Medical hypotheses
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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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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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Thromboembolism is considered the inciting cause of many vascular disorders including acute coronary syndrome (ACS), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and mesenteric ischemia. Adrenergia and inflammation are known to accompany these conditions, particularly among arterial thromboembolic disorders, but the teleologic basis of these associations remains poorly understood. We argue that thromboembolism may sometimes be the result, rather than the cause, of acute vascular events, and may be precipitated by underlying adrenergia. ⋯ Perhaps reducing adrenergia, rather than maintaining high cerebral perfusion pressure, may represent a counterintuitive strategy for treating stroke and for reducing reperfusion injury. Plausible mechanisms by which autonomic dysfunction may induce venous thrombosis are discussed, especially in those with baroreceptor dysfunction, immobilization, or dehydration. Unexplained hypercoagulability of cancer may also operate through tumor-induced adrenergia and inflammation.
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Tobacco exposure is implicated in many illnesses such as cardiovascular disease and cancer, but the mechanisms underlying these associations are poorly understood. The mechanisms by which tobacco induces pro-sympathetic and pro-inflammatory changes also remain elusive. Some studies have attributed these changes to the direct effects of nicotine, but such findings run counter to the pro-vagal, anti-inflammatory nature of the nicotinic pathway. ⋯ Tobacco-related cancers may be partly attributable to immunomodulatory properties of chronic nicotine exposure by dampening Th1 immunity and enabling tumoral evasion of immune surveillance. Other conditions associated with tobacco exposure may also operate through similar autonomic and immune dysfunctions. Therapeutic implications are discussed.
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Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. ⋯ Activation of the protein kinase R and subsequent nuclear factor-kappaB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein-Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.