Search Results (754)

Myopathy, Lactic Acidosis, and Sideroblastic Anemia type 2 (MLASA2) is a rare mitochondrial disorder caused by pathogenic variants (PVs) in the YARS2 gene (which encodes the Mt-TyrRS protein. We performed a comprehensive clinical–molecular synthesis by integrating a systematic review and meta-analysis of all published MLASA2 cases with survival modeling and three-dimensional structural mapping. Across the aggregated cohort, anemia (88.6%), sideroblastic phenotype (85.7%), and lactic acidosis (82.9%) were the most prevalent phenotypes. Fifteen PVs were identified, dominated by p.(Phe52Leu) (29.4%). Survival estimates were 94.1% at 10 years, 70.7% at 30 years, and 42.4% at 50 years; cardiomyopathy and diagnosis before age 10 were associated with decreased survival. We generated the first 3D structural map of all reported Mt-TyrRS PVs, identifying nine spatial hotspots across catalytic, anticodon-binding, and tRNA-binding domains. An integrated framework combining structural density, clinical severity, in silico predictions, and ΔΔG destabilization classified three clusters as High-risk, three as Medium-risk, and three as Low-risk. Among them, cluster 3, a large catalytic hotspot encompassing 44 residues and including nearly half of all MLASA2 cases, showed the strongest pathogenic convergence. This clinical–structural integration provides new insights for a better comprehension of MLASA2, enhancing variant interpretation and improving diagnostic and prognostic precision. Full article

Background: Acute necrotizing esophagitis (ANE), also known as “black esophagus,” is a rare but life-threatening condition typically occurring in critically ill patients with profound systemic disturbances. Extreme hyperglycemic crises represent an underrecognized precipitating factor, capable of inducing severe metabolic, inflammatory, and microvascular injury. Case Presentation: We report the case of a 54-year-old male admitted with altered mental status and severe dehydration, in whom initial laboratory evaluation revealed extreme hyperglycemia (serum glucose ~1000 mg/dL), metabolic acidosis, and early multiorgan dysfunction. During intensive care unit hospitalization, the patient developed anemia and severe thrombocytopenia, followed by evidence of upper gastrointestinal bleeding. Urgent upper gastrointestinal endoscopy demonstrated diffuse circumferential black necrosis of the distal esophageal mucosa with abrupt demarcation at the gastroesophageal junction, consistent with acute necrotizing esophagitis, along with associated erosive hemorrhagic gastritis. Comprehensive laboratory evaluation documented marked inflammatory activation and hematologic instability. Management and Outcome: Treatment consisted of aggressive metabolic correction, strict glycemic control, hemodynamic stabilization, infection management, and supportive gastrointestinal care. Progressive clinical and biological improvement was observed, with resolution of bleeding and partial recovery of hematologic parameters. Conclusions: This case highlights a severe hyperglycemic crisis as a major contributing factor within a multifactorial ischemic and inflammatory cascade leading to acute necrotizing esophagitis. Full article

Background: Many inhibitors have been discovered to target hypoxia-induced carbonic anhydrase IX (CAIX) due to its critical role in lung cancers. This study discovers a novel compound, 3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl-9Z,12Z-octadeca-9,12-dienoate, which is produced by the seagrass Cymodocea serrulata and has binding sites at CAIX that are distinct from those of current inhibitors. Methods: Compound and reference drug treatment for cell lines; Cell viability: MTT; Staining: Ao/PI/DAPI; MMP shifts and cell cycle: FACS; Gene and protein expression of CAIX, BAX, BAD: qPCR and Western blotting. Results: The compound binds to the CAIX protein, raises extracellular pH, and kills A549 cells [IC₅₀: 11.61 µM], producing results that are lower than those of the reference drug doxorubicin [13.7 µM]. The substance depolarised the electrical potential of the mitochondrial membrane, caused S-phase arrest, and fragmented DNA. Additionally, it downregulated CAIX by 0.9 times while increasing apoptotic mRNA, BAX and BAD by 5.2 and 3.08 times, respectively, as demonstrated by qPCR. Between 0 and 24 h, the untreated hypoxic cells had a ΔpHe of 0.15, but the compound-treated cells had a ΔpHe of 0.6 indicative of intracellular acidosis. MD simulations verify the stability of the CAIX–C1 complex for more than 100 ns, and in silico studies show a strong binding affinity of the molecule to CAIX [−7.55 kcal/mol]. Conclusions: This implies that the amount of extracellular alkalosis was increased by the combination of treatment and hypoxia induction. As a result, when the cells were deprived of O₂, the compound provided less defense against ROS. The compound binds to the glutamine and alanine amino acids at positions 242 and 392, respectively, at the central Zn atom of CAIX, which sets it apart from conventional sulphonamide CAIX inhibitors. This naturally occurring compound may be a potent CAIX inhibitor with newer binding sites, which could help treat hypoxic lung cancers. Full article

Membrane rupture, induced by lipid peroxidation, is a severe threat to osmotic balance, as membrane pores contribute to ferroptosis, an iron-dependent cell death. To alleviate osmotic stress, membrane constituents dynamically reconstruct the membrane and interact with intracellular molecules. Tumor-derived acidosis shift glycolysis-dependent metabolism toward lipid metabolism, increasing polyunsaturated fatty acids (PUFAs). PUFAs enhance membrane fluidity but make cancer susceptible to lipid peroxidation. Also, the ionization of phospholipids under low pH can accelerate membrane rupture. This stress can be mitigated by the redistribution of cholesterol, which maintains tension–compression balance and acts as antioxidants. When excessive reactive aldehydes—byproducts of lipid peroxidation—overwhelm cholesterol’s protective role, lipid peroxides promote membrane cracks. Moreover, a deficiency in glutathione can alter cholesterol’s function, turning it into a pro-oxidant. In contrast, ceramide, derived from membrane lipids, indirectly prevents ferroptosis by facilitating cytochrome c release. This review integrates recent findings on how membrane components and environmental stressors influence ferroptosis. It also suggests potential therapeutic strategies. This could advance our understanding of ferroptosis in cancer. Full article

Metabolic acidosis is common after kidney transplantation and has been linked to adverse renal outcomes. However, its relationship with histological injury in kidney allografts remains poorly characterized. We aimed to explore the association between metabolic acidosis and histopathological features in kidney allograft biopsies. This single-center, cross-sectional observational study included 63 adult kidney transplant recipients who underwent clinically indicated allograft biopsies. Metabolic acidosis was defined as a serum bicarbonate level < 22 mmol/L at the time of biopsy. Histological lesions were assessed according to the Banff classification. Lesion severity was evaluated using descriptive statistics, nonparametric comparisons, ordinal logistic regression, and multivariable logistic regression models adjusted for renal function, proteinuria, and time from transplantation. Sensitivity analyses additionally adjusted for hemoglobin and donor-related variables. Patients with metabolic acidosis exhibited numerically higher severity scores for both acute inflammatory lesions and chronic histological changes, including total inflammation and interstitial fibrosis/tubular atrophy (IFTA). Across ordinal analyses and multivariable regression models, consistent directional trends toward a greater histological injury burden were observed among acidotic patients; however, none of these associations reached statistical significance, and confidence intervals were wide. Sensitivity analyses yielded directionally consistent effect estimates. In this biopsy-based analysis, metabolic acidosis showed consistent directional trends toward a higher burden of inflammatory and chronic histological lesions, although these findings did not reach statistical significance. Full article

Background: Metabolic acidosis is a frequent and serious complication in critically ill neonates, particularly preterm infants, and is associated with an increased risk of mortality, intraventricular hemorrhage, and long-term neurodevelopmental impairment. Despite limited evidence, sodium bicarbonate (SB) is widely administered in neonatal intensive care units (NICUs) to correct acidosis, largely extrapolated from adult and pediatric practice. However, concerns have been raised about its potential adverse effects, including paradoxical intracellular acidosis, impaired cerebral autoregulation, and increased risk of neurological injury. Given the uncertainty regarding both its efficacy and safety, we conducted a systematic review and meta-analysis to evaluate the role of SB administration in the neonatal population. Methods: MEDLINE, Scopus, and the Cochrane Library were searched using specific medical subject headings and terms. We included all study published up to July 2025 that involved newborns treated with SB. The primary outcome was positive response to treatment, while secondary outcomes included mortality, morbidity, and long-term impairment. Results: We analyzed 10 studies (9 randomized and 1 unrandomized study, including 660 neonates). Pooled results from the randomized controlled studies showed no efficacy of SB in newborns. Data from one unrandomized study showed an increased risk for mortality (OR 13.1 p = 0.02), clinical seizures (OR 2.8, p = 0.01), and a combined outcome of death or neurological damage (OR 3.1 p < 0.01) for neonates treated with SB. Conclusions: Current evidence is insufficient to support the routine administration of SB in NICUs. Neonatologists have the responsibility to administer only drugs of proven efficacy, personalizing therapy on the basis of a pathology’s etiology, in order to reduce risk and optimize benefits. In the absence of robust, statistically significant data, the indiscriminate use of SB should be discouraged in current clinical practice. PROSPERO registration number: CRD420251132502. Full article

Repeated sprint ability (RSA) is a critical component of football, yet high-intensity effort leads to H⁺ accumulation. Sodium bicarbonate (SB) is an effective buffering agent, though evidence supporting its use among female football players remains limited. We conducted a randomized, double-blind, placebo-controlled, crossover trial (NCT06098794) to examine the acute effects of SB on RSA in recreational female football players. Eleven athletes completed two RSA sessions on a cycle ergometer under SB and placebo (PL) conditions. Each session involved 3 sets of 6 maximal 6 s sprints performed every 30 s, with a 5 min recovery between sets. Participants ingested 0.2 g·kg⁻¹ of the supplement 2 h prior to testing and 0.1 g·kg⁻¹ 1 h before the session. The results showed that SB induced a greater blood lactate accumulation (SB: 14.0 ± 4.32 vs. PL: 10.9 ± 3.55 mmol·L⁻¹, p = 0.010) and a greater elimination of CO₂ through breathing (p = 0.038), while maintaining muscle oxygenation. These physiological responses were accompanied by improved performance, as SB prevented a decline in mean power output from the first to the second set (SB: +1.4% vs. PL: −3.7%) and reduced the post-test drop in jump height (SB: −2.0% vs. PL: −8.2%). These findings suggest that SB supplementation may be useful to reduce muscular acidosis and fatigue in recreational female football players. Full article

Breast cancer screening, while vital for reducing mortality, faces significant limitations in sensitivity and specificity, particularly in dense breasts. Current modalities primarily detect anatomical changes, often missing biologically aggressive tumors at their earliest stages. The altered metabolism of cancer cells establishes a characteristic inverted pH gradient that drives tumor invasion, metastasis, and treatment resistance. This makes tumor acidity a compelling, functional biomarker for early detection. This review synthesizes the emerging role of pH as a diagnostic biomarker and provides a critical evaluation of advanced imaging techniques for its non-invasive or minimal measurement. We detail the biological underpinnings of tumor acidosis, emphasizing its regulation through glycolytic reprogramming and dysregulated proton transport. Our analysis encompasses a broad spectrum of pH-sensitive imaging modalities, including magnetic resonance methods such as Chemical Exchange Saturation Transfer (CEST) MRI for extracellular pH mapping and multi-nuclear Magnetic Resonance Spectroscopy (MRS) using ¹H, ³¹P, and ¹⁹F nuclei to probe various cellular compartments. Furthermore, we examine hyperpolarized ¹³C MRI for real-time metabolic flux imaging, where metrics such as the lactate-to-pyruvate ratio demonstrate significant predictive value for treatment response. The review also assesses optical and photoacoustic imaging techniques, which offer high sensitivity but are often constrained to superficial tumors. Imaging tumor pH provides a powerful functional window into the earliest metabolic shifts in breast cancer, far preceding macroscopic anatomical changes. The ongoing development and evidence support the role of the pH-sensitive imaging techniques in diagnosis, lesion characterization, and therapy. Additionally, it holds promise for supplementing breast cancer screening by enabling earlier, more specific detection and personalized risk stratification, ultimately aiming to improve patient outcomes. Full article

Background and Clinical Significance: Upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, is increasingly prescribed for autoimmune and inflammatory diseases. Although its therapeutic safety profile is well established, fatal intoxications have not been reported to date. Case Presentation: We describe the first fatal case of upadacitinib overdose in a 13-year-old girl. Following ingestion of approximately 600 mg (40 × 15 mg tablets Rinvoq^®), the patient presented with deep coma, profound bradycardia (~40 bpm) with third-degree atrioventricular block, conduction delay, hypotension, hypothermia, and metabolic acidosis. Laboratory tests showed hyperglycemia (17.8 mmol/L) and only minimal elevations in cardiac biomarkers (CK 57.03 U/L, CK-MB 30.64 U/L, troponin 0.003 ng/mL). Despite advanced resuscitation, the patient succumbed within a few hours. Forensic toxicology revealed extremely high concentrations of upadacitinib, 1.84 µg/mL (~1840 ng/mL) in blood and 70.3 µg/mL in gastric contents, far exceeding reported therapeutic plasma levels (Cmax 36.0 ± 8.8 ng/mL). This case establishes the first reported value for a lethal upadacitinib concentration in humans. The combination of conduction abnormalities, refractory shock, and minimal biomarker changes is consistent with an acute electrophysiological and hemodynamic collapse rather than myocardial infarction. Conclusions: The toxicity of upadacitinib in this case is characterized by profound central nervous system depression, severe cardiovascular (electrophysiological and hemodynamic) disturbances, and metabolic abnormalities (acidosis and hyperglycemia). These findings provide essential reference data for clinical and forensic toxicology, highlight the fatal potential of upadacitinib in overdose, and underscore the importance of secure medication storage and pharmacovigilance in households with adolescents. Full article

Background: The management of acute pulmonary embolism (PE) in the Emergency Department (ED) remains challenging, particularly in hemodynamically and respiratory stable patients with minimal symptoms. Diagnostic and therapeutic difficulties are further compounded when the condition is complicated by a mobile right atrial (RA) thrombus, representing an extreme-risk phenotype. Case Presentation: We report the case of a 65-year-old male with a single known venous thromboembolism risk factor-chronic venous insufficiency-who presented to the ED following a transient episode of severe dyspnea at home. On admission, he was hemodynamically and respiratory stable, without the need for oxygen supplementation. Arterial blood gas analysis revealed a metabolically compensated acidosis with elevated lactate, while cardiac biomarkers were moderately increased. Emergency point-of-care transthoracic echocardiography (POCUS-TTE) demonstrated severe right ventricular (RV) dysfunction and a large, mobile intracardiac thrombus prolapsing through the tricuspid valve. Computed Tomography Pulmonary Angiography confirmed pulmonary embolism and revealed a massive and extensive bilateral thrombotic burden (Qanadli score 32 points). Given the extreme risk for fatal embolization, immediate full-dose systemic thrombolysis with Alteplase (100 mg over 2 h) was initiated in the ED. Thrombolysis was completed without hemorrhagic complications. Follow-up POCUS-TTE at 2 h showed complete resolution of the intracardiac thrombus and significant improvement of RV function (RV/RA gradient reduced from 40 mmHg to 28 mmHg). Conclusions: This case highlights the effectiveness and safety of early systemic thrombolysis guided by ED POCUS-TTE in PE with a massive thrombotic burden, complicated by a mobile intracardiac thrombus, even in the absence of shock. Such prompt intervention may reduce mortality risk in intermediate-to-high-risk PE subsets, despite limited guidance in current clinical recommendations. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

Bupropion overdose can result in severe neurological and cardiovascular toxicity. We describe a 16-year-old girl who ingested 4.2 g of extended-release bupropion (90.3 mg/kg), presenting with seizures and out-of-hospital cardiac arrest. After 21 min of cardiopulmonary resuscitation, she was resuscitated and admitted with profound metabolic acidosis and electrocardiographic abnormalities. Serum testing confirmed markedly elevated bupropion levels. During hospitalization, she developed delayed rhabdomyolysis, hypoxic encephalopathy, and persistent neurological sequelae, including Parkinsonism and cognitive deficits. Supportive care led to gradual recovery, with normalization of cardiac conduction and drug clearance by day 20, though residual deficits remained at discharge after seven weeks. This case highlights the life-threatening complications of bupropion toxicity, the delayed risk of seizures, and the need for vigilance for secondary complications such as rhabdomyolysis. Full article

MLASA2 is a rare mitochondrial disorder with limited geographic representation in published medical literature. Here, we report the first confirmed case of MLASA2 in a Latin American 16-year-old male harboring a homozygous pathogenic variant p.(Asp311Glu) in the YARS2 gene. The patient presented with sideroblastic anemia and short stature, accompanied by other skeletal dysplasia features not previously associated with MLASA2, including epiphyseal dysplasia, rib edge widening, and poorly defined vertebral structures, but without lactic acidosis. Notably, the patient did not present exercise intolerance but recently exhibited reduced muscle strength. The p.(Asp311Glu) variant, located in the anticodon-binding domain of the mitochondrial tyrosyl-tRNA synthetase (Mt-TyrRS), was consistently predicted to be pathogenic by multiple in silico tools. Molecular modeling revealed that this variant destabilizes the ‘KMSKS’ motif, potentially compromising tRNA recognition fidelity and aminoacylation efficiency. Analysis of runs of homozygosity (ROH) revealed significantly elevated consanguinity (ROH: 31.93%), consistent with a consanguineous mating between biological parents. This case expands the geographic distribution of MLASA2, documents previously unreported phenotypes, suggests a novel pathogenic mechanism, and demonstrates the utility of genomic approaches for diagnosing rare mitochondrial disorders in the absence of complete clinical information and family history. Full article

Background/Objectives: The study aimed to evaluate the most significant factors that impact arterial blood gas parameters: pH, pO₂, pCO_2, and concentration of lactates. Methods: The study was a retrospective analysis of clinical data obtained from the patients’ records hospitalized at the Department of Pediatric Anesthesiology and Intensive Care. A total of 71 patients were enrolled in the study. A total of 479 measurements were performed for arterial blood, 41 were excluded. The analysis was performed for 438 results. The artificial neural network (ANN) regression models were applied, and the Least Absolute Shrinkage and Selection Operator (LASSO) regression was used. ANNs were built considering the following activation functions: hyperbolic tangent, linear, exponential, and logistic. The following three sets were separated: training, testing, and validation. In the case of LASSO regression, the regularization was applied, excluding insignificant variables from the model. Besides the machine learning techniques, the correlation between the variables was calculated. Results: The correlation coefficients for regression ANN models exceeded the value for testing set of 0.92. According to the sensitivity analysis, the most significant variable for pH was cCl⁻, for pO₂ it was pO₂/FiO₂, for pCO₂ it was Fshunt, and for concentration of lactates it was pH. In the case of LASSO regression for pH, the most significant factor was pCO₂, for pO₂ it was pO₂/FiO₂, for pCO₂ it was cCl⁻, and for concentration of lactates it was pCO₂. Conclusions: The results show the usefulness of machine learning methods in analyzing complex physiological relationships. Such techniques can help improve diagnostic accuracy and optimize therapeutic management in pediatric patients. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2–6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation. Full article