Medical hypotheses最新文献

{"title":"Creatine insufficiency as an energetic amplifier of brainstem dysfunction in ME/CFS and long COVID","authors":"Nikola Todorovic","doi":"10.1016/j.mehy.2025.111868","DOIUrl":"10.1016/j.mehy.2025.111868","url":null,"abstract":"","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111868"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sickle Cell Crisis – Home Oxygen in the Golden Half Hour, can prevent or stop a crisis, prevent complications and change the trajectory of disease","authors":"Sota Omoigui","doi":"10.1016/j.mehy.2025.111869","DOIUrl":"10.1016/j.mehy.2025.111869","url":null,"abstract":"<div><div>Reversible sickle cells (RSC) can become irreversible sickle cells (ISC)<!--> <!-->after repeated episodes of sickling.<!--> <!-->The reversible sickle cells can revert to their original flexible discoid shape when reoxygenated, but repeated or prolonged sickling can damage the cell membrane and make it impossible for the cells to return to their normal shape, becoming irreversible sickle cells. In-hospital oxygen therapy administered when patients are in a sickle cell crisis does not stop a crisis and does not reduce the pain. This is because patients are already in an irreversible sickle cell crisis; the cells have undergone cell damage and can no longer be resuscitated with oxygen. These sickle cells obstruct blood flow and have to be destroyed by the body in a process of hemolysis or phagocytosis. Such process leads to the known complications of sickle cell crisis including organ damage and severe anemia. However if oxygen is administered at home in the early stages of a crisis, preferably the golden half hour (30 mins), when the sickle cells are still reversible, it can restore the sickle cells to their normal discoid shape and prevents them from progressing to a critical mass of irreversible sickle cells, wherein the sickle cell crisis becomes established and intractable. The efficacy of home oxygen therapy in preventing and aborting a crisis in the golden half hour is very promising. Aborting a crisis would reduce ischemic and hemolytic complications, therefore lowering disability and mortality rates. In addition, it will reduce health care costs associated with SCD.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111869"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long COVID may be treatable with noradrenergic transmission reducing drugs","authors":"Paul J. Fitzgerald","doi":"10.1016/j.mehy.2025.111867","DOIUrl":"10.1016/j.mehy.2025.111867","url":null,"abstract":"<div><div>Long COVID remains a major public health problem throughout the world, even as cases of acute COVID infection have declined. With no well-established pharmacological treatments for long COVID, new approaches are urgently needed. This condition is associated with a wide range of deleterious symptoms, including: fatigue, post-exertional malaise, cognitive dysfunction, cardiovascular abnormalities such as tachycardia and hypertension, neurological abnormalities, and others. A unifying theme may be that norepinephrine and sympathetic nervous system signaling are systemically elevated in the condition, consistent with recent reports of autonomic abnormalities and systemic inflammation in long COVID. Further, many of the symptoms of long COVID, including neurological sequelae, may surprisingly be a consequence of elevated systemic noradrenergic signaling and could be treatable with existing noradrenergic transmission reducing drugs such as clonidine, guanfacine, propranolol, and prazosin. Since serotonin may counteract some of the physiological effects of norepinephrine, SSRIs (fluvoxamine, fluoxetine, citalopram, sertraline, paroxetine) may also be therapeutic in long COVID, where fluvoxamine has already shown therapeutic effects against acute COVID. Since acetylcholine may also counteract physiological effects of norepinephrine, the acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) may also have therapeutic properties in long COVID. If the above different classes of pharmacological agents can alone treat long COVID, then perhaps pairs of these drugs may have even greater therapeutic effects, if such pairs do not have significant metabolic interactions or side effects.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111867"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vestibular migraine, food triggers, and motion sickness: Revisiting an evolutionary hypothesis","authors":"Ariel A. Winnick ,&nbsp;Tzu-Pu Chang","doi":"10.1016/j.mehy.2026.111875","DOIUrl":"10.1016/j.mehy.2026.111875","url":null,"abstract":"<div><div>Patients with vestibular migraine (VM) are often prone to motion sickness, though the reason for this remains unclear. At the same time, migraine, and specifically VM, can be triggered by certain foods, but the underlying pathophysiology for this is also unknown. An earlier “toxin hypothesis” of motion sickness suggested that through evolution, the vestibular system developed as an alarm mechanism to detect ingested toxins, triggering the symptoms of motion sickness. Building on this idea, we revisit and extend it to an evolutionary hypothesis specifically linking VM and motion sickness. We propose that VM in migraineurs represents an overly sensitive alarm system capable of detecting even subtle neurotoxins in spoiled or degraded foods, substances commonly identified in modern society as migraine-triggers. This evolutionary hypothesis of VM provides a logical and contextual explanation for the observed links between VM, migraine-triggering foods, and motion sickness.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111875"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is hyperthermia mortality driven by maladaptive thermoregulation leading to hyperdynamic shock and secondary multi-organ failure?","authors":"Uri Gabbay","doi":"10.1016/j.mehy.2025.111853","DOIUrl":"10.1016/j.mehy.2025.111853","url":null,"abstract":"<div><div>Fever refers to an upward adjustment of the hypothalamic set-point temperature, to which the core body temperature subsequently equilibrates. In contrast, hyperthermia refers to excessive heat accumulation that raises the core body temperature above the hypothalamic set-point. Thus, an identical high core temperature may be induced by either fever or hyperthermia. Severe hyperthermia is a life-threatening condition with case-fatality exceeding 50 % in advanced stage. The prevailing explanation attributes death to direct thermal injury and systemic inflammatory response at hyperthermic temperatures above 40–41 °C. Some people may develop heat stroke while others not, under seemingly identical conditions. Infectious fever frequently reaches comparable temperatures without similar thermal injury and the consequent lethality. During the 2003 French heatwave, many elderly hyperthermia deaths occurred at relatively modest ambient temperatures (often &lt; 39 °C), suggesting that even moderate elevations can be fatal in frail individuals. Autopsy findings are often nonspecific, showing hypoperfusion and multi-organ injury rather than direct thermal damage. All these suggest additional mechanisms underline the fatal cascade in hyperthermia.</div><div>We propose a complementary hypothesis: while the trigger is hyperthermia, the proximate cause of death in hyperthermia may be a maladaptive cardiovascular response culminating in hyperdynamic, non-septic shock rather than direct or consequential multi-organ heat injury. Excessive heat activates thermoregulatory cutaneous and skeletal muscle vasodilation, considerably lowering systemic vascular resistance results in increase in cardiac output and redistribution of blood flow. When heat dissipation fails, sustained tachycardia and high-output circulation impose critical myocardial strain, leading to ischemia, metabolic exhaustion, contractile dysfunction, and ultimately destructive circulatory collapse. Multi-organ failure thus may arise secondarily from shock-induced hypoperfusion. This framework reconciles the lethality difference between fever and hyperthermia. The hypothesis may apparently explain elderly lethality during the 2003 heat wave in France. The hypothesis generates testable predictions, including early rises in cardiac biomarkers (e.g. copeptin, NT-proBNP), and neurological biomarkers (S100B and GFAP), and identifiable prolonged hyperdynamic circulation on hemodynamic monitoring. If validated, this model may redirect clinical management of hyperthermia beyond rapid cooling alone, to hemodynamic monitoring and adjunctive cardioprotective measures as central determinants of survival. It may improve early detection and management of at-risk patients.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111853"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145790076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipid nanoparticles for adsorptive sequestration of cocaine: a modeling hypothesis","authors":"Ryan Sasse","doi":"10.1016/j.mehy.2025.111857","DOIUrl":"10.1016/j.mehy.2025.111857","url":null,"abstract":"<div><div>This hypothesis presents a simple, design-level mass-balance estimate for anionic phospholipid nanoparticles engineered to capture small-molecule drugs, particularly cocaine, via surface binding. Using a Langmuir-type adsorption relation combined with a bulk mass-balance calculation, we obtain estimates linking liposome structural parameters to the nanoparticle dose required for a desired reduction in circulating cocaine. In an illustrative case, a suspension of 25 nm anionic liposomes can achieve a 95 % reduction in plasma cocaine if each square meter of liposome surface binds only ∼0.21 mg of cocaine. The model is intentionally minimal and does not attempt to account for detailed transport kinetics, metabolism, or multi-compartment pharmacokinetics, but instead provides an order-of-magnitude feasibility check for adsorption-based detoxification.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111857"},"PeriodicalIF":0.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145790077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naturally aged rats, characterized by persulfidation decline, provide an adequate translational preclinical model for BPH: A hypothesis","authors":"Marko Miler ,&nbsp;Vladimir Mijajlović ,&nbsp;Milica Vukojević ,&nbsp;Marija Mojić ,&nbsp;Branko Filipović ,&nbsp;Jasmina Živanović ,&nbsp;Vladimir Ajdžanović","doi":"10.1016/j.mehy.2025.111844","DOIUrl":"10.1016/j.mehy.2025.111844","url":null,"abstract":"<div><div>Benign prostatic hyperplasia (BPH) is a prevalent age-related disorder characterized by progressive prostate enlargement. Current preclinical models fail to replicate decline in persulfidation and chronic oxidative stress, inflammation, and cellular aging that drive human BPH pathology. We propose that a naturally aging rat model (middle to early old-aged) provides a superior alternative by mimicking BPH progression as a multifactorial aging-associated disease. Furthermore, we hypothesize that a decline in persulfidation (PSSH) may be a novel biomarker for oxidative stress susceptibility, allowing precision medicine approaches in BPH treatment. Naturally, aging models likely provide a more translationally relevant platform for preclinical drug testing, leading to improved therapeutic validation and regulatory approval. We propose multicenter validation of persulfidation biomarkers, integration into clinical trials, and their application in biomarker-guided BPH therapy. This hypothesis shifts BPH research towards a multi-dimensional aging-based disease model, facilitating biomarker-driven precision medicine strategies that could significantly improve treatment outcomes.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111844"},"PeriodicalIF":0.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does naturally absorbed lithium prevent amyloid deposition and inhibit abnormal tau phosphorylation in the brains of elderly female individuals?","authors":"Hirofumi Hirakawa ,&nbsp;Takeshi Terao ,&nbsp;Noriyuki Kimura","doi":"10.1016/j.mehy.2025.111845","DOIUrl":"10.1016/j.mehy.2025.111845","url":null,"abstract":"<div><div>Lithium, a known glycogen synthase kinase-3 (GSK-3) inhibitor, has been associated with reduced tau hyperphosphorylation, decreased β-amyloid peptide (Aβ) formation, and both neuroprotective and anti-inflammatory effects in Alzheimer’s disease (AD). We previously hypothesized that trace amounts of lithium might have a preventive effect against dementia and conducted an epidemiological study. We investigated the association between lithium levels in drinking water and the prevalence of AD across all 808 cities and wards in Japan. The study demonstrated a significant inverse association between lithium levels in drinking water and AD prevalence in females, but not in males or the overall population, after adjusting for several dementia-related factors. Building on the findings of our previous epidemiological research, we aim to conduct a clinical investigation. Accordingly, we propose the following hypothesis: in elderly female individuals without a history of psychiatric disorders, naturally absorbed lithium (i.e., exposure to environmental sources of lithium alone, such as food and drinking water) may prevent amyloid deposition, inhibit abnormal tau phosphorylation in the brain, and help preserve cognitive function.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111845"},"PeriodicalIF":0.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Controlled intracranial pressure elevation via cerebrospinal fluid infusion: a novel hemostatic hypothesis for hematoma expansion in traumatic brain contusion","authors":"Tianzun Li,&nbsp;Ji Xia,&nbsp;Yunpeng Dong,&nbsp;Jun Chen,&nbsp;Mingliang Ren","doi":"10.1016/j.mehy.2025.111837","DOIUrl":"10.1016/j.mehy.2025.111837","url":null,"abstract":"<div><div>Hematoma expansion (HE) following traumatic brain contusion has been recognized as a predictor of neurological deterioration and poor outcomes, but there is currently no effective hemostatic strategy to halt its progression. We propose a novel hypothesis: controlled infusion of artificial cerebrospinal fluid (aCSF) into the cerebrospinal fluid (CSF) space via an external ventricular drain (EVD) or lumbar drain to deliberately elevate intracranial pressure (ICP) within a defined therapeutic window. For instance, ICP could be increased to 25–30 mmHg over 30 minutes and then maintained at 20–25 mmHg for several hours. We expect that this sustained, global elevation will exert a tamponade effect on low-pressure microvascular bleeding within contused brain tissue, thereby promoting hemostasis. The rationale draws on the principle of compressive hemostasis, the demonstrated physiological tolerance to monitored ICP elevation when cerebral perfusion pressure is preserved, and the feasibility of adapting existing neurocritical care infrastructure. If validated, this minimally invasive, physiology-guided approach could address a critical therapeutic gap in early TBI management by limiting hematoma growth, which may reduce mortality, reoperation rates, and long-term disability.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111837"},"PeriodicalIF":0.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathogenesis of proximal caries: An expanded hypothesis","authors":"Frederico Barbosa de Sousa ,&nbsp;Nikolas Paganini Alves de Oliveira","doi":"10.1016/j.mehy.2025.111851","DOIUrl":"10.1016/j.mehy.2025.111851","url":null,"abstract":"<div><div>Proximal caries is the second most prevalent type of coronal caries, yet its current histopathogenesis theory presents many inconsistencies with oral biology. This paper proposes an expanded hypothesis (with four interrelated hypotheses) integrating overlooked anatomical and histological factors influencing lesion initiation, progression, and cavity formation and arrestment. First, the initiation and arrestment of proximal caries below the contact area would follow interdental gingival inflammation: swelling of the papillae reduces the entry of microscopic food particles that would otherwise clean the sub-contact area by abrasion, favoring biofilm accumulation. Repair of papillary gingival inflammation, by either toothbrushing or flossing, would resume the natural abrasive cleaning and arrest the initial lesion. Second, demineralization may begin in dentin before the enamel-dentin junction is demineralized, as microbial biofilm fluid undersaturated relative to dentin mineral diffuses through enamel pores, initiating a “first wave” of dentin demineralization preceding complete enamel layer demineralization. This would explain the epidemiological outcome of dark shadow subjacent to translucent enamel. Third, cavitated proximal lesions confined within the contact area may undergo natural arrestment through abrasive wear that removes cariogenic biofilm. Fourth, the radiographic aspect of structureless demineralized dentin depth (key for deciding when to treat restoratively) has been misled by an erroneous horizontal spread of dentin demineralization, hampering clinical lesion depth assessment. Together, these hypotheses reconcile clinical, radiographic, and histopathological inconsistencies in the current understanding of proximal caries. If confirmed, the expanded hypothesis may refine diagnostic criteria, improve management, and contribute to an evolutionary approach to proximal surface integrity.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111851"},"PeriodicalIF":0.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}