Pathophysiology : the official journal of the International Society for Pathophysiology最新文献

{"title":"Real-Time Single-Cell Measurement and Kinetic Modeling of Daunorubicin Uptake in Multidrug-Resistant Leukemia Cells Using a Microfluidic Biochip.","authors":"Yuchun Chen, Megan Chiem, Nandini Joshi, Paul C H Li","doi":"10.3390/pathophysiology33020028","DOIUrl":"10.3390/pathophysiology33020028","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Multidrug resistance (MDR) remains a major pathophysiological barrier to effective chemotherapy based on anthracyclines, including daunorubicin (DNR), in the treatment of leukemia. However, conventional population-level measurements of drug uptake do not resolve variability in uptake kinetics among individual leukemia cells, which may influence intracellular drug accumulation and therapeutic response. <b>Methods</b>: In this study, real-time DNR uptake was quantified at the single-cell level using a microfluidic biochip that enabled long-term cellular retention and continuous monitoring. Both wild-type drug-sensitive leukemia cells and a multidrug-resistant mutant overexpressing the P-glycoprotein (P-gp) efflux pump were examined. <b>Results</b>: Kinetic analysis revealed that DNR uptake in drug-sensitive cells was well described by a single dominant uptake process, whereas uptake in MDR cells required a model incorporating two kinetically distinct processes. In both cell populations, pronounced cell-to-cell variation was observed in uptake rates and intracellular drug retention, indicating substantial functional heterogeneity within phenotypically similar cells. This variability persisted following the treatment with an MDR inhibitor and obscured the differences between inhibitor-treated and untreated cells when the uptake was compared across different single cells. To overcome this limitation, a same-single-cell analysis (SASCA) approach was employed, enabling direct comparison of DNR uptake in the same individual cell before and after inhibitor exposure, thereby revealing enhanced intracellular DNR retention and accelerated uptake kinetics following inhibition. <b>Conclusions</b>: Together, these results demonstrate that real-time single-cell kinetic analysis reveals functionally relevant heterogeneity in multidrug-resistant leukemia cells and provides insight into the pathophysiology of MDR that cannot be obtained from population-averaged measurements.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypovolemic Shock in the Setting of Third Spacing with Concentric Left Ventricular Hypertrophy: A Physiology-Guided Management of Fluid Resuscitation-Case Report and Literature Review.","authors":"Akram M Eraky, Yasser Mokhtar, Guy Grabau, Adnan Khan, Mark Jarosz, Alisha Wright, Matthew Grounds, Kyle Kennedy","doi":"10.3390/pathophysiology33020027","DOIUrl":"10.3390/pathophysiology33020027","url":null,"abstract":"<p><p>Patients with preload-dependent conditions are at high risk of hemodynamic instability from both hypovolemia and hypervolemia. In hypovolemic states, the presence of third spacing may be misleading and obscure true intravascular volume status. Therefore, management of critically ill patients should be guided by a thorough understanding of physiology and pathophysiology to appropriately address hemodynamic derangements. Overreliance on rigid protocols and protocol-driven care without adequate clinical judgment may, in some cases, adversely affect patient outcomes. Herein, we present a case of hypovolemia-induced hypotension in the setting of third spacing and concentric left ventricular hypertrophy.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient Glycocalyx Remodeling by Intravenous Hyaluronidase in Atherosclerosis: A Hypothesis-Generating Review.","authors":"Andreas Pfützner, Tobias Gantner, Harald Burgard, Tilman Steinmeier, Eduard Stappler, Julia Jantz, Petra Wiechel","doi":"10.3390/pathophysiology33020026","DOIUrl":"10.3390/pathophysiology33020026","url":null,"abstract":"<p><p>Atherosclerosis remains the leading cause of death worldwide and imposes a major healthcare burden. Physiologically, elimination of cholesterol from the arterial wall depends on reverse cholesterol transport (RCT). RCT requires access to HDL and apolipoprotein A-I (ApoA-I) to lesional macrophages/foam cells. The endothelial glycocalyx is a dynamic and injury-sensitive layer of proteoglycans and glycosaminoglycans (including hyaluronan). It contributes to vascular barrier properties, leukocyte adhesion, mechanotransduction, and macromolecular transport. In atherosclerosis, glycocalyx structure and function are altered; this may facilitate entry/retention of atherogenic lipoproteins and may also alter transport conditions relevant to cholesterol efflux pathways. This article presents a mechanistic hypothesis: short, transient, systemic hyaluronidase exposure could temporarily remodel glycocalyx/extracellular matrix components and thereby facilitate conditions permissive for regulated transport processes relevant to RCT. However, the proposed link between glycocalyx remodeling and improved lesional cholesterol efflux remains theoretical. Direct in vivo evidence that the endothelial glycocalyx is a dominant barrier limiting HDL- or ApoA-I-mediated cholesterol efflux from plaque macrophages is currently limited. Moreover, glycocalyx degradation is widely associated with endothelial dysfunction, increased permeability, inflammation, and thrombosis, all of which could aggravate rather than ameliorate atherosclerosis. Human pharmacokinetic data indicate a very short plasma half-life of circulating hyaluronidase activity, suggesting that any systemic enzymatic effect is brief. Nevertheless, the biological consequences of repeated degradation-regeneration cycles, especially in high-risk states such as diabetes, inflammation, oxidative stress, or chronic kidney disease, remain incompletely understood. Evidence supporting clinical benefit in atherosclerosis is currently limited to heterogeneous animal experiments, historical uncontrolled reports, and a small number of anecdotal case observations, whereas randomized trials have only been performed in other settings such as acute myocardial infarction and do not establish efficacy for plaque regression. We therefore provide a balanced evaluation of knowns, uncertainties, alternative interpretations, potential risks, dosing unknowns, and a translational research agenda including mechanistic preclinical studies, biomarker development, imaging, and carefully designed early-phase clinical investigation.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards Global HPV Eradication: Single-Dose HPV Vaccination vs. Pseudoscience.","authors":"Reona Shiro, Ikuo Tsunoda","doi":"10.3390/pathophysiology33020025","DOIUrl":"10.3390/pathophysiology33020025","url":null,"abstract":"<p><p>Human papillomavirus (HPV) can cause cervical cancer. Global viral eradication relies on specific criteria, including a single host species and effective vaccines, a feat successfully achieved with smallpox and rinderpest. Although measles is also a candidate for elimination, its progress has been hindered by vaccine hesitancy based on misinformation about vaccine safety. Similarly, HPV is an ideal candidate for eradication due to its strict human infectivity and the proven vaccine efficacy in reducing cancer rates and establishing herd immunity. We highlighted the growing global consensus on single-dose HPV vaccination to improve feasibility and compliance with comparable effectiveness and safety to three-dose vaccination. Supporting this, we demonstrated that mice receiving a single HPV vaccine produced anti-HPV antibodies without a prolonged pro-inflammatory cytokine profile. On the other hand, in Japan, a nine-year suspension of proactive government recommendations occurred due to alleged adverse events termed \"HPV vaccination-associated neuro-immunopathic syndrome (HANS),\" drastically reducing vaccination rates, despite rigorous international studies have confirmed the vaccine's safety. Critical scientific evaluation demonstrated that HANS failed to meet the criteria for autoimmune diseases (Witebsky's postulates); no evidence has been presented that HANS is a novel autoimmune disease. The claim of molecular mimicry between HPV L1 and human proteins was based solely on flawed computational analyses. Furthermore, the hypothesis implicating a pathogenic role for aluminum adjuvants was unsupported by experimental evidence; HANS animal models were flawed methodologically and unreproducible experimentally. In summary, we believe that implementing worldwide HPV vaccination strategies, including gender-neutral and single-dose programs, as well as denouncing pseudoscientific claims hold the potential to eliminate high-risk HPV types globally.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining Obstructive Sleep Apnea: Multidimensional Phenotyping Beyond the Apnea-Hypopnea Index.","authors":"Harjinder Singh, Nida Qadir, Malti Bhamrah, William Rosales-Gonzalez, Paul Bhamrah, Naomi Ghildiyal, Brittany Monceaux, Cesar Liendo, Sheila Asghar, Jonathan Steven Alexander, Oleg Y Chernyshev","doi":"10.3390/pathophysiology33020024","DOIUrl":"10.3390/pathophysiology33020024","url":null,"abstract":"<p><p><b>Background:</b> Obstructive sleep apnea (OSA) is a complex and diverse disorder affecting almost one billion individuals worldwide. Severity of untreated OSA, measured by the apnea-hypopnea index (AHI), is noted to be associated with an increased all-cause and cardiovascular mortality. Although widely used, AHI insufficiently captures disease variability as there is a poor correlation of symptoms with the AHI. There lies individual susceptibility to the effects of OSA and that parameter alone poorly predicts cardiovascular outcomes without considering intermittent hypoxia and the hemodynamic effects of OSA. Recognition of clinical, polysomnographic, and neurophysiological phenotypes offers an opportunity to refine diagnosis, prognosis, and management strategies. <b>Methods:</b> We conducted a narrative synthesis of the literature involving 70 articles, focusing on quantitative and qualitative (Q2) clinical traits, polysomnographic parameters, and mechanistic insights that enable subclassification of OSA beyond AHI. Evidence from large cohorts, animal models, and pathophysiological studies were reviewed. <b>Results:</b> Phenotyping based on a Q2 analysis of polysomnographic respiratory event predominance, event duration, positional and REM dependence, hypoxic burden, and arousal characteristics reveals significant heterogeneity in risk profiles and therapeutic response. Apnea-predominant OSA correlates with a higher oxygen desaturation index and Epworth sleepiness scale. Hypopnea-predominant OSA correlates with a cardiometabolic disease burden and may show a more favorable response to surgical therapies. The duration of respiratory events is related to cardiovascular risk, and REM-predominant OSA independently predicts hypertension and adverse cardiovascular outcomes. Supine-predominant OSA demonstrates treatment responsiveness to auto-positive airway pressure and positional therapy. Respiratory effort-related arousals (RERAs), RERA-predominant OSA and the broader respiratory disturbance index (RDI) provide neurophysiological insight often missed by AHI-based classifications. Hypoxic burden, rather than AHI, emerged as a superior predictor of cardiovascular events and mortality. Finally, arousal frequency and periodic limb movements independently predict cardiovascular morbidity. <b>Conclusions:</b> Employing Q2-based phenotyping that incorporates clinical, polysomnographic, and neurophysiological markers improves risk stratification, prognosis, and individualized management of OSA. Future investigations should prioritize integrating phenotypic subclassification into diagnostic criteria and treatment planning to advance precision medicine in sleep apnea care.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Motor Development and Rehabilitation Outcomes in Apert Syndrome: Gross Motor Function Measures-Case Report.","authors":"Lorena Oreščanin, Zrinka Biloglav, Ivana Škrlec","doi":"10.3390/pathophysiology33010023","DOIUrl":"10.3390/pathophysiology33010023","url":null,"abstract":"<p><strong>Introduction: </strong>Apert syndrome is a rare genetic disorder characterized by craniofacial anomalies and limb malformations, often accompanied by neurodevelopmental abnormalities that can considerably affect motor development.</p><p><strong>Aim: </strong>The aim of this study was to document the progress in motor development of a girl with Apert syndrome, with an emphasis on assessing functional needs and evaluating the effects of a multidisciplinary rehabilitation approach.</p><p><strong>Materials and methods: </strong>Motor functions were evaluated using the Gross Motor Function Measure (GMFM-88) at 16 and 24 months of age. Rehabilitation consisted of an intensive physiotherapy program, Dynamic Movement Intervention (DMI), delivered in monthly cycles over eight months. The therapeutic approach focused on developing postural control, transitional positions, and functional mobility while stimulating sensorimotor integration and neuroplasticity.</p><p><strong>Results: </strong>The initial GMFM score was 29.00%, and the final assessment score reached 68.68%, representing a relative improvement of 136.83%. The most considerable progress was observed in sitting, crawling, and kneeling, with initial improvements in standing. Despite the limitations of this study, the results suggest a positive effect of early, intensive, and individualized rehabilitation combined with active family involvement.</p><p><strong>Conclusions: </strong>The outcomes highlight the importance of early assessment, continuous monitoring of motor development, and a multidisciplinary rehabilitation approach in children with Apert syndrome, with the GMFM serving as a valuable tool for evaluating gross motor function.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13029161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Sex, Age, and Inflammatory Cell Counts with Complicated Acute Appendicitis.","authors":"Said José Serrano Guzmán, Carlos Leyber Vargas Juárez, Marcos Hernández Gómez, José Roberto Luis Vásquez, Sergio Roberto Aguilar Ruiz, Juan Carlos Ramos Martínez, Joscelin Amaranta Macías Ríos, Edgar Gustavo Ramos Martínez, José Luis Cano Pérez, Jesús David Guzmán Ortiz, Martha Silvia Martínez Luna, Leticia Lorena Hernández González","doi":"10.3390/pathophysiology33010022","DOIUrl":"10.3390/pathophysiology33010022","url":null,"abstract":"<p><strong>Background/objectives: </strong>Sex and age influence inflammatory responses, but researchers have not fully characterized their combined association with complicated acute appendicitis (CAA). This study assessed the independent and interactive associations of sex, age, and inflammatory cell counts with CAA.</p><p><strong>Methods: </strong>We conducted a retrospective observational study of 708 patients with histopathologically confirmed uncomplicated appendicitis (UAA) or CAA. We analyzed demographic and clinical data, including preoperative complete blood counts, stratified by sex. We used multivariable logistic regression models with interaction terms to evaluate associations and possible effect modification by sex and age. We explored the direction and magnitude of these interactions by estimating marginal predicted probabilities.</p><p><strong>Results: </strong>The incidence of CAA was significantly higher in men than in women. In men with CAA, complete blood count analysis showed elevated neutrophil and monocyte counts and reduced lymphocyte counts. Male sex (odds ratio (OR) 2.197, 95% confidence interval (CI) 1.610-2.999), continuous age (1.017, 1.002-1.033), lymphocyte count (0.656, 0.526-0.820), monocyte count (1.551, 1.036-2.321), and platelet count (1.004, 1.001-1.006) were independently associated with CAA. Interaction analysis revealed significant interactions between neutrophils and both sex and age (<i>p</i> < 0.05), while lymphocyte counts showed significant interaction with age but not with sex.</p><p><strong>Conclusions: </strong>This study provides new insight into complex sex- and age-related immune cell patterns in CAA and may inform future diagnostic and management strategies by highlighting immune profile variability.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13028704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and Clinicoradiopathological Characterization of H3 K27-Altered Diffuse Midline Gliomas in Adults-A Retrospective Observational Study.","authors":"Kristof Babarczy, Bence L Radics, Lili Kiss, Alexandra Graczer, Bence Nagy, Sandor Dosa, Gyongyi Kelemen, Marton Balazsfi, Pal Barzo, Andras Voros, Peter Klivenyi, Levente Szalardy","doi":"10.3390/pathophysiology33010021","DOIUrl":"10.3390/pathophysiology33010021","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Diffuse midline glioma (DMG), H3 K27M-altered, represents a rare group of gliomas arising in midline structures of the central nervous system. Historically regarded as a pediatric entity, it is now increasingly recognized in adults. Although its relative prevalence among all midline diffuse gliomas and its clinical-radiological characteristics are well defined in children, these tumors remain less characterized in adults, and comparative evaluations with H3 K27 wildtype midline diffuse gliomas are limited. <b>Methods</b>: Consecutive adult patients with histopathologically confirmed diffuse glioma (WHO grade ≥ 2) diagnosed between 2016 and 2025 were retrospectively screened for midline tumor location, with systematic revision of imaging and pathology. For identified midline diffuse gliomas, comprehensive clinical, imaging, and immunohistochemical data were collected, and a detailed morphometric analysis was performed. H3 K27 alteration status was established immunohistochemically, with supplementary immunostaining when necessary. Descriptive and comparative analyses were conducted. <b>Results</b>: A total of 5% of the 541 adult diffuse gliomas were midline, and 23% of IDH wildtype midline gliomas were consistent with DMG, H3 K27-altered (all H3 K27M-mutant). The affected patients were significantly younger, and these tumors predominantly involved the thalamus and mesencephalon. Morphometric analyses revealed trends toward fewer high-grade features in H3 K27-altered tumors, with composite scores demonstrating significant discriminatory ability. The overall survival was not significantly different between groups but showed associations with ring-like enhancement as well as adjuvant and salvage therapies in the overall midline cohort. <b>Conclusions</b>: This study provides population-based prevalence estimates for DMG, H3 K27M-altered, and complements the limited literature with comparative clinical-radiological and morphometric data of potential prognostic relevance.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13028753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining Obstructive Sleep Apnea: Treatment in the Modern Era.","authors":"Jose Redondo, Kori B Ascher, Alexandre R Abreu","doi":"10.3390/pathophysiology33010020","DOIUrl":"10.3390/pathophysiology33010020","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Obstructive sleep apnea (OSA) is a highly prevalent and heterogeneous disorder associated with substantial cardiometabolic morbidity. Although continuous positive airway pressure (CPAP) remains first-line therapy, long-term effectiveness is frequently limited by suboptimal adherence. Advances in airway devices, surgical techniques, neuromodulation, and pharmacologic therapies have expanded the therapeutic landscape and created opportunities for individualized, mechanism-based treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a selective, narrative review with structured quantitative synthesis of randomized controlled trials, comparative cohorts, long-term follow-up studies, registries, and mechanistic investigations addressing OSA therapies beyond CPAP. Evidence spanning oral appliances, upper-airway and skeletal surgery, hypoglossal nerve stimulation, neuromuscular electrical stimulation, positional therapy, and pharmacologic interventions targeting metabolic and non-anatomical endotypes was integrated. Outcomes of interest included apnea-hypopnea index (AHI), oxygenation, blood pressure, patient-reported symptoms, durability, safety, and real-world adherence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Mandibular advancement devices (MADs) consistently reduced AHI relative to placebo and produced symptom relief comparable to CPAP in mild-to-moderate OSA, largely due to superior adherence. Palatal surgery yielded meaningful short-term improvement in selected patients but demonstrated limited long-term durability. In contrast, maxillomandibular advancement (MMA) achieved the largest and most durable reductions in OSA severity, with efficacy comparable to CPAP and superior to other surgical modalities in appropriate skeletal phenotypes. Hypoglossal nerve stimulation (HNS) produced substantial, durable improvements in AHI and symptoms with high adherence, supported by randomized trials, long-term follow-up, and real-world registry data; newer bilateral and proximal stimulation systems may further broaden candidacy. Neuromuscular electrical stimulation and positional therapy provided modest, phenotype-dependent benefits, primarily as adjunctive or early-stage interventions. A major advance is the emergence of metabolic and endotype-targeted pharmacotherapy: longitudinal data demonstrate a dose-dependent relationship between weight change and OSA progression or regression, while randomized trials show that GLP-1-based therapies-particularly dual GLP-1/GIP agonism with tirzepatide-produce large, clinically meaningful reductions in AHI and cardiometabolic risk in obesity-associated OSA. Additional pharmacologic strategies targeting ventilatory loop gain and arousal threshold further support an endotype-driven treatment paradigm.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Contemporary OSA management is shifting from a CPAP-centric model toward a precision-guided, multimodal framework that aligns therapy with dominant anatomic and phys","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13029657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertension and Diabetes Cooperatively Drive HSP90 Activation, HSP70 Suppression, and Left Ventricular Interstitial Expansion: Relevance to Maladaptive Myocardial Remodeling.","authors":"Anastasia P Sklifasovskaya, Mikhail L Blagonravov, Madina M Azova, Sergey V Kurevlev, Vyacheslav A Goryachev, Sergey P Syatkin, Tatyana Yu Zotova, Daniil Yu Prokofiev","doi":"10.3390/pathophysiology33010019","DOIUrl":"10.3390/pathophysiology33010019","url":null,"abstract":"<p><strong>Background: </strong>Arterial hypertension (AH) and insulin-dependent diabetes mellitus (DM) are major comorbid risk factors for accelerated myocardial damage, yet the behavior of key stress-adaptive heat shock proteins HSP70 and HSP90 under combined stress remains unclear. This study aimed to characterize the expression profiles of HSP70 and HSP90 in left ventricular cardiomyocytes during isolated and comorbid AH and DM, and to evaluate their association with structural remodeling and expansion of interstitial elements.</p><p><strong>Methods: </strong>The study was conducted in accordance with the European Convention for the Protection of Vertebrate Animals (ethical approval No. 26, RUDN Institute of Medicine, 18 February 2021) on 25 male rats divided into five groups (<i>n</i> = 5 each): control-38-week-old Wistar-Kyoto (WKY) rats; AH-38-week-old spontaneously hypertensive rats (SHR); long-term AH-57-week-old SHR; DM-38-week-old WKY rats with streptozotocin-induced insulin-dependent DM (65 mg/kg, i.p.); AH+DM-38-week-old SHR with STZ-induced DM. After 30 days of DM, left ventricular (LV) tissue was analyzed by immunohistochemistry (IHC) for HSP70/HSP90 protein expression and by RT-qPCR for mRNA levels. Increased stromal elements in myocardium were quantified morphometrically as interstitial stromal volume fraction (%) on hematoxylin and eosin-stained sections.</p><p><strong>Results: </strong>HSP90 was significantly upregulated in all pathological groups. The most pronounced increase occurred in isolated DM, with a 4.0-fold rise in HSP90-positive area (21.80% vs. 5.45% in control) and a 1.82-fold increase in mRNA. In the AH+DM group, HSP90 mRNA expression was extremely elevated (25.93-fold), accompanied by a 3.7-fold increase in protein. In contrast, HSP70 protein was elevated only in the 38-week AH group (27.68% vs. 19.70% control, <i>p</i> ≤ 0.05), remained unchanged in isolated DM (19.50%), and was significantly reduced in AH+DM (14.71%, <i>p</i> ≤ 0.05), despite a modest 1.64-fold mRNA upregulation in DM. Morphometric analysis revealed progressive expansion of interstitial elements, most severe in AH+DM (9.43% stromal volume vs. 4.81% in control, <i>p</i> ≤ 0.05).</p><p><strong>Conclusions: </strong>Comorbid AH and DM provoke synergistic HSP90 upregulation, while HSP70 expression is markedly suppressed, indicating a shift from an adaptive to a maladaptive cellular-stress response. The imbalance between HSP90 and HSP70 may represent a key molecular mechanism underlying accelerated structural and functional deterioration of the myocardium in cardiometabolic comorbidity.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13029717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}