Medical hypotheses最新文献

{"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":"2025-12-23","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":"Climate change and the decline in human core body temperature: A hypothesis of physiological adaptation","authors":"Nina Mehta ,&nbsp;Andy Goren","doi":"10.1016/j.mehy.2025.111866","DOIUrl":"10.1016/j.mehy.2025.111866","url":null,"abstract":"<div><div>Average human core body temperature has decreased over the past two centuries. While reduced infections and modern lifestyles have likely contributed to this observation, we hypothesize that increasing global temperatures as a result of human activity are driving a physiological adaptation by resetting thermoregulatory set points. This shift may reflect short-term plasticity rather than genetic evolution. Understanding these changes requires considering metabolic, immune, and demographic factors, as well as acknowledging limitations in historical temperature measurements. Recognizing this trend could reshape our understanding of human health in the context of climate change.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111866"},"PeriodicalIF":0.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841639","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":"Reinterpreting autism through the analogy of inflammation: a hypothesis of non-specific neurodevelopmental response","authors":"Zhengbing Zhou ,&nbsp;Saralah Devi Mariamdaran Chetiyar ,&nbsp;Beiyong Cui","doi":"10.1016/j.mehy.2025.111865","DOIUrl":"10.1016/j.mehy.2025.111865","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) is conventionally viewed as a discrete disease. This paper proposes an alternative hypothesis: ASD traits may represent the brain’s adaptive responses to early neurodevelopmental divergence rather than markers of a unified pathology. Drawing an analogy with inflammation, we suggest ASD symptoms are non-specific, stable outcomes of early Central Nervous System (CNS) perturbations, some impairing, others benign or advantageous. This hypothesis emphasizes multifactorial etiology involving genetic susceptibility, environmental exposure, and immune factors. Just as inflammation varies in severity and function, so too do ASD traits. By reframing autism as a symptom complex, not a singular disease, we support a shift away from causal reductionism and toward individualized care. This perspective offers a more integrative framework for understanding ASD and reduces stigma by recognizing neurodiversity. It also highlights implications for clinical practice and early intervention strategies.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111865"},"PeriodicalIF":0.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841716","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":"From perinatal thiamine insufficiency to growth-phase airway phenotypes: A developmental hypothesis on craniofacial growth, functional oral tongue space, and collapsibility","authors":"Björn U. Winter","doi":"10.1016/j.mehy.2025.111864","DOIUrl":"10.1016/j.mehy.2025.111864","url":null,"abstract":"<div><div>Craniofacial growth, oral posture, and airway collapsibility arise from interacting developmental, metabolic, and biomechanical factors, yet the potential contribution of perinatal micronutrient status remains underexplored. It is hypothesized that perinatal thiamine (vitamin<!--> <!-->B1) insufficiency, by constraining thiamine-dependent flux through pyruvate/α-ketoglutarate dehydrogenases and transketolase in the pentose phosphate pathway, creates a bio-energetic/redox bottleneck in cranial neural crest cells during critical windows of craniofacial morphogenesis and palatogenesis. The developmental phenotype is expected to include subtle maxillo-mandibular undergrowth and palatal shape changes that reduce functional oral tongue space, favor mouth breathing, and promote a downward resting position of the hyoid bone, thereby increasing upper airway collapsibility and sleep-disordered breathing (SDB) risk. Perinatal thiamine status is both measurable and modifiable. The model can be tested using biomarker-anchored cohorts, organoid/animal systems, and finite element simulations. Modern, highly processed diets may induce functional thiamine scarcity via increased demand, reduced availability, and increased losses, thereby priming early developmental risks even without frank deficiency. If corroborated, perinatal micronutrition plus interceptive functional/orthopedic care may lessen the burden of a hyoid-descent-prone airway phenotype while respecting SDB heterogeneity.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"207 ","pages":"Article 111864"},"PeriodicalIF":0.8,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841638","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":"2025-12-17","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":"Dysregulation of mitochondrial dynamics as a central mechanism driving diabetic peripheral neuropathy and a target for disease-modifying therapy","authors":"M.D. Pandareesh ,&nbsp;H.S. Bhumika","doi":"10.1016/j.mehy.2025.111855","DOIUrl":"10.1016/j.mehy.2025.111855","url":null,"abstract":"<div><div>Diabetic peripheral neuropathy (DPN) is among the most prevalent and disabling complications of diabetes mellitus, characterized by chronic pain, sensory loss, and neurodegeneration. Despite significant advances in diabetes care, DPN remains without disease-modifying therapy, as current treatments address only symptoms rather than underlying mechanisms. Mounting evidence implicates mitochondrial dysfunction as the central pathogenic event linking metabolic stress to neuronal injury. We hypothesize that dysregulation of mitochondrial dynamics, such as excessive fission, impaired fusion, defective mitophagy, and suppressed biogenesis, constitutes the key molecular driver of DPN. This imbalance results in mitochondrial fragmentation, oxidative stress, and energy failure within peripheral neurons. Mitochondrial balance restoration through modulation of the AMPK-SIRT1-PGC-1α signaling axis, normalization of fission–fusion balance, and enhancement of antioxidant capacity may therefore modify disease progression. This hypothesis is supported by various experimental and clinical data demonstrating altered mitochondrial morphology, reduced ATP production, and increased ROS generation in diabetic nerves. The hypothesis predicts that interventions targeting mitochondrial dynamics will preserve axonal integrity and restore bioenergetic function. Validation of this concept would shift DPN therapy from symptomatic relief toward mechanism-based, disease-modifying strategies.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111855"},"PeriodicalIF":0.8,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786531","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":"Can severe anaemia limit carbon dioxide clearance under acute carbon dioxide load","authors":"Sampath Gnanarathne ,&nbsp;Ashani Ratnayake ,&nbsp;U.A. Isurindi","doi":"10.1016/j.mehy.2025.111854","DOIUrl":"10.1016/j.mehy.2025.111854","url":null,"abstract":"<div><div>Carbon dioxide (CO₂) transport in blood is often underemphasized in clinical discussions compared to oxygen transport. Red blood cells and haemoglobin are integral to CO₂ carriage, especially via carbaminohaemoglobin and buffering systems. This hypothesis is based on delayed hypercapnic encephalopathy observed in anaemic patients after laparoscopic surgery using carbon dioxide pneumoperitoneum. We hypothesize that severe anaemia reduces the blood’s CO₂ carrying capacity, predisposing to hypercarbia under acute CO₂ loading conditions. The body has a large capacity to handle excretion of CO₂. This capacity may be significantly reduced in severe anaemia, but can be clinically apparent in acute exogenous CO₂ loads, such as the creation and maintenance of CO₂ pneumoperitoneum. This can lead to delayed clearance of CO₂ and hypercapnic encephalopathy. This hypothesis highlights the need for alternative perioperative strategies such as revising transfusion triggers and considering delayed extubation in vulnerable individuals.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111854"},"PeriodicalIF":0.8,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786534","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":"2025-12-14","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":"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":"2025-12-13","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}

{"title":"A dual-mRNA nanotherapy hypothesis for glioblastoma restoring PTEN and enabling EGFRvIII-specific immunity","authors":"K. Trideva Sastri ,&nbsp;Prabitha Prabhakaran ,&nbsp;G.S. Namratha ,&nbsp;M. Manjusri","doi":"10.1016/j.mehy.2025.111852","DOIUrl":"10.1016/j.mehy.2025.111852","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains a leading cause of cancer mortality within brain and central nervous system (CNS) tumours. The Global Burden of Disease (GBD) estimates 246,253 deaths from brain/CNS cancers worldwide in 2019, rising to ∼258,627 deaths in 2021, underscoring a growing global toll. In population-based registries, GBM accounts for ∼51.5 % of malignant primary brain tumours (U.S., 2017–2021), with poor outcomes despite standard therapy. Typical median survival is ∼12–15 months, with &lt;10 % five-year survival, highlighting an urgent unmet need. The study proposes to hypothesise a dual-payload, dual-targeted mRNA nanotherapy for PTEN (phosphatase and tensin homolog)-deficient, (epidermal growth factor receptor vIII) EGFRvIII − positive GBM that (i) restores PTEN to suppress oncogenic PI3K–AKT signaling and reduce immunosuppression, and (ii) introduces EGFRvIII as a tumour-specific neoantigen to enhance immune recognition. Molecular epidemiology supports this rationale: PTEN is altered in ∼33 % of GBMs (The Cancer Genome Atlas, TCGA), and EGFRvIII is present in ∼30 % of newly diagnosed GBMs. Our approach integrates in silico design (major histocompatibility complex MHC-I binding/processing optimisation, and ML codon optimisation), in vitro validation (PTEN rescue, PD-L1 down-modulation, enhanced EGFRvIII/MHC-I display, and T-cell cytotoxicity), and in vivo testing in orthotopic syngeneic models to demonstrate synergistic tumour control and survival benefits. A dual-ligand nanoparticle is proposed to cross the blood–brain barrier and home to GBM cells, addressing delivery and the “immune-cold” microenvironment to promote antigen spreading and durable immunity. If validated, this platform could convert GBM from an immune-cold to an immune-hot state, improve survival beyond current standards, and establish a generalisable nanomedicine framework that couples tumour-suppressor restoration with neoantigen-driven immunity for hard-to-treat cancers.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"206 ","pages":"Article 111852"},"PeriodicalIF":0.8,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786533","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}