Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

Tumour metabolism can be imaged with a novel imaging technique termed hyperpolarised carbon-13 (13C)-MRI using probes, i.e., endogenously found molecules that are labeled with 13C. Hyperpolarisation of the 13C label increases the sensitivity to a level that allows dynamic imaging of the distribution and metabolism of the probes. Dynamic imaging of [1-13C]pyruvate metabolism is of particular biological interest in cancer because of the Warburg effect resulting in the intratumoural accumulation of [1-13C]pyruvate and conversion to [1-13C]lactate. Numerous preclinical studies in breast cancer and other tumours have shown that hyperpolarised 13C-pyruvate has potential for metabolic phenotyping and response assessment at earlier timepoints than the current clinical imaging techniques allow. The clinical feasibility of hyperpolarised 13C-MRI after the injection of pyruvate in patients with breast cancer has now been demonstrated, with increased 13C-label exchange between pyruvate and lactate present in higher grade tumours with associated increased expression of the monocarboxylate transporter 1 (MCT1), the transmembrane transporter mediating intracellular pyruvate uptake, and lactate dehydrogenase (LDH) as the enzyme catalysing the conversion of pyruvate to lactate. Furthermore, a study in patients with breast cancer undergoing neoadjuvant chemotherapy suggested that early changes in 13C-label exchange can distinguish between patients who reach pathologic complete response (pCR) and those who do not. This review summarises the current literature on preclinical and clinical research on hyperpolarised 13C-MRI with [1-13C]-pyruvate in breast cancer imaging.

Pyruvic acid has numerous applications in the food, chemical, and pharmaceutical industries. The high costs of chemical synthesis have prevented the extensive use of pyruvate for many applications. Metabolic engineering and traditional strategies for mutation and selection have been applied to microorganisms to enhance their ability to produce pyruvate. In the past decades, different microbial strains were generated to enhance their pyruvate production capability. In addition to the development of genetic engineering and metabolic engineering in recent years, the metabolic transformation of wild-type yeast, E. coli, and so on to produce high-yielding pyruvate strains has become a hot spot. The strategy and the understanding of the central metabolism directly related to pyruvate production could provide valuable information for improvements in fermentation products. One of the goals of this review was to collect information regarding metabolically engineered strains and the microbial fermentation processes used to produce pyruvate in high yield and productivity.

Non-genital warts are benign cutaneous growths caused by infection with the human papillomavirus. Although warts can resolve spontaneously, patients might seek treatment due to discomfort or social ostracism. This review summarises high-quality studies investigating the efficacy of chemical and physical destructive wart therapies.
We performed a literature review (up to June 2021) of published articles for wart management from MEDLINE and Embase databases. We considered systematic reviews, randomised controlled trials (RCTs), cohort studies and case series. We included studies that investigated chemical or physical destructive therapies.
Fifteen therapies were evaluated and included salicylic acid, cryotherapy, silver nitrate, phenol, cantharidin, glycolic acid, pyruvic acid, citric acid, formic acid, trichloroacetic acid, monochloroacetic acid, zinc, laser, surgery and electrocautery. Very few treatment options have been studied through RCTs.
To attenuate transmission, hygienic practices need to be adopted in conjunction with any treatment. Important considerations when treating patients with warts include the location of the wart, the evidence supporting the proposed treatment and potential adverse effects of treatment.

After traumatic brain injury (TBI), cerebral metabolism can become deranged, contributing to secondary injury. Cerebral microdialysis (CMD) allows cerebral metabolism assessment and is often used with other neuro-monitoring modalities. CMD-derived parameters such as the lactate/pyruvate ratio (LPR) show a failure of oxidative energy generation. CMD-based abnormal metabolic states can be described following TBI, informing the etiology of physiological derangements. This systematic review summarizes the published literature on microdialysis-based abnormal metabolic classifications following TBI. Original research studies in which the populations were patients with TBI were included. Studies that described CMD-based classifications of metabolic abnormalities were included in the synthesis of the narrative results. A total of 825 studies underwent two-step screening after duplicates were removed. Fifty-three articles that used CMD in TBI patients were included. Of these, 14 described abnormal metabolic states based on CMD parameters. Classifications were heterogeneous between studies. LPR was the most frequently used parameter in the classifications; high LPR values were described as metabolic crisis. Ischemia was consistently defined as high LPR with low CMD substrate levels (glucose or pyruvate). Mitochondrial dysfunction, describing inability to use energy substrate despite availability, was identified based on raised LPR with near-normal levels of pyruvate. This is the first systematic review summarizing the published literature on microdialysis-based abnormal metabolic states following TBI. Although variability exists among individual classifications, there is broad agreement about broad definitions of metabolic crisis, ischemia, and mitochondrial dysfunction. Identifying the etiology of deranged cerebral metabolism after TBI is important for targeting therapeutic interventions.

BACKGROUND: Cerebral ischemia due to hypoxia is a major cause of secondary brain injury and is associated with higher morbidity and mortality in patients with acute brain injury. Hyperoxia could improve energetic dysfunction in the brain in this setting. Our objectives were to perform a systematic review and meta-analysis of the current literature and to assess the impact of normobaric hyperoxia on brain metabolism by using cerebral microdialysis.
METHODS: We searched Medline and Scopus, following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement; we searched for retrospective and prospective observational studies, interventional studies, and randomized clinical trials that performed a hyperoxia challenge in patients with acute brain injury who were concomitantly monitored with cerebral microdialysis. This study was registered in PROSPERO (CRD420211295223).
RESULTS: We included a total of 17 studies, with a total of 311 patients. A statistically significant reduction in cerebral lactate values (pooled standardized mean difference [SMD] - 0.38 [- 0.53 to - 0.23]) and lactate to pyruvate ratio values (pooled SMD - 0.20 [- 0.35 to - 0.05]) was observed after hyperoxia. However, glucose levels (pooled SMD - 0.08 [- 0.23 to 0.08]) remained unchanged after hyperoxia.
CONCLUSIONS: Normobaric hyperoxia may improve cerebral metabolic disturbances in patients with acute brain injury. The clinical impact of such effects needs to be further elucidated.

Under natural conditions, plants constantly encounter various fluctuating environmental stresses, which potentially restrict plant growth, plant development and even limit crop productivity. In addition to carbon fixation activity in C4 photosynthesis, NADP-dependent malic enzyme (NADP-ME) has been suggested to play important roles in diverse stress responses in plants. NADP-ME is one of the essential enzymes metabolizing malate, which is important for stabilizing cytoplasmic pH, controlling stomatal aperture, increasing resistance to aluminum excess and pathogen. Pyruvate, another product of NADP-ME reaction, participates in the synthesis of defense compounds such as flavonoids and lignin, which are involved in stresses tolerance such as mechanical wounding and pathogen invasion. Moreover, NADP-ME provides essential reductive coenzyme NADPH in the biosynthesis of flavonoids and lignin. On the other hand, NADPH is crucial for reactive active species (ROS) metabolizing systems such as the ascorbate-glutathione pathway and NADPH-dependent thioredoxin reductase, and is also required by apoplastic oxidative burst in most plant-pathogen interactions. This mini-review is largely focus on the characteristics of gene expression and activity of NADP-ME, as well as its interaction with ROS signaling under a variety of biotic and abiotic stress responses, which will provide a theoretical foundation for breeding of stress resistant crops.

BACKGROUND: Objective interpretation of laboratory test results used to diagnose and monitor diabetes mellitus in part requires the application of biological variation data (BVD). The quality of published BVD has been questioned. The aim of this study was to quality assess publications reporting BVD for diabetes-related analytes using the Biological Variation Data Critical Appraisal Checklist (BIVAC); to assess whether published BVD are fit for purpose and whether the study design and population attributes influence BVD estimates and to undertake a meta-analysis of the BVD from BIVAC-assessed publications.
METHODS: Publications reporting data for glucose, HbA1c, adiponectin, C-peptide, fructosamine, insulin like growth factor 1 (IGF-1), insulin like growth factor binding protein 3 (IGFBP-3), insulin, lactate and pyruvate were identified using a systematic literature search. These publications were assessed using the BIVAC, receiving grades A, B, C or D, where A is of highest quality. A meta-analysis of the BVD from the assessed studies utilised weightings based upon BIVAC grades and the width of the data confidence intervals to generate global BVD estimates.
RESULTS: BIVAC assessment of 47 publications delivered 1 A, 3 B, 39C and 4 D gradings. Publications relating to adiponectin, C-peptide, IGF-1, IGFBP-3, lactate and pyruvate were all assessed as grade C. Meta-analysis enabled global BV estimates for all analytes except pyruvate, lactate and fructosamine.
CONCLUSIONS: This study delivers updated and evidence-based BV estimates for diabetes-related analytes. There remains a need for delivery of new high-quality BV studies for several clinically important analytes.

BACKGROUND: Prevention and detection of secondary brain insults via multimodality neuromonitoring is a major goal in patients with severe traumatic brain injury (TBI).
OBJECTIVE: Explore the underlying pathophysiology and clinical outcome correlates as it pertains to combined monitoring of ≥2 from the following variables: partial brain tissue oxygen tension (PbtO(2)), pressure reactivity index (PRx), and lactate pyruvate ratio (LPR).
METHODS: Data sources included Medline, EMBASE, and evidence-based databases (Cochrane DSR, ACP Journal Club, DARE, and the Cochrane Controlled Trials Register). The PRISMA recommendations were followed. Two authors independently selected articles meeting inclusion criteria. Studies enrolled adults who required critical care and monitoring in the setting of TBI. Included studies reported on correlations between the monitored variables and/or reported on correlations of the variables with clinical outcomes.
RESULTS: Thirty-four reports were included (32 observational studies and 2 randomized controlled trials) with a mean sample size of 34 patients (range 6-223), and a total of 1,161 patient-observations. Overall methodological quality was moderate. Due to inter-study heterogeneity in outcomes of interest, study design, and in both number and type of covariates included in multivariable analyses, quantitative synthesis of study results was not undertaken.
CONCLUSIONS: Several literature limitations were identified including small number of subjects, lack of clinical outcome correlations, inconsistent probe location, and overall moderate quality among the included studies. These limitations preclude any firm conclusions; nevertheless we suggest that the status of cerebrovascular reactivity is not only important for cerebral perfusion pressure optimization but should also inform interpretation and interventions targeted on PbtO(2) and LPR. Assessment of reactivity can be the first step in approaching the relations among cerebral blood flow, oxygen delivery, demand, and cellular metabolism.

Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection.