneumothorax.
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Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. ⋯ In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.