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Karstoft K.,Copenhagen University | Christensen C.S.,Copenhagen University | Pedersen B.K.,Nordic Bioscience | Solomon T.P.J.,Copenhagen University
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Glycemic control improves with physical activity, but the optimal exercise mode is unknown. CopyrightObjective: The objective of the study was to determine whether interval-based exercise improves postprandial glucose tolerance and free-living glycemia more than oxygen consumption- and time duration-matched continuous exercise.Design: This was a crossover, controlled study with trials performed in randomized order.Setting: The study was conducted in hospitalized and ambulatory care.Patients: Patients diagnosed with type 2 diabetes mellitus (n=10, no withdrawals) participated in the study.Interventions: Subjects performed three 1-hour interventions: 1) interval walking (IW; repeated cycles of 3 min of slow and fast walking); 2) continuous walking (CW); and 3) control (CON). Oxygen consumption (VO2) was measured continuously to match mean VO2between exercise sessions (∼75% VO2peak).Main Outcome Measures: A mixed-meal tolerance test (MMTT; 450 kcal, 55% carbohydrate) with stable glucose isotopic tracers was provided after each intervention, and glucose kinetics were measured during the following 4 hours. Free-living glycemic control was assessed for approximately 32 hours after the MMTT using continuous glucose monitoring.Results: VO2was well matched between the exercise interventions. IW decreased the mean and maximal incremental plasma glucose during theMMTTwhen compared with the CON (mean 1.2± 0.4 vs 2.0 ± 0.5 mmol/L, P < .001; maximal 3.7 ± 0.6 vs 4.6 ± 0.7 mmol/L, P = .005) and mean when compared withCW(1.7±0.4 mmol/L, P=.02). No differences in the mean or maximal incremental plasma glucose values were seen between the CW and CON. The metabolic clearance rate of glucose during theMMTTwas increased in theIWcompared withCW(P=.049) andCON(P<.001). Continuous glucose monitoring mean glucose was reduced in IW compared with CW for the rest of the intervention day (8.2±0.4 vs 9.3±0.7 mmol/L, P=.03), whereas no differences were found between IW and CW the following day.Conclusions: One interval-based exercise session improves glycemic control in type 2 diabetes mellitus subjects when compared with an oxygen consumption- and time duration-matched continuous exercise session. © 2014 by the Endocrine Society.

Karsdal M.A.,Nordic Bioscience | Christiansen C.,Nordic Bioscience | Ladel C.,Merck KGaA | Henriksen K.,Nordic Bioscience | And 2 more authors.
Osteoarthritis and Cartilage | Year: 2014

For both economic and ethical reasons, identification of the optimal treatment for each individual patient is a pressing concern, not only for the patients and their physician, but also health care payers and the pharmaceutical industry. In the field of osteoarthritis (OA) this is of particular relevance, due to the heterogeneity of the disease and the very large number of affected individuals. There is a need to pair theright patients with the right therapeutic modes of action. At present, the clinical trial failures in OA may be a consequence of both bona fide treatment failures and trial failures due to clinical design deficiencies. Tools are needed for characterization and segregation of patients with OA. Key lessons may be learned from advances with another form of arthritis, namely rheumatoid arthritis (RA).Personalized health care (PHC) may be more advantageous for a number of specific indications which are characterized by costly therapy, low response rates and significant problems associated with trial and error prescription, including the risk of serious side effects. We discuss the use of diagnostic practices guiding RA treatment, which may serve as a source of key insights for diagnostic practices in OA. We discuss the emerging concept of PHC, and outline the opportunities and current successes and failures across the RA field, as the OA field collects further data to support the hypothesis. We attempt to outline a possible path forward to assist patients, physicians, payers and the pharmaceutical industry in assuring the 'right' patients are treated with the 'right drug' in OA. Finally we highlight methods for possible segregation of OA patients that would allow identification of patient subtypes, such as OA driven by inflammation that may be ideally suited for PHC and for targeted therapies. © 2013 Osteoarthritis Research Society International.

Siebuhr A.S.,Nordic Bioscience | Bay-Jensen A.C.,Nordic Bioscience | Leeming D.J.,Nordic Bioscience | Plat A.,Roche Holding AG | And 3 more authors.
Arthritis Research and Therapy | Year: 2013

Introduction: Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).Methods: The LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment.Results: At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R2= 0.09, P = 0.0001) and at Week 52 (R2= 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R2= 0.006, P = 0.0015) and strongly at 52 weeks (R2= 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group.Conclusions: Baseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment. Trial registration: ClinicalTrials.gov: NCT00106535. © 2013 Siebuhr et al.; licensee BioMed Central Ltd.

Bay-Jensen A.C.,Nordic Bioscience | Platt A.,Roche Holding AG | Byrjalsen I.,Nordic Bioscience | Vergnoud P.,Synarc Laboratories | And 2 more authors.
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker. Methods: The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared. Results: At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose. Conclusions: TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist. © 2014 The Authors.

Bay-Jensen A.C.,Nordic Bioscience | Karsdal M.A.,Nordic Bioscience | Vassiliadis E.,Nordic Bioscience | Wichuk S.,University of Alberta | And 4 more authors.
Arthritis and Rheumatism | Year: 2013

Objective Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS. Methods VICM was measured in serum samples from healthy controls (n = 35), control patients with rheumatoid arthritis (RA) (n = 47), and patients with AS (n = 201). The optimal cutoff for diagnostic sensitivity and specificity was determined by receiver operating characteristic curve analysis. Baseline and 2-year spine radiographs were available from 118 AS patients, and were scored using the modified Stoke AS Spine Score (mSASSS). We assessed correlations with patient demographic characteristics (age, disease duration), disease activity (Bath AS Disease Activity Index [BASDAI], C-reactive protein level), and disease severity (mSASSS) using Spearman's rho. The independent association of VICM with 2-year radiographic progression, defined as a change of >0 in the mSASSS or the development of a new syndesmophyte, was analyzed by multivariate regression. Results Levels of degraded VICM were significantly higher in both RA patients and AS patients than in healthy controls (both P < 0.001). AS patients with the highest levels of VICM had the largest burden of disease (P < 0.01), i.e., highest mSASSS score and BASDAI. VICM levels were significantly and independently associated with radiographic progression after 2 years (β = 0.69, P = 0.0005). Patients with both a high VICM level and a high baseline mSASSS had the highest risk of radiographic progression (odds ratio 13 for mSASSS change, 32 for new syndesmophytes), with progression occurring in 67% of these patients. Conclusion The present findings show that serum VICM may be of prognostic value in AS. The data also suggest that citrullination may be relevant in AS pathogenesis. Copyright © 2013 by the American College of Rheumatology.

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