A new look at osteoarthritis: Threshold potentials and an analogy to hypocalcemia.

Cartilage is a tissue that consist of very few cells embedded in a highly negatively charged extracellular matrix (ECM). This tissue is dealing with several electrical potentials which have been shown to control the production of ECM. Cartilage is present at joints and is constantly prone to degradation. Failing to repair the damage will result in the occurrence of osteoarthritis (OA). This perspective aims to link biophysical insights with biomolecular research in order to provide an alternative view on the possible causes of OA. Firstly, we hypothesize the existence of a threshold potential, which should be reached in order to initiate repair but if not met, unrepaired damage will evolve to OA. Measurements of the magnitude of this threshold electrical potential would be a helpful diagnostic tool. Secondly, since electrical potential alterations can induce chondrocytes to synthesize ECM, a cellular sensor must be present. We here propose an analogy to the hypocalcemia 'unshielding' situation to comprehend electrical potential generation and explore possible sensing mechanisms translating the electrical message into cellular responses. A better understanding of the cellular voltage sensors and down-stream signalling mechanisms may lead to the development of novel treatments for cartilage regeneration.

Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review.

OBJECTIVE: To systematically review the literature on the relationship between markers of inflammation and pain in patients with knee osteoarthritis (OA). METHODS: We searched MEDLINE, Web of Science and EMBASE databases from inception until June 2021. Eligible articles had to report on the association between inflammation (as measured by effusion, synovitis, baker's cysts, cytokines and C-reactive protein) and pain in patients with radiographic knee OA. Two reviewers independently performed a screening on title and abstracts, data extraction and risk of bias assessment using the Newcastle-Ottawa Scale (NOS). A best evidence synthesis was conducted for each inflammatory sign included in this review. RESULTS: 37 studies were included. Articles reported on the following measures: effusion or synovitis assessed via ultrasound (n = 9) or magnetic resonance imaging (MRI) (n = 17); baker's cyst (n = 3); cytokine concentrations (n = 11); and C-reactive protein levels (n = 4). The strength of the association between inflammation and pain does not exceed the moderate level (i.e., correlation coefficient values ranging from 0.19 to 0.61). Moderate levels of evidence were found for the association between synovitis (measured with ultrasound or contrast enhanced MRI) and pain. The levels of evidence between effusion (assessed via ultrasound), effusion/synovitis (assessed via non-contrast enhanced MRI), Baker's cyst, cytokines, C-reactive protein and pain were conflicting. CONCLUSIONS: Different inflammatory markers are associated with pain but the correlation ranges from weak to moderate, and the quality of evidence from conflicting to moderate. Further research is needed to strengthen the level of evidence and to establish mechanisms.

Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study.

Increased fracture risk in patients with Ehlers-Danlos syndromes has been reported, but the reasons for it are incompletely understood. We aimed to investigate possible determinants of this increased risk and found that hEDS/HSD patients present with a cortical bone size deficit compared with control subjects, possibly related to lower mechanical loading. INTRODUCTION: The Ehlers-Danlos syndromes (EDS) comprise a group of heritable connective tissue disorders caused by defects in the biosynthesis, secretion, and/or organization of fibrillar collagens which might impair bone strength. Our aim was to compare fracture prevalence, volumetric and areal bone mineral density (BMD), bone geometry, muscle size and the muscle-bone interaction, body composition and longitudinal changes therein between patients with hypermobile EDS (hEDS) or hypermobility spectrum disorder (HSD), and healthy control subjects. METHODS: Cross-sectional data comprised 39 female hEDS/HSD patients (age 41 ± 11 years) and 43 age-matched controls. After 8 years, 27 hEDS/HSD and 17 control subjects were re-evaluated. Tibial trabecular and cortical volumetric BMD, bone mineral content (BMC), cortical bone geometry, and lower leg muscle cross-sectional area (CSA) were measured using pQCT. Body composition, areal BMD, and BMC were determined by DXA. RESULTS: At baseline, patients with hEDS/HSD presented with a smaller cortical bone area, smaller cortical thickness and muscle CSA, and a higher fracture prevalence than control subjects (all p < 0.05). No differences in areal or volumetric BMD were found. Longitudinally, muscle CSA decreased in both groups and muscle density decreased in the hEDS/HSD group (p < 0.001) whereas all bone parameters remained unchanged. CONCLUSION: hEDS/HSD patients have a cortical bone size deficit compared with controls, possibly contributing to their increased fracture risk. They presented with decreased muscle CSA but normal bone/muscle area ratio, suggesting that this bone size deficit is likely secondary to decreased mechanical loading. Further, there were no arguments for accelerated bone loss in hEDS/HSD subjects.

Generalized Hyperalgesia in Children and Adults Diagnosed With Hypermobility Syndrome and Ehlers-Danlos Syndrome Hypermobility Type: A Discriminative Analysis.

OBJECTIVE: Lowered pressure-pain thresholds have been demonstrated in adults with Ehlers-Danlos syndrome hypermobility type (EDS-HT), but whether these findings are also present in children is unclear. Therefore, the objectives of the study were to determine whether generalized hyperalgesia is present in children with hypermobility syndrome (HMS)/EDS-HT, explore potential differences in pressure-pain thresholds between children and adults with HMS/EDS-HT, and determine the discriminative value of generalized hyperalgesia. METHODS: Patients were classified in 1 of 3 groups: HMS/EDS-HT, hypermobile (Beighton score ≥4 of 9), and healthy controls. Descriptive data of age, sex, body mass index, Beighton score, skin laxity, and medication usage were collected. Generalized hyperalgesia was quantified by the average pressure-pain thresholds collected from 12 locations. Confounders collected were pain locations/intensity, fatigue, and psychological distress. Comparisons between children with HMS/EDS-HT and normative values, between children and adults with HMS/EDS-HT, and corrected confounders were analyzed with multivariate analysis of covariance. The discriminative value of generalized hyperalgesia employed to differentiate between HMS/EDS-HT, hypermobility, and controls was quantified with logistic regression. RESULTS: Significantly lower pressure-pain thresholds were found in children with HMS/EDS-HT compared to normative values (range -22.0% to -59.0%; P ≤ 0.05). When applying a threshold of 30.8 N/cm2 for males and 29.0 N/cm2 for females, the presence of generalized hyperalgesia discriminated between individuals with HMS/EDS-HT, hypermobility, and healthy controls (odds ratio 6.0). CONCLUSION: Children and adults with HMS/EDS-HT are characterized by hypermobility, chronic pain, and generalized hyperalgesia. The presence of generalized hyperalgesia may indicate involvement of the central nervous system in the development of chronic pain.

Exoskeleton plantarflexion assistance for elderly.

Elderly are confronted with reduced physical capabilities and increased metabolic energy cost of walking. Exoskeletons that assist walking have the potential to restore walking capacity by reducing the metabolic cost of walking. However, it is unclear if current exoskeletons can reduce energy cost in elderly. Our goal was to study the effect of an exoskeleton that assists plantarflexion during push-off on the metabolic energy cost of walking in physically active and healthy elderly. Seven elderly (age 69.3±3.5y) walked on treadmill (1.11ms2) with normal shoes and with the exoskeleton both powered (with assistance) and powered-off (without assistance). After 20min of habituation on a prior day and 5min on the test day, subjects were able to walk with the exoskeleton and assistance of the exoskeleton resulted in a reduction in metabolic cost of 12% versus walking with the exoskeleton powered-off. Walking with the exoskeleton was perceived less fatiguing for the muscles compared to normal walking. Assistance resulted in a statistically nonsignificant reduction in metabolic cost of 4% versus walking with normal shoes, likely due to the penalty of wearing the exoskeleton powered-off. Also, exoskeleton mechanical power was relatively low compared to previously identified optimal assistance magnitude in young adults. Future exoskeleton research should focus on further optimizing exoskeleton assistance for specific populations and on considerate integration of exoskeletons in rehabilitation or in daily life. As such, exoskeletons should allow people to walk longer or faster than without assistance and could result in an increase in physical activity and resulting health benefits.

Lower insulin sensitivity is related to lower relative muscle cross-sectional area, lower muscle density and lower handgrip force in young and middle aged non-diabetic men.

OBJECTIVES: This study investigated whether an association between insulin resistance (IR) and muscle parameters is appreciable in young healthy men, independent of obesity. Furthermore, markers of muscle metabolism and hormones/possible determinants, were explored. METHODS: 358 healthy young men were divided into a less and more insulin sensitive (LIS [age=33.2±5.4, BMI=23.4±2.3] and MIS [age=35.5±5.3, BMI=28.1±3.7]) group based on upper and lower quartile of HOMA-IR. Muscle cross-sectional area (CSA), -density, handgrip force, serum testosterone, estradiol, SHBG, Vitamin 25(OH)D, creatinine, IGF-1, IGFBP-3 and leptin levels were compared between these groups, correcting for differences in age, physical activity and fat mass. Correlations between HOMA-IR and these parameters, and between muscle measures and biochemical parameters, were calculated. RESULTS: LIS is related to lower relative muscle CSA, muscle density, muscle/fat CSA ratio, relative handgrip force and level of physical activity. Furthermore, lower levels in SHBG, testosterone, Vitamin 25(OH)D and higher leptin, IGF-1 and IGFBP-3 levels were observed in LIS. Bio available T, FT, TE2, FE2, bioavailable E2, serum and urinary creatinine levels did not differ between groups. CONCLUSION: Differences in muscle performance are already present in healthy men with lower insulin sensitivity and could be possibly modifiable risk factors for the development of type 2 diabetes.

Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, as is the prevalence of obesity and type 2 diabetes. It is increasingly recognized that an impaired pattern in adipokine secretion could play a pivotal role in the development of NAFLD. We performed a systematic review to evaluate the potential link between newly described adipokines and liver histology in biopsy-proven NAFLD patients. A computerized literature search was performed in PubMed, EMBASE and Web of Science electronic databases. Thirty-one cross-sectional studies were included, resulting in a total of seven different investigated adipokines. Studies included in this review mainly had a good methodological quality. Most adipokines were suggested to be involved in the inflammatory response that develops within the context of NAFLD, either at hepatic or systemic level, and/or hepatic insulin resistance. Based on literature, clinical studies suggest that chemerin, resistin and adipocyte-fatty-acid-binding protein potentially are involved in NAFLD pathogenesis and/or progression. However, major inconsistency still exists, and there is a high need for larger studies, together with the need of standardized assays to determine adipokine levels.

Association between insulin resistance, lean mass and muscle torque/force in proximal versus distal body parts in healthy young men.

OBJECTIVES: The purpose of this study was to investigate whether there is already an association of insulin resistance (IR) with muscle mass and -force/torque in an adult population and whether this relationship is the same in distal and proximal body parts. METHODS: 358 Healthy young men were divided into a more insulin sensitive (MIS) (n=89) and a less insulin sensitive (LIS) group (n=89), respectively using lower and upper quartiles of HOMA-IR index (Homeostasis Model Assessment of IR). Muscle force/torque and lean mass, were compared between the two groups. RESULTS: LIS subjects had higher absolute thigh lean mass, but not higher thigh muscle torque, resulting in a lower torque per kg muscle. In upper arm, lean mass was higher in LIS subjects, but also absolute muscle torque resulted higher. For handgrip force, the LIS and MIS group had similar results, despite a trend towards higher forearm lean mass in LIS subjects. Lean mass % of total lean mass is lower in LIS subjects in more distal body parts. CONCLUSIONS: Already in a young healthy population, IR seems to be associated with lower force/torque per muscle mass and lower lean mass % of total lean mass predominantly in more distal body parts.

Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: a meta-analytic review.

The aim of this review is to determine the relationship between gestational age (GA) and prevalence, type, distribution, and severity of cerebral palsy (CP). Epidemiological studies with cohorts expressed by GA were assessed. A comprehensive meta-analysis and meta-regression was performed on four fetal age categories. Studies of children with CP as a target population were added. Twenty-six articles met the inclusion criteria. The prevalence of CP decreases significantly with increasing GA category: 14.6% at 22 to 27 weeks' gestation, 6.2% at 28 to 31 weeks, 0.7% at 32 to 36 weeks, and 0.1% in term infants. Interestingly, a significant decrease in prevalence of CP starts only from a GA of 27 weeks onwards. In preterm infants, spastic CP is predominant. In term infants, the non-spastic form of CP is more prevalent than in preterm infants. Bilateral spastic CP is most prevalent in both preterm and term infants. However, the proportion of unilateral spastic CP in term infants is substantial. No relationship could be detected between severity of CP and GA. There is a strong need for an international, well-described, and generally accepted classification system for subtypes and severity of CP.

Carbohydrate availability affects ammonemia during exercise after beta 2-adrenergic blockade.

PURPOSE: Beta-adrenergic blockade increases blood ammonia concentration during exercise. The purpose of this study was to assess the role of decreased carbohydrate availability in this process. METHODS: Wistar rats (N = 47) were injected intravenously with a selective beta 2-adrenoceptor blocker (ICI 118,551), placebo, or beta 2-blocker + glucose 1 h before a treadmill exercise test. Blood samples were taken to measure the concentration of ammonia, glucose, lactic acid, free fatty acids (FFA), glycerol, branched-chain amino acids (BCAA), and muscle samples for determination of glycogen content. RESULTS: Beta 2-adrenergic blockade shortened running time to exhaustion (23 +/- 4.3 min compared to 44 +/- 5.2 min with placebo), increased blood ammonia levels (146.7 +/- 16.21 micromol x L(-1) compared to 47.5 +/- 0.92 micromol x L(-1) with placebo) and prevented exercise-induced glycogen breakdown in soleus and gastrocnemius muscles. Pre-exercise supplementation of glucose during beta 2-blockade restored exercise-induced glycogen breakdown and reduced blood ammonia concentration during exercise (66.5 +/- 5.65 mmol x L(-1)) but did not improve exercise capacity (26 +/- 3.2 min) when compared with beta2-blockade alone. CONCLUSION: The results suggest that the enhanced rise in blood ammonia concentration during exercise after beta-blockade is caused by impaired carbohydrate availability.

Influence of some phospholipase A2 and cytochrome P450 inhibitors on rat arterial smooth muscle K+ currents.

The hyperpolarizing factor that is liberated by vascular endothelial cells in response to various agonists, and known to induce relaxation by opening of smooth muscle K+ channels, has been suggested to be a product of cytochrome P450 dependent arachidonic acid metabolism. In this study, the direct influence of two phospholipase A2 inhibitors and of five structurally and mechanistically different cytochrome P450 inhibitors on K+ currents in freshly isolated vascular smooth muscle cells from the rat aorta was investigated. On stepping the cell membrane potential from -70 mV to a series of depolarized test potentials, a noisy outward current developed at test potentials > +10 mV, which showed no appreciable inactivation during the voltage pulse. It was largely abolished by 3 mM external tetraethylammonium chloride (TEA), suggesting that it predominantly consisted of current through large-conductance Ca(2+)-activated K+ channels. The phospholipase A2 inhibitor quinacrine considerably inhibited this TEA-sensitive current, while 4-bromophenacylbromide exerted no effect. The cytochrome P450 inhibitors proadifen and miconazole reversibly decreased the amplitude of I(K), while clotrimazole and 1-aminobenzotriazole had no effect. Conversely, 17-octadecynoic acid increased whole-cell I(K). These results show that some phospholipase A2 and cytochrome P450 inhibitors may interfere with K+ channel activation in the rat arterial smooth muscle cell. The relevance of these findings to studies on the involvement of cytochrome P450 dependent metabolism in the generation of the endothelium-derived hyperpolarizing factor in intact arteries is discussed.

Effect of branched-chain amino acids (BCAA), glucose, and glucose plus BCAA on endurance performance in rats.

PURPOSE: The purpose of this study was to assess the effects of pre-exercise administration of branched-chain amino acids (BCAA), glucose, and glucose plus BCAA on time to exhaustion during treadmill exercise in rats. METHODS: Wistar rats were injected intraperitoneally with 1 mL of saline (0.9% NaCl), BCAA (30 mg), glucose (100 mg), or glucose plus BCAA 5 min before either 45 min of submaximal exercise (N = 32) or running to exhaustion (N = 24). After the submaximal exercise test, blood was collected for the measurement of ammonia, BCAA, free tryptophan (free TRP), glucose, free fatty acid, and lactic acid, and muscle samples were taken from the m. soleus for determination of glycogen content. RESULTS: Mean run time to exhaustion was significantly longer after BCAA administration (158+/-26 min) compared with that after saline (118+/-35 min)(P<0.05) but not compared with that after glucose administration (179+/-21 min). When glucose is administered before exercise, the supplementary administration of BCAA had no additional effect on performance (171+/-12 min). The data on blood ammonia, ratio of free TRP/BCAA, and muscle glycogen did not provide a clue for explaining the higher endurance performance after BCAA supplementation. CONCLUSION: The results support the hypothesis that the effect of BCAA administration on performance could be related to carbohydrate availability during exercise.

Progesterone-transforming enzyme activity in the hypothalamus of the male rat.

The aim of the present study was to assess the activities of the progesterone (Pr) transforming enzyme systems 3alpha-oxidoreductase (3alpha-OR), 5alpha-reductase (5alpha-R) and 20alpha-oxidoreductase (20alpha-OR) in the hypothalamus of the male rat, at different stages of sexual maturation and following castration and adrenalectomy. Special attention was paid to transformation to 3alpha-reduced compounds previously shown to inhibit FSH synthesis and secretion. Homogenates of hypothalamic tissue were incubated with 14C-progesterone. Pr-metabolites were isolated, identified by gas chromatography/mass-spectrometry (GC/MS) and measured by liquid scintillation counting (LSC). In adult rats a ratio of 6:2.5:1 for 5alpha-R:3alpha-OR:20alpha-OR enzyme- activities was found. The hypothalamic 5alpha-R and particularly 3alpha-OR activities were considerably higher before puberty (10-20 day old rats) than in adulthood. Adrenalectomy in adult rats resulted in an increased activity of the three enzyme systems. No significant changes were seen following castration. Among the isolated metabolites, 3alpha-hydroxy-pregn-4-en-20-one (3alpha-Pr) and 3alpha-hydroxy-5alpha-pregnane-20-one (5alpha,3alpha-Pr) were identified. Conversion to both these neurosteroids was considerably higher during prepuberty than in adulthood. The finding that before puberty the hypothalamus has a markedly increased capacity to convert Pr to 3alpha-reduced compounds, such as 3alpha-Pr, known to effectively inhibit FSH release, warrants further research into the mechanisms regulating the hypothalamic formation of biologically active Pr derivatives and their role in the regulation of gonadotropin secretion.

Inhaled salbutamol decreases blood ammonia levels during exercise in normal subjects.

The present study examines the effect of salbutamol, a beta2-adrenoreceptor agonist, on blood ammonia levels during an incremental cycle exercise test in healthy non-asthmatic subjects. Blood ammonia levels were lower after inhalation of 400 mcg of salbutamol than after placebo during submaximal exercise: 33+/-2 micromol x l(-1) v.s. 48+/-9 micromol x l(-1) at 220 W and 39+/-2 micromol x l(-1) v.s. 50+/-4 micromol x l(-1) at 260 W. At peak exercise there were no significant differences. The results suggest that beta2-adrenoreceptors are involved in the regulation of blood ammonia during exercise.

Pre-exercise branched-chain amino acid administration increases endurance performance in rats.

This study investigated the effects of pre-exercise branched-chain amino acid (BCAA) administration on blood ammonia levels and on time to exhaustion during treadmill exercise in rats. Adult female Wistar rats were trained on a motor driven treadmill. After a 24-h fast, rats were injected intraperitoneally (i.p.) with 1 mL of placebo or BCAA (30 mg), 5 min before performing 30 min of submaximal exercise (N = 18) or running to exhaustion (N = 12). In both cases, rats were sacrificed immediately following exercise, and blood was collected for the measurement of glucose, nonesterified fatty acid (NEFA), lactic acid, BCAA, ammonia, and free-tryptophan (free-TRP) levels. Control values were obtained from sedentary rats that were subjected to identical treatments and procedures (N = 30). Plasma BCAA levels increased threefold within 5 min after BCAA administration. Mean run time to exhaustion was significantly longer (P < 0.01) after BCAA administration (99 +/- 9 min) compared with placebo (76 +/- 4 min). During exercise, blood ammonia levels were significantly higher (P < 0.01) in the BCAA treated compared with those in the placebo treated rats both in the 30-min exercise bout (113 +/- 25 mumol.L-1 (BCAA) vs 89 +/- 16 mumol.L-1) and following exercise to exhaustion (186 +/- 44 mumol.L-1 (BCAA) vs 123 +/- 19 mumol.L-1). These data demonstrate that BCAA administration in rats results in enhanced endurance performance and an increase in blood ammonia during exercise.

Effects of acute cardioselective and non-selective beta-adrenergic blockade on plasma ammonia levels in exercising dogs.

The aim of this study was to assess plasma ammonia levels during acute treadmill exercise in dogs after intravenous administration of a single dose of different cardioselective (atenolol) and non-selective (sotalol and propranolol) beta-adrenergic blocking drugs. The experiments were performed on 6 male mongrel dogs (20-25 kg) trained to run on a motor driven treadmill. After administration of saline or atenolol, there was no significant increase in plasma ammonia during exercise; propranolol and sotalol however, both non-selective beta-blockers, produced a significant increase in plasma ammonia. Plasma levels of alanine and glutamine were not altered during exercise compared with resting values, and were not modified by the administration of beta-blockers. It is not clear whether the different effects on exercise induced hyperammonemia are due to different effects on muscle ammonia formation or on the ammonia clearance by the liver.

Effects of acute non-selective beta-adrenergic blockade on plasma ammonia levels in exercising dogs.

The purpose of the present study was to document exercise induced hyperammoniemia after blockade of the beta-adrenoceptors and to investigate the effect of administration of branched-chain amino acids (BCAA) and glucose in these conditions. Seven dogs, chronically instrumented with a catheter in the deep jugular vein and a Doppler probe around the carotid artery were trained to perform a ten-minute treadmill exercise test. Administration of propranolol i.v. prior to exercise increases plasma ammonia at peak exercise compared with placebo (78 +/- 7.9 vs 25 +/- 5.1 mumol/l; p < 0.05). This effect of propranolol on plasma ammonia during exercise is enhanced by the administration of BCAA (108 +/- 15 vs 78 +/- 7.9 mumol/l; p < 0.05), and diminished by the administration of glucose (42 +/- 7.7 vs 78 +/- 7.9 mumol/l; p < 0.05). These results suggest that increased metabolisation of BCAA is involved in the ammonia formation after beta-adrenergic blockade.

Effect of adrenergic receptor blockade on plasma testosterone response to exercise in conscious dogs.

The aim of this study was 1) to establish the relationship between testosterone (T) levels and the intensity and duration of exercise in conscious dogs, and 2) to investigate the involvement of the sympathetic system in the response of plasma T to acute exercise. The experiments were performed on 14 male mongrel dogs (20-25 kg) trained to run on a motor driven treadmill. Testosterone (T), cortisol, epinephrine, norepinephrine, lactate and haematocrit were measured in arterial blood samples. A brief intensive exercise (leading to exhaustion within 5 or 20 min) induced a marked increase in plasma T, while during more prolonged (60 min) exercise plasma T showed an initial increase followed by a secondary decrease. Blockade of the beta adrenergic receptors with propranolol (Inderal 0.5 mg/kg i.v.) did not modify the changes of plasma T during exercise, but blockade of alpha adrenergic receptors with phentolamine (Regitine 0.5 mg/kg) lowered the exercise induced rise in plasma T.