Osteoarthritis (OA) of the knee is the most frequent form of arthritis and a cause of pain and disability. Combined nonpharmacologic and pharmacologic treatments are recommended as the optimal ...treatment approach, but no evidence supports the recommendation.
To assess the clinical benefits of an intra-articular corticosteroid injection given before exercise therapy in patients with OA of the knee.
We performed a randomized, blinded, placebo-controlled clinical trial evaluating the benefit of intra-articular corticosteroid injection vs placebo injection given before exercise therapy at an OA outpatient clinic from October 1, 2012, through April 2, 2014. The participants had radiographic confirmation of clinical OA of the knee, clinical signs of localized inflammation in the knee, and knee pain during walking (score >4 on a scale of 0 to 10).
Participants were randomly allocated (1:1) to an intra-articular 1-mL injection of the knee with methylprednisolone acetate (Depo-Medrol), 40 mg/mL, dissolved in 4 mL of lidocaine hydrochloride (10 mg/mL) (corticosteroid group) or a 1-mL isotonic saline injection mixed with 4 mL of lidocaine hydrochloride (10 mg/mL) (placebo group). Two weeks after the injections, all participants started a 12-week supervised exercise program.
The primary outcome was change in the Pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire (range, 0-100; higher scores indicate greater improvement) at week 14. Secondary outcomes included the remaining KOOS subscales and objective measures of physical function and inflammation. Outcomes were measured at baseline, week 2 (exercise start), week 14 (exercise stop), and week 26 (follow-up).
One hundred patients were randomized to the corticosteroid group (n = 50) or the placebo group (n = 50); 45 and 44 patients, respectively, completed the trial. The mean (SE) changes in the KOOS Pain subscale score at week 14 were 13.6 (1.8) and 14.8 (1.8) points in the corticosteroid and placebo groups, respectively, corresponding to a statistically insignificant mean difference of 1.2 points (95% CI, -3.8 to 6.2; P = .64). We found no statistically significant group differences in any of the secondary outcomes at any time point.
No additional benefit results from adding an intra-articular injection of 40 mg of corticosteroid before exercise in patients with painful OA of the knee. Further research is needed to establish optimal and potentially synergistic combinations of conservative treatments.
clinicaltrialsregister.eu Identifier: 2012-002607-18; clinicaltrials.gov Identifier: NCT01945749.
Computed tomography (CT) is a common modality employed for musculoskeletal imaging. Conventional CT techniques are useful for the assessment of trauma in detection, characterization and surgical ...planning of complex fractures. CT arthrography can depict internal derangement lesions and impact medical decision making of orthopedic providers. In oncology, CT can have a role in the characterization of bone tumors and may elucidate soft tissue mineralization patterns. Several advances in CT technology have led to a variety of acquisition techniques with distinct clinical applications. These include four-dimensional CT, which allows examination of joints during motion; cone-beam CT, which allows examination during physiological weight-bearing conditions; dual-energy CT, which allows material decomposition useful in musculoskeletal deposition disorders (e.g., gout) and bone marrow edema detection; and photon-counting CT, which provides increased spatial resolution, decreased radiation, and material decomposition compared to standard multi-detector CT systems due to its ability to directly translate X-ray photon energies into electrical signals. Advanced acquisition techniques provide higher spatial resolution scans capable of enhanced bony microarchitecture and bone mineral density assessment. Together, these CT acquisition techniques will continue to play a substantial role in the practices of orthopedics, rheumatology, metabolic bone, oncology, and interventional radiology.
Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism ...may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases.
We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model.
FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver.
The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.
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•FGF21 and GDF15 were highly increased in MASLD following glucagon stimulation.•Plasma FGF21 and GDF15 levels correlated with insulin, but not glucagon.•FGF21 was unaffected by glucagon stimulation when insulin levels were constant.•No direct effect of glucagon on FGF21 and GDF15 secretion•The increase of FGF21 and GDF15 by glucagon in MASLD may depend on insulin.
Glucagon is essential for glucose control and increased levels of glucagon (hyperglucagonemia) observed in patients with type 2 diabetes contribute to their hyperglycemia. Recently, hyperglucagonemia ...has also been found in individuals with non-alcoholic fatty liver disease (NAFLD) as well as impaired actions of glucagon on amino acid catabolism. Whether glucagon actions on hepatic glucose production are impaired is unknown. We investigated the acute effects of a single bolus of glucagon (0.2mg) on glucose dynamics in 18 normoglycemic individuals (age: 51±3 years, BMI; 31± 0.8kg/m2, hepatic fat content: 20±2%, fasting glucose: 5.5±0.1mM) with magnetic resonance imaging verified NAFLD and 22 controls (age: 38±3 years, BMI; 24± 0.8kg/m2, hepatic fat content: 4±0.1%, fasting glucose: 5.0±0.1mM) . On a separate day, a mixture of amino acids (14 g/L; 331 mg/min/kg body weight) was infused intravenously for 45min to evaluate the actions of endogenous glucagon on glucose dynamics. Glucose levels (see figure) were significantly increased in individuals with NAFLD 60min after the glucagon bolus and during the amino acid infusion with a maximal difference of 0.5mM 30min into the infusion. These data suggest that the actions of glucagon on hepatic glucose production are not impaired by NAFLD. Therefore, the hyperglucagonemia in patients with NAFLD may constitute a diabetogenic risk factor.
Disclosure
S.Kjeldsen: None. H.Vilstrup: None. F.V.Schiødt: Advisory Panel; Novo Nordisk. A.Møller: None. E.B.Rashu: None. L.Gluud: Advisory Panel; Novo Nordisk, Consultant; Pfizer Inc., Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. S.B.Haugaard: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. J.Rungby: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Bayer AG, Novo Nordisk, Pfizer Inc. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Merck & Co., Inc., Mercodia AB. N.J.Jensen: None. M.Nilsson: None. N.Heinz: None. J.D.Nybing: None. F.H.Linden: None. E.Høgh-schmidt: n/a. M.P.Boesen: None. S.Madsbad: None.
Funding
NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.
Glucagon regulates hepatic glucose production and hyperglucagonemia contributes to diabetes. Equally important, glucagon may regulate amino acid (AA) levels that in turn control glucagon secretion. ...Hepatic steatosis may uncouple glucagon's effect on AA metabolism causing impaired actions of glucagon (resistance) on AA metabolism but not glucose production, thereby creating a diabetogenic circle. In order to quantify glucagon's effect on AA metabolism, we developed and evaluated a glucagon sensitivity test. The test consists of a bolus-infusion of glucagon (200 μg) and an AA infusion (330 mg/min/kg body weight for 45 min) on two separate days following an overnight fast. Liver fat was measured using magnetic resonance imaging. Preliminary data from six individuals without diabetes (HbA1c < 48mmol/mol) including three lean controls (CON) (mean ± SD; Age: 32 ± 7 years, liver fat: 4.1 ± 1 %, BMI; 22 ± 2 kg/m2) and three individuals with obesity (OBE) (47 ± 12 years, 12 ± 6 %, 30 ± 4 kg/m2) are presented. A glucagon injection reduced AA levels 29% less in OBE compared to CON (dAUC0-120min; 41 ± 6 vs. 29 ± 10 mmol/L x min) during the fasted state. AA levels increased 33% more in OBE compared to CON during an AA infusion (iAUC0-45min; 118 ± 28 vs. 89 ± 12 mmol/L x min). We conclude that glucagon sensitivity towards AA metabolism may be evaluated by a bolus-infusion of glucagon and an AA infusion, and that hepatic steatosis may cause glucagon resistance.
A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and ...glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6–25 kg/m2, 30 individuals with a BMI ≥ 25–40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.
•A glucagon sensitivity test towards hepatic amino acid catabolism was developed.•Pilot studies leading to the final glucagon test are presented.•A novel glucagon sensitivity index is presented.•The test may be an important tool to investigate glucagon resistance.
Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the ...International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPIB (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPIB is feasible. This trial was registered at www.isrctn.org as #ISRCTN 87866680.
Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 ...consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.
ObjectiveTo explore the comparative effectiveness of pharmacological interventions for hand osteoarthritis (OA).MethodsWe systematically searched Embase, MEDLINE, and the Cochrane Central Register of ...Controlled Trials from inception until 26 December 2021, for randomised trials of pharmacological interventions for people with hand OA. Two reviewers independently extracted study data and assessed the risk of bias. We calculated the effect sizes for pain (standardised mean differences) using Bayesian random effects models for network meta-analysis (NMA) and pairwise meta-analysis. Based on a pre-specified protocol, we prospectively registered the study at PROSPERO, CRD42021215393.ResultsWe included 72 trials with 7609 participants. 65 trials (n=5957) were eligible for the quantitative synthesis, investigating 29 pharmacological interventions. Oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids’ NMA effect sizes were −0.18 (95% credible interval −0.36 to 0.02) and −0.54 (−0.83 to −0.24), respectively, compared with placebo, and the result was consistent when limiting evidence to the pairwise meta-analysis of trials without high risk of bias. Intra-articular hyaluronate, intra-articular glucocorticoids, hydroxychloroquine, and topical NSAIDs’ NMA effect sizes were 0.22 (−0.08 to 0.51), 0.25 (0.00 to 0.51), −0.01 (−0.19 to 0.18), and −0.14 (−0.33 to 0.08), respectively, compared with placebo. Oral NSAIDs were inferior to oral glucocorticoids with an NMA effect size of 0.36 (0.01 to 0.72). No intervention was superior to placebo when stratifying for thumb and finger OA.ConclusionOral NSAIDs and glucocorticoids are apparently effective pharmacological interventions in hand OA. Intra-articular therapies and topical NSAIDs were not superior to placebo.
In arterial hypertension risk factor evaluation, including LV mass measurements, and risk stratification using risk charts or programs, is generally recommended. In heart failure NT‐proBNP has been ...shown to be a marker of LV dimensions and of prognosis. If the same diagnostic and prognostic value is present in arterial hypertension, risk factor evaluation would be easier. In 36 patients with arterial hypertension, electrocardiographic LV hypertrophy and preserved left ventricular function, NT‐proBNP was eight‐fold higher than in healthy subjects. The log NT‐proBNP correlated with LV mass index (R=0.47, P=0.0002) measured by magnetic resonance imaging. In other subjects with arterial hypertension a significant but weak correlation to diastolic properties has been demonstrated. As for prognosis, a recent study in patients with hypertension, electrocardiographic left ventricular hypertrophy and preserved LV function demonstrated that NT‐proBNP was a very strong prognostic marker, especially combined with a history of cardiovascular disease. Patients with high NT‐proBNP and known cardiovascular disease had a seven‐fold increase in CV events compared to patients with low NT‐proBNP and no CV disease, while patients with either high NT‐proBNP or CV disease had a three–four‐fold increased risk. In conclusion NT‐proBNP predicts LV mass in hypertensive patients and is a very strong prognostic marker in these patients. This could indicate a use of NT‐proBNP in the future for risk stratification and perhaps monitoring of treatment in patients with arterial hypertension.
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