Schneider SS, Pentecost BT, Banas AR
… +4 more, Dalier A, Narayanaswamy V, Gotschlich EC, Arcaro KF
Med Hypotheses
· 2025 Dec · PMID 41404433
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Chronic inflammation likely contributes to breast cancer risk, but epidemiologic studies are inconclusive. Two types of inflammatory episodes in breast tissue, referred to here as clinical mastitis and subclinical mastit...Chronic inflammation likely contributes to breast cancer risk, but epidemiologic studies are inconclusive. Two types of inflammatory episodes in breast tissue, referred to here as clinical mastitis and subclinical mastitis, have received little to no attention as risk factors for breast cancer. Clinical mastitis represents an painful inflammatory state of the breast that in most cases will be quickly treated and resolved. In contrast, subclinical mastitis remains undetected in most cases and may represent inflammation. Based on the concentration of sodium (Na) and cytokines in milk, several publications suggest that subclinical mastitis is relatively common and can persist for extended periods. We propose that subclinical mastitis is a modifiable risk factor for breast cancer. This chronic subclinical inflammatory profile in breast tissue may cause genetic instability and perturb epigenetic mechanisms leading to cancer. We suggest studies to determine the extent that subclinical mastitis is associated with breast cancer risk.
Darvish MR, Sung J, Williamson JN
… +3 more, Mulyana B, Chen X, Yang Y
Med Hypotheses
· 2025 Jun · PMID 40574877
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Previous studies have found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract and the hyperexcitability of the cortico-reticulospinal tract at the hemisphere opposite to th...Previous studies have found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract and the hyperexcitability of the cortico-reticulospinal tract at the hemisphere opposite to the lesion side, i.e., the contralesional hemisphere. While motor deficits and recovery mechanisms have been extensively studied, the role of sensory feedback in motor control has received less attention. We hypothesize that sensory-motor reorganization influences the stretch reflex and contributes to post-stroke spasticity. Effective motor function depends on the sensorimotor network, which integrates proprioceptive, tactile, and vibratory sensory inputs to guide movement and facilitate sensorimotor plasticity. Following stroke, these sensory pathways may undergo significant reorganization, leading to disrupted feedback loops and maladaptive changes in motor pathways. Recent studies have reported a hemispheric shift of somatosensory processing following a stroke. We propose to test our hypothesis by quantitatively analyzing the extent to which reorganization of sensory feedback pathways affects the stretch reflex. Testing our hypothesis will provide novel insights into the pathophysiological mechanisms underlying post-stroke spasticity. This will facilitate the development of customized rehabilitation strategies tailored to individual patient needs including improving their sensory feedback during movement exercise and other therapeutical intervention.
Lee EJ, Tsang C, Pérez MLG
… +2 more, Abouzari M, Djalilian HR
Med Hypotheses
· 2025 Feb · PMID 42052332
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Central sensitization (CS) denotes aberrant processing of sensory stimuli within the central nervous system, wherein innocuous inputs activate pain pathways, leading to pain hypersensitivity. Features observed in CS cond...Central sensitization (CS) denotes aberrant processing of sensory stimuli within the central nervous system, wherein innocuous inputs activate pain pathways, leading to pain hypersensitivity. Features observed in CS conditions are often present in patients with long COVID, suggesting a potentially shared pathophysiological mechanism. We hypothesize that elevated levels of calcitonin gene-related peptide (CGRP), a neuropeptide known to play an integral role in the development of CS, may contribute to the persistent symptoms observed in long COVID. This article explores the role of CGRP within the context of CS and proposes its potential relationship to long COVID.
Williamson JN, Mulyana B, Peng RH
… +4 more, Jain S, Hassaneen W, Miranpuri A, Yang Y
Med Hypotheses
· 2024 Nov · PMID 39525858
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Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract and a maladaptive increase in indirect contralesional motor pathways. How the somatosensory system...Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract and a maladaptive increase in indirect contralesional motor pathways. How the somatosensory system adapts to the change in the use of motor pathways and the role of adaptive sensory feedback to the abnormal movement control of the paretic arm remains largely unknown. We hypothesize that following a unilateral stroke, there is an adaptive hemispheric shift of somatosensory processing toward the contralesional sensorimotor areas to provide sensory feedback support to the contralesional indirect motor pathways. This research could provide new insights related to somatosensory reorganization after stroke, which could enrich future hypothesis-driven therapeutic rehabilitation strategies from a sensory or sensory-motor perspective. Understanding how somatosensory information shifts may provide a target for a novel method to therapeutically prevent and mitigate the emergence and expression of upper limb motor impairments, following a stroke.
Med Hypotheses
· 2024 Sep · PMID 39372948
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While many risk factors are modifiable, there remains a compelling need for novel approaches to prevent cognitive impairment. We propose that unstable carotid plaque causes microemboli that, in turn, cause microinfarcts...While many risk factors are modifiable, there remains a compelling need for novel approaches to prevent cognitive impairment. We propose that unstable carotid plaque causes microemboli that, in turn, cause microinfarcts and other adverse pathophysiological cerebral processes, which individually do not manifest clinically but cumulatively manifest as cognitive decline and ultimately cognitive impairment. Animal models support multiple cerebral microemboli having adverse effects on cognition. By addressing the source for microembolization by endarterectomy or stenting, patients with high-grade atherosclerotic stenosis may have better cognitive outcomes. If our hypothesis is verified, then treatment of carotid plaque at elevated risk of generating cerebral microemboli would be effective in preserving cognition, regardless of whether the stenosis is high-grade or causing cerebral hemispheric hypoperfusion.
Zhu CS, Chen W, Qiang X
… +3 more, Lou L, Li J, Wang H
Med Hypotheses
· 2024 May · PMID 38617026
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Inflamm-aging is a condition of low-grade and chronic systemic inflammation characterized by a systemic increase in multiple inflammatory biomarkers such as tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive p...Inflamm-aging is a condition of low-grade and chronic systemic inflammation characterized by a systemic increase in multiple inflammatory biomarkers such as tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), and CXCL9 (MIG) in experimental and clinical settings. However, despite the recent identification of extracellular procathepsin L (pCTS-L) as a novel mediator of inflammatory diseases such as sepsis, its possible role in inflamm-aging was previously not investigated. In the present study, we compared blood levels of pCTS-L and other 62 cytokines and chemokines between young and aged Balb/C mice by Western blotting and Cytokine Antibody Arrays. In light of the surprising finding of a marked increase in blood pCTS-L levels in aged mice, we propose that blood pCTS-L levels may serve as another biomarker of inflamm-aging. Given the capacity of pCTS-L in inducing various cytokines (e.g., TNF and IL-6), it will be important to test the hypothetic role of pCTS-L in inflamm-aging under experimental and clinical conditions.
Med Hypotheses
· 2024 Apr · PMID 38585412
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Duchenne Muscular Dystrophy (DMD) is marked by genetic mutations occurring in the DMD gene, which is widely expressed in the cardiovascular system. In addition to developing cardiomyopathy, patients with DMD have been re...Duchenne Muscular Dystrophy (DMD) is marked by genetic mutations occurring in the DMD gene, which is widely expressed in the cardiovascular system. In addition to developing cardiomyopathy, patients with DMD have been reported to be susceptible to the development of symptomatic hypotension, although the mechanisms are unclear. Analysis of single-cell RNA sequencing data has identified potassium voltage-gated channel subfamily Q member 5 (KCNQ5) and possibly ryanodine receptor 2 (RyR2) as potential candidate hypotension genes whose expression is significantly upregulated in the vascular smooth muscle cells of DMD mutant mice. We hypothesize that heightened KCNQ5 and RyR2 expression contributes to decreased arterial blood pressure in patients with DMD. Exploring pharmacological approaches to inhibit the KCNQ5 and RyR2 channels holds promise in managing the systemic hypotension observed in individuals with DMD. This avenue of investigation presents new prospects for improving clinical outcomes for these patients.
Med Hypotheses
· 2024 Feb · PMID 40303985
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Cardiogenic dementia (CD), recognized since the late 1970s, manifests as altered consciousness and cognition due to heart conditions. Its elusive molecular mechanisms present diagnostic and management challenges. Emergin...Cardiogenic dementia (CD), recognized since the late 1970s, manifests as altered consciousness and cognition due to heart conditions. Its elusive molecular mechanisms present diagnostic and management challenges. Emerging research implicates ryanodine receptor type 2 (RyR2) mediated intracellular Ca2+ leaks in myocardial infarction (MI)-linked cognitive impairment. We hypotheses that intravenous delivery of neuron-targeted exosomes loaded with RyR2-targeting siRNA (si-RyR2) to cerebral regions could rectify Ca2+ imbalance, curbing neurotoxic protein generation tied to CD. To investigate, si-RyR2 exosomes will be administered to MI-induced mice, with hippocampal samples analyzed for Ca2+ levels, β-amyloid, and p-tau. Results hold promise for advancing CD treatment insights.
Pernomian L, Tan W, McCarthy C
… +1 more, Wenceslau CF
Med Hypotheses
· 2023 Oct · PMID 37744557
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The major pathophysiological characteristic of hypertension is the occurrence of small artery remodeling and endothelial dysfunction. There is also solid evidence showing that microcirculation abnormalities occur prior t...The major pathophysiological characteristic of hypertension is the occurrence of small artery remodeling and endothelial dysfunction. There is also solid evidence showing that microcirculation abnormalities occur prior to the onset of hypertension. However, the mechanism(s) that trigger these changes prior to the elevation of blood pressure are unknown, and this may limit our ability to identify the cause of this disease and effectively treat it. In hypertension, as with aging, the vasculature becomes less susceptible to repair. One of the reasons is because endothelial cells start to deteriorate and present with exacerbated endothelial-to-mesenchymal transition (EndMT). Likewise, vascular smooth muscle cells (VSMC) also dedifferentiate into a synthetic phenotype, whereby they start to produce and secrete extracellular vesicles with a high migration and proliferation capacity for repairing vascular injury. Uncontrolled EndMT and/or VSMC phenotype switching contributes to vascular diseases, but the initial trigger for these conditions is unidentified. Importantly, EndMT and synthetic VSMC exhibit plasticity and can return to adopt an endothelial cell-like fate and present contractile phenotype again, respectively. Therefore, in this hypothesis we will take advantage of this plasticity, and we propose to manipulate this fate by inducing partial cellular reprogramming without passing through the pluripotent state. Specifically, we suggest that activation of the three master transcription factors, Oct-4, Sox-2, and Klf-4 (collectively termed OSK) will reprogram endothelial cells and prevent and reduce EndMT and VSMC synthetic phenotype. It was recently shown that activation of OSK was able to restore lost vision in old mice, and cancer risk was reduced by excluding c-Myc. Therefore, OSK treatment could provide new possibilities for vascular rejuvenation and treatment of hypertension.
Metcalf C, Klein SL, Read JM
… +8 more, Riley S, Cummings D, Guan Y, Kwok KO, Huachen Z, Jiang CQ, Lam TH, Lessler J
Med Hypotheses
· 2023 Sep · PMID 37744025
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Antibodies are a core element of the immune system's defense against infectious diseases. We hypothesize that antibody titres might therefore be an important predictor of survival in older individuals. This is important...Antibodies are a core element of the immune system's defense against infectious diseases. We hypothesize that antibody titres might therefore be an important predictor of survival in older individuals. This is important because biomarkers that robustly measure survival have proved elusive, despite their potential utility in health care settings. We present evidence supporting the hypothesis that influenza antibody titres are associated with overall survival of older individuals, and indicate a role for biological sex in modulating this association. Since antibody titres can be modulated by vaccination, these results have important implications for public health policy on influenza control in aging populations.
Med Hypotheses
· 2023 Jun · PMID 37144026
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The pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has brought with it many changes in the way with live, work, and socialise. One...The pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has brought with it many changes in the way with live, work, and socialise. One such change is an increase in the use of videoconferencing for communication with friends, family and work colleagues, and doing presentations, while physically distancing. We demonstrate an increase in the use of ring lights during the pandemic, and argue that this increased exposure to blue light may lead to a growing burden of macular degeneration in coming years.
Med Hypotheses
· 2023 Apr · PMID 37007799
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Recent lines of evidence suggest the intriguing hypothesis that consuming common culinary herbs of the mint family might help prevent or treat Covid. Individual citizens could easily explore the hypothesis using ordinary...Recent lines of evidence suggest the intriguing hypothesis that consuming common culinary herbs of the mint family might help prevent or treat Covid. Individual citizens could easily explore the hypothesis using ordinary kitchen materials. I offer a philosophical framework to account for the puzzling lack of public health messaging about this interesting idea.
Med Hypotheses
· 2023 Feb · PMID 36742015
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Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVI...Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19.
Med Hypotheses
· 2023 Feb · PMID 36718314
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Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 u...Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (-mRNAs) is impeded. Sustained presence of -mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the -mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of -mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.
Med Hypotheses
· 2023 Jan · PMID 36540082
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Patients with diabetes often have severe hyperglycemia triggered by novel coronavirus disease 2019 (COVID-19). Insulin treatment should be the main approach to the control of acute hyperglycemia in patients with severe a...Patients with diabetes often have severe hyperglycemia triggered by novel coronavirus disease 2019 (COVID-19). Insulin treatment should be the main approach to the control of acute hyperglycemia in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, clinical investigation found that insulin treatment is associated with a significant increase in mortality risk in patients with diabetes and SARS-CoV-2 infection. The reason for this high mortality rate remains obscure. Previous studies have demonstrated that insulin is an activator of Na/H exchanger (NHE) which could decrease extracellular pH and increase intracellular pH and glycolysis. Here, the author emphasizes insulin may contribute to SARS-CoV-2 cell entry and multiplication in host cells through activation of Na/H exchange. Additionally, the inhibition of Na /H exchange activity or glycolytic flux can result in reduced mortality in patients with COVID-19 and diabetes mellitus during insulin treatment.
Walters AS, Li Y, Karroum EG
… +5 more, Champion D, Weinstock LB, Bagai K, Afrin LB, Spruyt K
Med Hypotheses
· 2022 Oct · PMID 36505961
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Restless Legs Syndrome (RLS) is characterized by bothersome leg discomfort accompanied by an urge to move to obtain relief and symptoms are worse at night and on lying down. There is at least partial and temporary relief...Restless Legs Syndrome (RLS) is characterized by bothersome leg discomfort accompanied by an urge to move to obtain relief and symptoms are worse at night and on lying down. There is at least partial and temporary relief with activity. It is also an opioid responsive disorder, often accompanied by iron deficiency with or without anemia, and inflammation may be a precipitating factor in some cases. We created two in-vivo opiate receptor knock out mouse models of RLS - a triple opiate receptor knock-out mouse and a mu opiate receptor knock-out mouse. Both sets of animals were restless during the sleep period as is also true of RLS. Both of our knockout models showed statistically significantly decreased Hemoglobin and Hematocrit indicating anemia and both models showed statistically significant decreases in serum iron suggestive of either iron deficiency anemia or inflammatory anemia. The rest of the hematologic studies were not consistent enough to determine which of these two types of anemia was present in either model. An additional experiment in normal wild type mice showed a statistically significant decrease in serum iron when an opiate receptor blocker was used. To our knowledge this is the first demonstration that deficiency of endogenous opioids might play a role in the production of anemia. Our hypothesis is that an intact endogenous opiate system is necessary for red cell homeostasis. The presence of opioid receptors both on red blood cells and on various immunologically based white blood cells suggest mechanisms by which deficiency in the endogenous opiate system could cause anemia of either the iron deficiency or inflammatory types. The administration of opioid agonists or antagonists to iron deficient cultures of red blood cell precursors is a next step in determining the role of the endogenous opiate system in the maintenance of red cell homeostasis and in the possible prevention of iron deficiency or inflammatory anemia where iron dysregulation is key.
Med Hypotheses
· 2022 Nov · PMID 36317071
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Interferons (IFN), first described 1957 by Isaacs and Lindemann, are antiviral proteins generated in cells after viral infections. One of several interferon-induced effector mechanisms is the so called 2-5A / RNaseL syst...Interferons (IFN), first described 1957 by Isaacs and Lindemann, are antiviral proteins generated in cells after viral infections. One of several interferon-induced effector mechanisms is the so called 2-5A / RNaseL system: Interferon is produced in the virus-affected cells and released. After binding to cell membrane receptors of adjacent cells, 2-5 A synthetase (oligoadenylate synthetase, OAS) is generated, attaches to dsRNA section areas of the viral RNA and catalyses the production of 2-5 oligoadenylates from ATP. In 2-5 oligoadenylates, several adenosine residues (3-4 and more) are combined via phosphodiester binding in the unusual 2'-5' positions of the riboses. 2-5 oligoadenylates activate a RNaseL which degrades the viral RNA. Recently, characteristic gene mutations and other disturbances concerning the interferon system were detected in patients with severe COVID-19, leading to problems of 2-5 oligoadenylate synthesis and the activation of RNAseL. In order to circumvent these problems, we hypothesize that a direct application of 2-5 oligoadenylates, included in an inhalation spray, may be effective in treatment of severe COVID-19 infections of the respiratory system. In contrast to some other anti-COVID-19 drugs, oligoadenylates act inside the cells (like e.g. Paxlovid) and are therefore independent of cell surface mutations of the virus. For confirmation of our hypothesis, proof of concept investigations in vitro are suggested, before a possible clinical application can be considered.
Bax A, Shen Y, Kakeshpour T
… +1 more, Fennelly KP
Med Hypotheses
· 2022 Nov · PMID 36317052
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Migration to the lungs of an initial upper airway infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other respiratory pathogens can lead to pneumonia, associated with progression from mild to...Migration to the lungs of an initial upper airway infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other respiratory pathogens can lead to pneumonia, associated with progression from mild to severe symptoms. Chemical pneumonitis or bacterial pneumonia may be caused by the 'macroaspiration' of large volumes of oropharyngeal or gastroesophageal secretions into the lower respiratory tract. 'Microaspiration', , a similar mechanism but involving much smaller amounts of oropharyngeal secretions, is considered the pathogenetic mechanism for most pneumonias, including that associated with COVID-19. Here, we hypothesize an alternative mechanism: Rather than by microaspiration, these fluids enter the lungs as microdroplets that are generated by snoring and then carried by the inspired airstream. Laboratory measurements indicate that snoring generates (a) comparable numbers and sizes of oral fluid droplets as loud speaking and (b) total fluid quantities that are similar to those reported for microaspiration. Snoring propensity is strongly correlated to known risk factors for severe COVID-19, including male gender, age, obesity, diabetes, obstructive sleep apnea, and pregnancy. Therefore, more research is urgently needed to determine if various methods that decrease snoring can prevent progression to pneumonia after initial infection of the upper airways.