Medical hypotheses
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Over a decade ago, I formulated the hypothesis that cumulative effects of exposure to high intracranial pressure (ICP) may contribute to the development of Alzheimer's disease (AD), though not necessarily in an exclusive way. In addition to individual ICP characteristics (high 'physiological' ICP) and diseases causing ICP elevation, various activities with significant Valsalva effort, such as weightlifting and wind instrument playing, can generate very high ICPs. Recent studies of normal-pressure hydrocephalus (NPH), glaucoma and Alzheimer's disease provide supportive evidence for this hypothesis. ⋯ Recently, similarities in pathophysiology between glaucoma and AD have been noted, with increased processing of amyloid precursor protein (APP) and up-regulation of beta-amyloid protein expression in retinal ganglion cells (RGCs). Given this link between AD and glaucoma, evidence for a causal relationship between repetitive intermittent ICP elevations and AD is gained from research indicating that high resistance wind instrument playing raises IOP and may result in glaucomatous damage. To test the validity of the hypothesis that exposure to repetitive but nonsustained ICP elevations may predispose to AD a non-invasive, epidemiological study is proposed in this paper.
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Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. ⋯ Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.
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The disorders of Alzheimer's disease, vascular dementia and normal pressure hydrocephalus are all causes of dementia in the elderly population. It is often the case that it is clinically very difficult to tell these diseases apart. ⋯ It is proposed the manifestation of the dementia in any one patient is dependant on the way that the pulsations interact with the brain and its venous and perivascular drainage. This interaction is predominately dependant on the compliance of the craniospinal cavity and the chronicity of the increased pulse wave stress.
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Normal pressure hydrocephalus, Alzheimer's disease and syringomyelia appear to be completely unrelated diseases, however, they share a reduction in subarachnoid space compliance as part of their pathophysiology. This paper discusses the physiology of pulsatile fluid flow and its relationship to compliance/impedance. Unlike continuous or non-pulsatile flow where the vessel resistance and pressure gradient are the major determinants of the volume of fluid flowing, when the fluid flow in a vessel pulsates then the vessel compliance/impedance becomes important. ⋯ Therefore, there is an increase in outflow vessel impedance. The venous blood, CSF and interstitial brain/spinal cord fluid all have significantly pulsatile flow and an increase in the impedance of the fluid outflow in each disease would limit the volume of these fluids as they attempt to cross the subarachnoid space. It is hypothesised that a reduction in the efficiency of the outflow of venous blood, CSF and interstitial brain/spinal cord fluid would lead to the accumulation of CSF in NPH, cord fluid in syringomyelia and delay the excretion of beta amyloid via the interstitial drainage pathways in AD.
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Bone marrow-derived hematopoietic stem cells (HSC) can exhibit tremendous differentiation activity in numerous non-hematopoietic organs. This enigmatic process is called as 'stem cell plasticity' (SCP). HSC may promote structural and functional repair in several organs such as heart, liver, brain, and skeletal muscle via the SCP. ⋯ Activation of the local myocardial RAS after injury may be related to homing and engraftment of the HSC to the cardiac tissue. Regenerating myocardial tissue may exert regulatory functions on circulating or resident HSC via the locally active RAS. Understanding the exact molecular basis of SCP in relation to local tissue RAS could offer new frontiers in the better management of ischemic cardiac diseases.