The regional turnover of cartilage collagen matrix in late-stage human knee osteoarthritis.

OBJECTIVE: Cartilage collagen has very limited repair potential, though some turnover and incorporation has not been fully excluded. We aim to determine the regional turnover of human osteoarthritis cartilage. DESIGN: Patients scheduled for knee joint replacement surgery due to osteoarthritis were recruited in this prospective study of four weeks duration. Deuterium oxide (D2O) was administered orally by weekly boluses at 70% D2O, initially 150 ml followed by three boluses of 50 ml. Cartilage from the medial tibia plateau was sampled centrally, under the meniscus, and from osteophytes and treated enzymatically with hyaluronidase and trypsin. Samples were analysed for deuterium incorporation in alanine using mass spectrometry and for gene expression by real-time reverse transcriptase polymerase chain reaction. RESULTS: Twenty participants completed the study: mean (SD) age 64 ± 9.1 years, 45% female, BMI 29.5 ± 4.8 kg/m2. Enzymatically treated cartilage from central and submeniscal regions showed similar enrichments at 0.063% APE, while osteophytes showed significantly greater enrichment at 0.072% APE (95% confidence interval of difference) [0.004-0.015]). Fractional synthesis rates were similar for central 0.027%/day and submeniscal cartilage 0.022%/day but 10-fold higher in osteophytes 0.22%/day [0.098-0.363]. When compared to central cartilage, submeniscal cartilage had increased gene expression of MMP-3 and decreased lubricin expression. Untreated cartilage had higher turnover (enrichments at 0.073% APE) than enzymatically treated cartilage (0.063% APE). CONCLUSIONS: In OA, despite regional differences in gene expression, the turnover of the articular cartilage matrix across the entire joint surface is very limited, but higher turnover was observed in osteophyte cartilage.

Muscle protein breakdown is impaired during immobilization compared to during a subsequent retraining period in older men: no effect of anti-inflammatory medication.

Muscle inactivity reduces muscle protein synthesis (MPS), whereas a subsequent period of rehabilitation resistance training (retraining) increases MPS. However, less is known regarding muscle protein breakdown (MPB) during such conditions. Furthermore, nonsteroidal anti-inflammatory drugs (NSAIDs) may have a dampening effect on MPB during periods of inactivity in older individuals. Thus, we measured the average MPB, by use of the deuterated water methodology, during an immobilization period and a subsequent retraining period in older individuals with and without NSAID treatment. Eighteen men (60-80 years: range) were randomly assigned to ibuprofen (1200 mg/d, Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2 weeks and retrained for 2 weeks, and 2 × 20 g of whey protein was ingested daily during both periods. Besides MPB, the protein expression of different muscle degradation signaling molecules was investigated. MPB was lower during immobilization compared to retraining (p < 0.01). NSAID treatment did not affect the MPB rate during immobilization or retraining (p > 0.05). The protein expression of muscle degradation signaling molecules changed during the study intervention but were unaffected by NSAID treatment. The finding that MPB was lower during immobilization than during retraining indicates that an increased MPB may play an important role in the muscle protein remodeling processes taking place within the initial retraining period. Moreover, NSAID treatment did not significantly influence the MPB rate during 2 weeks of lower limb immobilization or during 2 weeks of subsequent retraining in older individuals.

Lower basal and postprandial muscle protein synthesis after 2 weeks single-leg immobilization in older men: No protective effect of anti-inflammatory medication.

Muscle inactivity may reduce basal and postprandial muscle protein synthesis (MPS) rates in humans. Anti-inflammatory treatment alleviates the MPS impairments in younger individuals. The present study explored the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) upon MPS during a period of inactivity in older humans. Eighteen men (age 60-80 years) were allocated to ibuprofen (1200 mg/day, Ibu) or control (Plc) groups. One lower limb was cast immobilized for 2 weeks. Postabsorptive and postprandial MPS was measured before and after the immobilization by L-[ring-13 C6 ]-phenylalanine infusion. The protein expression of select anabolic signaling molecules was investigated by western blot. Basal (0.038 ± 0.002%/h and 0.039 ± 0.005%/h, Plc and Ibu, respectively) and postprandial (0.064 ± 0.004%/h and 0.067 ± 0.010%/h, Plc and Ibu, respectively) MPS rate were higher pre-immobilization compared to basal (0.019 ± 0.005%/h and 0.020 ± 0.010%/h, Plc and Ibu, respectively) and postprandial (0.033 ± 0.005%/h and 0.037 ± 0.006%/h, Plc and Ibu, respectively) MPS rate post-immobilization (p < 0.001). NSAID treatment did not affect the suppression of MPS (p > 0.05). The anabolic signaling were in general reduced after immobilization (p < 0.05). These changes were unaffected by NSAID treatment (p > 0.05). Basal and postprandial MPS dropped markedly after 2 weeks of lower limb immobilization. NSAID treatment neither influenced the reduction in MPS nor the anabolic signaling after immobilization in healthy older individuals.

Myopathic changes in patients with long-term fatigue after COVID-19.

OBJECTIVE: To investigate the peripheral nerve and muscle function electrophysiologically in patients with persistent neuromuscular symptoms following Coronavirus disease 2019 (COVID-19). METHODS: Twenty consecutive patients from a Long-term COVID-19 Clinic referred to electrophysiological examination with the suspicion of mono- or polyneuropathy were included. Examinations were performed from 77 to 255 (median: 216) days after acute COVID-19. None of the patients had received treatment at the intensive care unit. Of these, 10 patients were not even hospitalized. Conventional nerve conduction studies (NCS) and quantitative electromyography (qEMG) findings from three muscles were compared with 20 age- and sex-matched healthy controls. RESULTS: qEMG showed myopathic changes in one or more muscles in 11 patients (55%). Motor unit potential duration was shorter in patients compared to healthy controls in biceps brachii (10.02 ± 0.28 vs 11.75 ± 0.21), vastus medialis (10.86 ± 0.37 vs 12.52 ± 0.19) and anterior tibial (11.76 ± 0.31 vs 13.26 ± 0.21) muscles. All patients with myopathic qEMG reported about physical fatigue and 8 patients about myalgia while 3 patients without myopathic changes complained about physical fatigue. CONCLUSIONS: Long-term COVID-19 does not cause large fibre neuropathy, but myopathic changes are seen. SIGNIFICANCE: Myopathy may be an important cause of physical fatigue in long-term COVID-19 even in non-hospitalized patients.

Skeletal muscle morphology and regulatory signalling in endurance-trained and sedentary individuals: The influence of ageing.

Muscle mass in humans is inversely associated with circulating levels of inflammatory cytokines, but the interaction between ageing and training on muscle composition and the intra-muscular signalling behind inflammation and contractile protein synthesis and degradation is unknown. We studied 15 healthy life-long endurance runners, 12 age-matched untrained controls, 10 young trained and 12 young untrained individuals. Thigh muscle composition was investigated by magnetic resonance imaging (MRI), where non-contractile intramuscular tissue (NCIT) area (fat and connective tissue) was found to be greater in older but lower in trained individuals. Subcutaneous adipose tissue was also lower in trained individuals but was not affected by age. In vastus lateralis biopsies, no influence of age or training was found on levels of endomysial collagen, determined by Sirius Red and Collagen III staining, whereas perimysial organisation tended to be more complex in older individuals. No clear difference with training was seen on intramuscular inflammatory signalling, whereas lower protein levels of NFkB subunits p105, p50 and p65 were observed with ageing. Gene expression of IL6 and TNFα was not different between groups, while IL1-receptor and TNFα-receptor1 levels were lower with age. Myostatin mRNA was lower in older and trained groups, while expression of MuRF1 was lower in trained individuals and FoxO3 expression was greater in aged groups. The association of increased muscle NCIT with age-associated muscle loss in humans is not accompanied by any major alterations in intramuscular signalling for inflammation, but rather by direct regulatory factors for protein synthesis and proteolysis in skeletal muscle.

Acute acalculous cholecystitis in a patient with primary Epstein-Barr virus infection: a case report and literature review.

Epstein-Barr Virus (EBV) infection can lead to infectious mononucleosis syndrome with the typical symptoms of fever, pharyngitis, and lymphadenopathy. Self-limited mild to moderate elevation of liver enzymes and hepatosplenomegaly are common. However, cholecystitis is not usually considered part of a primary EBV infection and ultrasound scan (USS) of the liver and gallbladder is not routinely performed. Acute acalculous cholecystitis (AAC) caused by etiologies other than primary EBV infection is often associated with severe illness and antibiotic treatment and surgery may be needed. We present a case with primary EBV infection and AAC and a literature review. Our patient was a 34-year-old woman with clinical, biochemical and serological signs of primary EBV infection (lymphocytes 7.6×10˄9/l, monocytes 2.6×10˄9/l, positive early antigen IgM test and 14 days later positive early antigen IgG test). During admission, increasing liver function tests indicated cholestasis (alanine aminotransferase 61 U/l, alkaline phosphatase 429 U/l and bilirubin 42µmol/l). USS revealed a thickened gallbladder wall indicating cholecystitis but no calculus. All other microbiological tests were negative. The literature search identified 26 cases with AAC and acute EBV infection; 25 cases involved females. Sore throat was not predominant (six reported this), and all cases experienced gastrointestinal symptoms. Our and previous published cases were not severely ill and recovered without surgical drainage. In conclusion primary EBV infection should be considered in cases of AAC, especially in young women. In cases associated with EBV infection neither administration of antibiotics nor surgical drainage may be indicated.

Diphtheria-tetanus-pertussis vaccine administered simultaneously with measles vaccine is associated with increased morbidity and poor growth in girls. A randomised trial from Guinea-Bissau.

BACKGROUND: Combined vaccination with diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) has been associated with increased mortality in observational studies. Among children missing MV and a dose of DTP and oral polio vaccine (OPV), we conducted a randomised trial of providing MV+DTP+OPV simultaneously, as currently recommended, or MV+OPV only, and examined the effect on morbidity and growth. We hypothesised that the MV+OPV group would experience less morbidity and grow better. Due to previous observations of sex differences in the non-specific effects of vaccinations, we analysed all data stratified by sex. METHODS: At the Bandim Health Project in Guinea-Bissau, 568 children who were due to receive MV and who were missing either DTP3 or DTP booster were enrolled in the study. A subgroup of 332 children was followed intensively to register adverse events and infections in the first month after vaccination. A subgroup of 276 children was followed every third month for a year to monitor growth. All children were followed for one year for infectious diseases, consultations, and hospitalisations. RESULTS: As expected, adverse events were more common in the MV+DTP+OPV group; diarrhoea and use of medication were increased among girls but not among boys (both p=0.02, test of interaction between DTP and sex). Febrile disease with vesicular rash, as well as consultations and hospitalisations tended to be more common in the MV+DTP+OPV group than in the MV+OPV group; the hazard ratio (HR) for febrile disease with vesicular rash was 1.86 (1.00; 3.47). The strongest tendencies for more febrile diseases and hospitalisations in the MV+DTP+OPV group were found in girls. Overall, growth did not differ by randomisation group. However, results differed by sex. Girls in the MV+DTP+OPV group had a consistent pattern of worse z-scores for weight, height, and mid-upper-arm-circumference (MUAC) than girls in the MV+OPV group. The effect was opposite for boys, with boys in the MV+OPV group faring worse than those in the MV+DTP+OPV group, the interaction test for sex and DTP being significant for weight at 6 and 9 months, for MUAC at 12 months and for weight-for-height at 3 and 9 months after randomisation. CONCLUSION: This is the first randomised trial of the non-specific effects of DTP and supports that these effects may be sex-differential and of clinical and anthropometric importance. Combined vaccination with DTP+MV+OPV may be detrimental for girls.