Elevated Lactate Research Articles

Clinical characteristics and prognosis of amyopathic dermatomyositis patients with interstitial lung disease: insights from a retrospective cohort

Abstract Introduction The diagnosis of amyopathic dermatomyositis with interstitial lung disease (ADM-ILD) is challenging due to the lack of typical skin features and overlapping syndromes. We aimed to determine the characteristics and prognosis of patients with ADM-ILD to further guide their clinical management. Methods A retrospective cohort study comprising 190 Chinese patients diagnosed with interstitial lung disease (ILD) was conducted. Patients were stratified into four groups using the Sontheimer criteria and predominant high-resolution computed tomography (HRCT) patterns. Demographic features, clinical presentation, laboratory parameters, duration of ILD, and follow-up data were analysed. Results There were significant differences in the clinical parameters among the 190 patients with ILD in the amyopathic dermatomyositis (ADM, n = 69) and control (n = 121) groups. The ADM with nonspecific interstitial pneumonia (NSIP) group (n = 46) presented increased haemoglobin (125.93 ± 12.91 g/L, p = 0.005), creatine kinase-MB (15.19 ± 8.58 U/L, p < 0.001), and partial pressure of oxygen (93.08 ± 26.20 mmHg, p = 0.003) levels and decreased β2-microglobulin (2.61 ± 1.21 mg/L, p = 0.039) levels compared to the control-NSIP group (n = 92). The ADM with organizing pneumonia (OP) group (n = 23) had a greater percentage of females (7/16, p = 0.023) and higher alanine aminotransferase (30.30 ± 20.67 U/L, p = 0.039) and aspartate aminotransferase (53.35 ± 65.86 U/L, p = 0.003) levels than the control-OP group (n = 29). Both the ADM-NSIP and OP groups presented elevated lactate dehydrogenase (LDH) levels (290.61 ± 86.49 U/L, p = 0.009; 317.35 ± 181.32 U/L, p = 0.003, respectively) and increased anti-nuclear antibody (ANA) positivity rates (82.61%, p = 0.01; 73.91%, p < 0.001, respectively). Notably, 81.26% of patients with ADM-NSIP/OP had LDH levels above normal. The serum LDH levels could be used to distinguish patients with ADM-NSIP/OP (sensitivity: 73.91%, specificity: 82.64%). Survival was shorter among patients with ADM-OP than among control patients (p = 0.002). Cox multivariate analysis revealed that age (p = 0.002), smoking status (p = 0.011), anti-melanoma differentiation-associated gene 5 (MDA5) antibody (p = 0.017), and white blood cell count (p = 0.004) were independent predictors of shorter survival. Conclusions Elevated serum LDH levels in patients predominantly presenting with NSIP or OP patterns may indicate the presence of ADM-ILD. The identified prognostic factors underscore the importance of early detection and personalized management strategies for optimizing outcomes in patients with ADM-ILD.

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME. Analysis of 18F-FDG uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of Endosulfine alpha (ENSA-K63la), a crucial step that triggers STAT3-CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. Therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

HIF-1α/HO-1-Mediated Ferroptosis Participates in Polystyrene Nanoplastics-Induced Intergenerational Cardiotoxicity.

To explore the intergenerational cardiotoxicity of nanoplastics, maternal mice were exposed to 60 nm polystyrene nanoplastics (PS-NP) during pregnancy and lactation. The results showed that PS-NP can enter the hearts of offspring and induce myocardial fiber arrangement disorder, acidophilic degeneration of cardiomyocytes, and elevated creatine kinase isoenzymes (CK-MB) and lactate dehydrogenase (LDH) levels after maternal exposure to PS-NP at 100 mg/kg during pregnancy and lactation. Mechanistically, KEGG analysis of RNA sequencing showed the participation of hypoxia-inducible factor-1 (HIF-1) and ferroptosis in PS-NP-induced cardiotoxicity. Key features of ferroptosis, including Fe2+ accumulation, mitochondrial injury, oxidative stress, GPX4 downregulation, and FTH1, ACSL4, and SLC7A11 upregulation, were detected. Furthermore, PS-NP treatment upregulated the expressions of HIF-1α and HO-1, and PS-NP-induced ferroptosis can be alleviated by inhibition of HIF-1α using si-HIF-1α. This study provided an insightful reference for the intergenerational cardiotoxicity assessment of PS-NP.

A Pilot Study on Qualitative Metabolomics to Characterize Lewis Lung Carcinoma in Mice

Metabolomics is a powerful tool that can be used to identify different stages in cancer development. In this study, the metabolomic profile of Lewis lung carcinoma (LLC) was characterized in C57BL/6 mice bearing LLC tumors. Magnetic resonance spectroscopy (nuclear magnetic resonance—NMR) was applied using a 400 MHz 1H NMR spectrometer. Two types of metabolites (polar and non-polar) were identified on LLC based on the analysis of methanol/water and chloroform extracts collected from lung cancer samples in mice. The investigated metabolomics show that the neoplastic processes of growing LLC on mice may affect carbohydrate; alanine and glutamate; leucine and isoleucine; lysine; creatine; and choline metabolism, whereas hypoxia states were identified due to elevated lactate in lung cancer tissues. The metabolomic profile of Lewis lung carcinoma could be considered to be a valuable biomarker in translational lung cancer research.

Blood lactate as a predictor of clinical outcomes and health-care resource needs in combat abdominal injuries

Background. Combat abdominal injuries (CAI) are cha­racterized by high mortality and occupy a leading position among the issues of battlefield surgery. It is very important to evaluate early and accurately the severity of CAI, which will allow starting correct treatment in time, preventing possible complications and improving clinical outcomes. The low sensitivity of commonly used cardiovascular parameters to detect the initial manifestations of tissue hypoperfusion induced by blood loss dictates the need to use more effective markers that reflect metabolic changes in tissues. The aim of this study is to determine the predictive efficacy of serum lactate regarding the risk of death and health-care resources needs in patients with CAI. Materials and methods. We examined 86 injured servicemen with CAI who were randomized into two groups — survivors and nonsurvivors. The predictive efficacy of capillary blood lactate and its clearance regarding the risk of death and health-care resource needs in CAI were studied. Six consecutive (within 48 h) measurements of lactate and lactate clearance corresponding to each measurement (except the first) were evaluated for each patient. Logistic regression models were constructed and analyzed to assess the influence of lactate level and lactate clearance on the risk of death and need for vasopressor support during medical evacuation to the Role 3 (after performing an emergency surgery). A correlation analysis was conducted on the association between lactate and the need for RBC transfusion, as well as assessment of the CAI severity using the Admission Trauma Score (AdTS). Results. In the group of nonsurvivors, lactate was higher (p = 0.001) at all stages of the study. We determined that an increase in the lactate level at the time of admission of a victim with CAI to the forward surgical team (LacpreOP) increased the risk of death by 1.5 times for every 1 mmol/l of lactate elevation (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.22–1.85), and the chances of the need for vasopressor support during medical evacuation to the Role 3 — by 1.7 times for every 1 mmol/l of lactate elevation (OR 1.7, 95% CI 1.05–1.86). A strong positive correlation (ρ = 0.8) was found between LacpreOP and the need for RBC transfusion during the first 24 h after injury, as well as a moderate positive correlation (ρ = 0.5) between LacpreOP and CAI severity assessment on the AdTS. Conclusions. The results of the study indicate the high predictive efficacy of lactate regarding the risk of death (OR 1.5, 95% CI 1.22–1.85) and the need for vasopressor support during medical evacuation of victims with CAI to the Role 3 (OR 1.7, 95% CI 1.05–1.86). There was a positive correlation between lactate and the need for RBC transfusion du­ring first 24 h after injury (ρ = 0.8), as well as between lactate level and CAI severity according to the AdTS (ρ = 0.5).

Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.

Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM. This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed. Patients exhibited diverse phenotypes, including exercise intolerance (8%), progressive myopathy (22%), isolated PEO (24%), and PEO plus (42%). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32%, elevated CK in 54%, reduced creatinine in 76%, and elevated GDF15 in 86% of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity. This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.

Persistent Lactate Elevation in a Patient with Asthma Exacerbation and a Congenital Portosystemic Shunt: A Case Report and Literature Review

Persistent Lactate Elevation in a Patient with Asthma Exacerbation and a Congenital Portosystemic Shunt: A Case Report and Literature Review

The value of blood lactate and lactate clearance rate in evaluating the prognosis of athletes with heat illness of varying degrees after high-intensity exercise

BackgroundHeat stroke, a severe heat illness with organ damage, is a major cause of cause irreparable organ damage and higher death rates among military persons and athletes.ObjectivesTo study the changes in blood lactate (Lac) levels and lactate clearance rate (LCR) in athletes with heat illness of varying degrees after high-intensity exercise and to evaluate their prognostic value.Material and methodsIn present study, acute care unit admitted 36 heat sickness patients following high-intensity exercise from December 2019 to July 2024, with comprehensive medical records, for retrospective study. The study population consisted of two groups of high level athletes: the favourable Prognosis Group (< 7 days, 22 cases), comprising 21 males and 1 female with a mean age of 21.8 ± 2.7 years, and the bad Prognosis Group (≥ 7 days, 14cases), consisting of 14 males with a mean age of 22.6 ± 3.2 years. Lac levels were assessed at admission (0 h) and early in therapy (2 h, 6 h), and the LCR was computed. Lac and LCR values at each time point were compared between the two groups to see how they affected patient prognosis.ResultsAfter 2 and 6 h of therapy, lactate levels decreased significantly in the good prognosis group (1.2 ± 0.5 mmol/L at 2 h and 0.8 ± 0.3 mmol/L at 6 h), but remained elevated in the poor prognosis group (4.2 ± 1.2 mmol/L at 2 h and 3.5 ± 1.5 mmol/L at 6 h). Core body temperature normalized in both groups, but the good prognosis group showed a more rapid decline, with temperatures of 37.4 ± 0.6 °C at 2 h and 36.8 ± 0.4 °C at 6 h in the good prognosis group, and 38.8 ± 0.8 °C at 2 h and 38.2 ± 0.9 °C at 6 h in the poor prognosis group. Notably, a significant positive correlation existed between lactate levels and APACHE II scores at admission (P < 0.01). Furthermore, logistic regression analysis revealed that the 2-hour lactate clearance rate (LCR) (R2 = 0.83) was an independent predictor of outcomes.ConclusionsThe study suggests that athletes with elevated lactate levels after heat illness may be at higher risk of adverse outcomes. The 2-hour lactate clearance rate (LCR) appears to be a valuable prognostic indicator, with potential applications in evaluating the severity of heat illness and guiding treatment decisions. Furthermore, dynamic monitoring of lactate levels in conjunction with LCR may provide valuable insights into the clinical management and prognosis of athletes with heat-related illnesses.

Predictors of 7-day mortality in critically ill patients with hyperglycemic crisis : Asingle center retrospective analysis.

The main aim of the study was to identify point of care available laboratory and clinical predictors of 7‑day mortality in critically ill patients with a hyperglycemic crisis. Aretrospective study of 990 patients with the first hospitalization due to hyperglycemia was performed. Patients were classified as having diabetic ketoacidosis (DKA) or being in a hyperosmolar hyperglycemic state (HHS) according to the recommendations of the American Diabetes Association (ADA). Patients not fulfilling the ADA criteria for DKA or HHS were summarized in athird group (unclassifiable hyperglycemia, UCH). The primary outcome was 7‑day mortality, potentially relevant factors were analyzed as secondary outcomes. Overall, the 7‑day mortality was 7.5%, with no significant differences between DKA (7.8%), HHS (14.5%) and UCH (6.1%). Blood lactate levels were significantly higher in nonsurvivors than survivors in all three groups (mean level of 6.3 mmol/l vs. 3.4 mmol/l in DKA, 5.3 mmol/l vs. 3.1 mmol/l in HHS, 5 mmol/l vs. 2.5 mmol/l in UCH). Measured and calculated osmolality were significantly higher in nonsurvivors in the DKA group (measured osmolality 359 mosmol/kg vs. 338 mosmol/kg, calculated osmolality 315 mosmol/kg vs. 305 mosmol/kg) and patients with UCH (354 mosmol/kg vs. 325 mosmol/kg; 315 mosmol/kg vs. 298 mosmol/kg) but not in patients with HHS. Survival analysis for the DKA group showed no significant differences in 7‑day mortality when patients were compared by the ADA criteria of severity (severe, moderate, or mild). Patients with elevated calculated osmolality (> 320 mosmol/kg) and lactate (> 4 mmol/l) had the lowest 7‑day survival rate (66.7%). Our data showed that elevated lactate levels were associated with higher mortality in all types of hyperglycemic crises.

Myocardial Infarction-Associated Shock: A Comprehensive Analysis of Phenotypes, SCAI Classification, and Outcome Assessment.

Background and Objectives: In-hospital mortality associated with myocardial infarction complicated by cardiogenic shock (MI-CS) remains critically high. A particularly challenging form, mixed shock (MS), combines features of cardiogenic shock (CS) with distributive elements such as vasodilation and reduced vascular resistance. MS is associated with elevated mortality rates and presents unique diagnostic and therapeutic challenges. This study aimed to analyze the clinical, historical, instrumental, and laboratory characteristics of the primary phenotypes of MI-CS, stratified according to the Society for Cardiovascular Angiography and Interventions (SCAI) shock severity scale. Materials and Methods: In this single-center, retrospective observational study, we reviewed the medical records of 1289 patients admitted to the emergency cardiology department from 1 January to 12 December 2020. Among them, 117 patients were identified as having MI-CS and were divided into two groups: MS (n = 48) and isolated CS (n = 69). The data were analyzed using the SCAI shock classification. Logistic regression analysis was employed to identify predictors of mortality and improved survival outcomes. Results: Patients with MS were older (80 years [71.0; 83.0] vs. 73 years [64.0; 81.0], p = 0.035). The overall mortality rate was significantly higher in the MS group (68% vs. 53%, RR = 1.438, 95% CI: 1.041-1.986, p = 0.03). Logistic regression identified mechanical ventilation (OR = 8.33, 95% CI: 2.54-22.80, p = 0.012), elevated lactate levels (OR = 1.20, 95% CI: 1.02-1.41, p = 0.026), and cardiopulmonary resuscitation (CPR) (OR = 7.97, 95% CI: 2.51-24.40, p < 0.0001) as independent predictors of mortality. Conversely, the use of an intra-aortic balloon pump (IABP) (OR = 0.22, 95% CI: 0.06-0.80, p = 0.021) and a higher body mass index (BMI) (OR = 0.91, 95% CI: 0.84-0.99, p = 0.038) were associated with reduced mortality risk. Conclusions: MS in the context of MI-CS represents a distinct clinical phenotype with specific hemodynamic features and significantly worsened outcomes. The identification of mortality predictors, such as mechanical ventilation, elevated lactate levels, and CPR, alongside protective factors like IABP use and a higher BMI, underscores the importance of early and tailored therapeutic interventions. These findings highlight the need for further studies to refine treatment protocols and improve outcomes in this high-risk population.

The Role of [18F]FDG PET and Clinicopathologic Factors in Detecting and Predicting Bone Marrow Involvement in Non-Hodgkin Lymphoma.

Background/Objectives: This study evaluates the diagnostic accuracy of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) using bone marrow biopsy (BMB) and clinical follow-up as reference standards. It further identifies predictive factors for bone marrow involvement (BMI) in non-Hodgkin lymphoma (NHL) patients. Methods: NHL patients who underwent [18F]FDG PET and BMB at diagnosis in a tertiary cancer center were included in this study. Diagnostic accuracy was analyzed, and logistic regression was performed to identify BMI predictors using Stata software version 17. A retrospective analysis of 262 NHL patients was conducted. Results: Concordance rates between [18F]FDG PET and BMB and between [18F]FDG PET and clinical follow-up were 75.6% and 88.1%, respectively. The primary cause of discordance between [18F]FDG PET and BMB was the detection of extra-iliac focal hypermetabolic bone marrow lesions by [18F]FDG PET, which were negative on BMB. The sensitivity, specificity, and accuracy of [18F]FDG PET were 62.9%, 80%, and 75.6%, respectively, with BMB as a reference, and 74.1%, 97.5%, and 88.2%, respectively, with clinical follow-up as a reference. The focal bone marrow [18F]FDG pattern was the most reliable indicator of BMI. Univariate logistic regression showed that advanced NHL stage, elevated alkaline phosphatase, thrombocytopenia, leukopenia, and elevated lactate dehydrogenase were significant predictors of BMI. Multivariate analysis revealed advanced NHL stage and thrombocytopenia as clinical predictors. Conclusions: [18F]FDG PET is a reliable tool for assessing BMI, providing comprehensive total-body evaluation and identifying extra-iliac involvement beyond the scope of BMB. The collective interpretation of molecular imaging, clinical, and biochemical factors is crucial for predicting BMI.

Diffuse Large B-Cell Lymphoma/High Grade B-Cell Lymphoma with MYC and BCL6 Rearrangements: a study of 60 Cases.

Classification of cases of diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (HGBL) with MYC and BCL6 rearrangements, also known as BCL6 double hit lymphoma (DHL), is controversial. We assessed 60 cases of BCL6-DHL and compared this cohort to 224 cases of DHL with MYC and BCL2 rearrangements (BCL2-DHL) and 217 cases of DLBCL not otherwise specified. Compared with the DLBCL cohort, BCL6-DHL patients had more aggressive clinical features such as frequent extranodal involvement, high-stage disease, high IPI score and elevated serum lactate dehydrogenase level (p <0.01 for all). Compared with the BCL2-DHL cohort, BCL6-DHL patients had similarly aggressive clinical features but a lower frequency of germinal center B-cell (GCB) immunophenotype and MYC and BCL2 double expression. Patients with BCL6-DHL showed an overall survival (OS) intermediate between patients with DLBCL and BCL2-DHL. Following induction with R-CHOP chemotherapy, BCL6-DHL patients demonstrated a poor OS similar to BCL2-DHL patients and worse than that of DLBCL patients (p = 0.024). However, among patients who received R-EPOCH, there was no significant difference in OS among the three groups (p = 0.146). Gene expression profiling showed that 60% of BCL6-DHL cases had a double hit (DH)-like signature compared with 10% of DLBCL-GCB and 93% of BCL2-DHL. The DH-like signature in BCL6-DHL cases was associated with a GCB immunophenotype. Based on these data, we suggest that BCL6-DHL cases are clinically more aggressive than DLBCL and patients may benefit from a more aggressive therapy than R-CHOP. The data also suggest that BCL6-DHL as currently defined, is heterogeneous and that neoplasms with a GCB immunophenotype are more likely to have DH-like signature and behave more aggressively. Lastly, we suggest that BCL6-DHL cases deserve to be recognized separately in a lymphoma classification to facilitate further understanding of these neoplasms and for optimal patient management.

Angiotensin-converting gene and hypoxic exercise tolerance: a randomized crossover trial.

Hypoxic training enhances endurance sports tolerance. However, individual responses vary due to physiological differences. This study investigated the relationship between genetic factors and exercise tolerance in hypoxic conditions. This randomized crossover study included 22 male university students (age 20.8±1.3 years, peak oxygen uptake 54.5±6.5 mL/min/kg). Incremental load tests were conducted to assess the symptomatic limit on separate days under normoxic and hypoxic conditions (oxygen concentration 15.4±0.8%) using an ergometer. The initial test environment was randomized. The peak oxygen uptake and blood lactate were monitored every minute, and Δ peak oxygen uptake (peak oxygen uptake under hypoxia - peak oxygen uptake under normoxia) was calculated. Sixteen genotypes linked to exercise tolerance (such as angiotensin-converting enzyme [ACE]) were examined. Peak oxygen uptake significantly decreased under hypoxia (p<0.01). Δ peak oxygen uptake varied among individuals (minimum: 0.7 and maximum: - 18.9). Among analyzed genetic polymorphisms, ACE-II genotypes showed significantly greater Δ peak oxygen uptake than ACE-ID/ACE-DD genotypes (p=0.02). ACE-II genotypes exhibited lower blood lactate elevation at peak exercise in normoxic (p=0.01) and hypoxic (p=0.03) conditions. Participants with the ACE-II genotype had lower lactate concentrations and greater reductions in peak oxygen uptake under hypoxic conditions. Optimizing hypoxic training requires individualized programs incorporating genetic analysis.

The role of neutrophilia in hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality outcome in critically ill COVID-19 patients.

COVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis, yet the key players driving this association remain unclear. It is generally assumed that organ damage causes toxic acidosis, but since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes, we asked if metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients. Based on prospective mortality outcome, critically ill COVID-19 patients were divided into ICU- survivors and ICU-non-survivors. Samples were analyzed to explore if correlations exist between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils, platelets, and PBMCs for glycolytic activities. Arterial blood gas analyses showed remarkable hypoxemia in non-survivors with no consistent differences in PCO2 or [HCO3 -]. The hemoglobin oxygen dissociation curve revealed a right-shift, consistent with lower blood-pH and elevated blood lactate in non-survivors. Metabolic analysis of different blood cells revealed increased glycolytic activity only when considering the total number of neutrophils. This indicates the role of neutrophilia in hyperlactatemia and lung damage, subsequently contributing to mortality outcomes in severe SARS-CoV-2 infection.

Clinical features and prognosis of anti-MDA5-positive dermatomyositis with coexistent anti-aminoacyl-tRNA synthetase antibodies.

This study aimed to evaluate the incidence and clinical significance of coexistence of anti-aminoacyl-tRNA synthetase (anti-ARS) antibody in patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5 + DM). We assessed a cohort of 246 consecutive patients with anti-MDA5 + DM. Clinical characteristics and survival rates were compared between patients with and without anti-ARS antibodies. Of these 246 patients, 15 (15/246, 6.1%) were positive for anti-ARS antibodies. The anti-ARS-positive group had a higher proportion of mechanic's hands (53.3% vs 25.5%, P = 0.019), and the positivity rates for antinuclear antibody (ANA) (80.0% vs 50.6%, P = 0.033) and anti-Ro52 antibodies (93.3% vs 62.3%, P = 0.013) were also higher. However, the CRP levels were comparatively low [4.0 (0.5, 7.8) vs 6.0 (3.1, 12.2), P = 0.019]. In the overall population, no difference in survival rates was observed between anti-MDA5 + DM patients with or without anti-ARS antibodies (log-rank P = 0.339). The multivariate Cox regression analysis revealed that elevated lactate dehydrogenase (LDH) levels and the presence of rapidly progressive interstitial lung disease (RPILD) were associated with poor prognosis [hazard ratios of 1.002 (95% CI 1.001, 1.002, P < 0.001) and 11.096 (95% CI 5.006, 24.598, P < 0.001), respectively]. Among the 246 patients with anti-MDA5 + DM, only 15 patients (6.1%) tested positive for anti-ARS antibodies. The presence of anti-ARS antibodies is associated with the occurrence of mechanic's hands, as well as an increased positive rate of ANA and anti-Ro52 antibodies. Elevated LDH levels and the presence of RPILD are poor prognostic risk factors for patients with anti-MDA5 + DM. Key Points • The presence of anti-ARS antibodies is associated with the occurrence of mechanic's hands, as well as an increased positive rate of ANA and anti-Ro52 antibodies. • Elevated LDH levels and the presence of RPILD are poor prognostic risk factors for patients with anti-MDA5 + DM. • Understanding the clinical characteristics of these patients will help clinicians to develop individualised treatment plans for each patient.

Risk Factors of Hemophagocytic Lymphohistiocytosis in Adults with Fever of Unknown Origin: A Retrospective Study.

Hemophagocytic lymphohistiocytosis (HLH) is a critical syndrome with a high mortality rate. In clinical practice, some patients with fever of unknown origin (FUO) can develop HLH, further complicating the diagnosis and treatment. However, studies on HLH in adults with FUO are limited. This study aimed to investigate the clinical characteristics of adult patients with FUO to facilitate the early identification of those at high risk of developing HLH. We collected data from hospitalized patients with FUO between January 2014 and December 2020. Risk factors for HLH in adults with FUO were analyzed using univariate and multivariate analysis. A total of 988 patients with FUO were included in the study. The incidence of HLH in adults with FUO was 6.4%, with hematological tumors being the primary cause. Multivariate analysis indicated that skin rash and elevated alanine aminotransferase, total bilirubin, triglycerides, lactate dehydrogenase, and ferritin levels were independent risk factors for HLH in adults with FUO. This study revealed the incidence rate, etiology distribution, and risk factors for HLH in adults with FUO. Comprehensive assessment of clinical and laboratory data at admission can assist in the early identification of FUO patients at risk for HLH.

The mitochondriotropic antioxidants AntiOxBEN2 and AntiOxCIN4 are structurally-similar but differentially alter energy homeostasis in human skin fibroblasts.

Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six‑carbon (C6) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN2) and caffeic acid (AntiOxCIN4) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C6-TPP (but not AntiOxBEN2 and AntiOxCIN4) induce cell death in human skin fibroblasts. This indicates that C6-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN2 and AntiOxCIN4. Remarkably, C6-TPP and AntiOxBEN2 (but not AntiOxCIN4) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented (i.e. by using a glucose-free, galactose-containing medium), AntiOxBEN2 induced cell death whereas AntiOxCIN4 did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN2 and AntiOxCIN4 display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.

The Role of Lactate Metabolism in Heart Failure and Cardiogenic Shock: Clinical Insights and Therapeutic Implications.

Heart failure (HF) is associated with poor prognosis, especially when it progresses to cardiogenic shock (CS), where survival rates substantially decline. A key area of interest is the role of blood lactate as a biomarker in these conditions. Lactate is produced under normal physiological conditions but increases with impaired tissue perfusion, a hallmark of HF and CS. Elevated lactate levels result from increased production, reduced clearance, or both, and are often associated with worse outcomes. Traditionally considered a byproduct of anaerobic metabolism, lactate is now recognized as an important energy substrate, particularly in myocardial tissue during periods of metabolic stress. Recent studies suggest that dynamic lactate monitoring, including lactate clearance (LC), may provide critical insights into patient prognosis and response to therapy. Serial measurements of lactate have been shown to predict survival in critically ill patients, including those with HF and CS. In CS, elevated lactate levels correlate with increased mortality risk, and LC is emerging as an important parameter in treatment protocols. Despite growing evidence of lactate's clinical relevance, research is needed to establish standardized thresholds and optimal monitoring timelines. Understanding the complexities of lactate metabolism and its role in HF and CS could lead to improved risk stratification and more personalized treatment approaches.

Brain energy homeostasis: the evolution of the astrocyte-neuron lactate shuttle hypothesis.

The brain's substantial metabolic requirements, consuming a substantial fraction of the body's total energy despite its relatively small mass, necessitate sophisticated metabolic mechanisms for efficient energy distribution and utilization. The astrocyte-neuron lactate shuttle (ANLS) hypothesis has emerged as a fundamental framework explaining the metabolic cooperation between astrocytes and neurons, whereby astrocyte-derived lactate serves as a crucial energy substrate for neurons. This review synthesizes current understanding of brain energy metabolism, focusing on the dual roles of lactate as both an energy substrate and a signaling molecule. We examine the molecular underpinnings of metabolic compartmentalization, particularly the differential expression of lactate dehydrogenase (LDH) isozymes between astrocytes and neurons, which facilitates directional lactate flux. Recent evidence has challenged aspects of the classical ANLS model, revealing greater metabolic flexibility in neurons than previously recognized, including substantial LDHA expression and direct glucose utilization capabilities. Our recent studies on LDHB-deficient neurons provide new insights into the compensatory mechanisms and limitations of neuronal lactate metabolism, suggesting a more nuanced understanding of the ANLS hypothesis. Furthermore, we discuss lactate's emerging role as a signaling molecule in synaptic plasticity, memory formation, and neuroprotection, particularly in ischemic conditions where elevated lactate levels correlate with enhanced neuronal survival through prostaglandin E2-mediated vasodilation. This comprehensive review integrates classical perspectives with recent advances, providing an updated framework for understanding brain lactate metabolism and its therapeutic implications in neurological disorders.

Does p-lactate increase in patients with GSD1 after ingesting a meal with common-size sources of fructose and galactose? Observations from a prospective, non-blinded, crossover pilot study.

Ingestion of fructose and galactose may result in elevated lactate concentrations in patients with glycogen storage disease type 1 (GSD1). In this randomized cross-over pilot study, 7 patients with GSD 1a (6) and GSD1b (1) orally consumed a common-size fructose and galactose from either 200 mL of skimmed milk, 200 mL juice or 200 mL water. This was given after a night with their usual dietary treatment using either cornstarch, glycosade or continuous feed. P-lactate and -glucose were measured 2 h before dosing (T = -120 min and -60 min). At baseline (T = 0), p-lactate, p-glucose, p-triglycerides, p-uric acid and p-alanine were measured just before dosing. P-lactate and p-glucose were measured every 30 min for 4 h. Four hours after the consumption (T = 240 min, end-of-test), levels of p-lactate, p-glucose, p-triglycerides, p-uric acid and p-alanine were measured. P-lactate increased in three patients with mean of 0.3 mmol/L (range 0.2-0.6 mmol/L) after consuming milk. The highest level was seen after 60 min. A decrease was seen in three patients. P-lactate increased in four patients with a mean increase at 1.3 mmol/L (range 0.2-2.2 mmol/L) after consuming 200 mL juice. A peak increase was seen after the first 30 min in two patients whereas the peak in the remaining two patients was at 60 min; all values decreased to baseline values after further 60 min. In two patients, p-lactate was unchanged, respectively, decreased after juice ingestion. Calculation of galactose and fructose AUC percentage change after challenge did not reveal consistent increase or decreases.