ABSTRACT
OBJECTIVES: Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage. METHODS: Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes. RESULTS: OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the tricarboxylic acid (TCA) cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions. CONCLUSION: This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.
Subject(s)
Cartilage, Articular , Osteoarthritis , Humans , Animals , Cattle , Chondrocytes/metabolism , Cartilage, Articular/metabolism , Osteoarthritis/metabolism , Energy Metabolism , Glucose/metabolism , Cells, CulturedABSTRACT
Sixteen patients with previously intractable neurogenic pain were treated with carbamazepine (CBZ) for a period of six weeks. CBZ initial daily dosage of 400 mg was increased by a similar amount every second week to a maximum of 1,200 mg. Single dose kinetic studies prior to initiating CBZ therapy showed that these patients metabolised the drug similarly to healthy controls. Side effects, including rash (3) and ataxia (3), necessitated discontinuation of treatment in six patients. A further three patients withdrew because of lack of effect. Of the seven patients who completed the protocol, five showed a significant fall in pain score at all dosage increments with a maximum effect at the highest dose (p less than 0.01). In the seven patients for whom data was available at all three CBZ dosages, there was a significant correlation between sedation scores and CBZ concentrations (p less than 0.005). CBZ may be of value in the management of chronic neurogenic pain. Further controlled studies are indicated.
Subject(s)
Carbamazepine/therapeutic use , Pain, Intractable/drug therapy , Adolescent , Adult , Aged , Brachial Plexus/injuries , Carbamazepine/administration & dosage , Carbamazepine/metabolism , Clinical Trials as Topic , Female , Herpesviridae Infections/complications , Humans , Kinetics , Male , Middle Aged , Neuralgia/complications , Neuralgia/etiology , Pain, Intractable/etiology , Peripheral Nerve InjuriesABSTRACT
In a small open dose-finding study the i.v. dose of ICI 35 868 required to induce anaesthesia in healthy adults was 2 mg kg-1. Comparison of this dose with Althesin 0.05 ml kg-1 for i.v. induction, both injected over 30 s suggests that they have similar effects on heart rate, arterial pressure and breathing. The mean times to loss of eyelash reflex were 57 +/- SD 10.1 s (ICI 35 868) and 46 +/- 3.9s (Althesin). The new drug was associated with pain and discomfort on injection in seven of 10 patients, but with less involuntary movement than occurred with Althesin.
Subject(s)
Alfaxalone Alfadolone Mixture , Anesthesia, Intravenous/methods , Anesthetics , Phenols , Adolescent , Adult , Alfaxalone Alfadolone Mixture/administration & dosage , Alfaxalone Alfadolone Mixture/pharmacology , Anesthetics/administration & dosage , Anesthetics/pharmacology , Double-Blind Method , Drug Administration Schedule , Drug Evaluation , Hemodynamics/drug effects , Humans , Middle Aged , Phenols/administration & dosage , Phenols/pharmacology , PropofolABSTRACT
A double-blind comparison of glycopyrrolate with atropine as the anticholinergic component of premedication was made in 200 patients undergoing minor or intermediate surgical procedures. Glycopyrrolate was associated with a smaller increase in heart rate, but there was no difference between the drugs in respect of cardiac arrhythmia, change in arterial pressure, control of secretions in the upper respiratory tract, frequency of nausea and vomiting after operation or subjective well-being of the patients.
Subject(s)
Atropine , Glycopyrrolate , Preanesthetic Medication , Pyrrolidines , Adolescent , Adult , Aged , Atropine/pharmacology , Blood Pressure/drug effects , Clinical Trials as Topic , Double-Blind Method , Female , Glycopyrrolate/pharmacology , Heart Rate/drug effects , Humans , Male , Middle Aged , Pyrrolidines/pharmacology , Random AllocationABSTRACT
A survey is presented of current trends in molecular spectroscopy research using optical methods. The scientific interests of workers in this field and areas of currently active research are reviewed.
