Publications by authors named "Finn P Reinholt"

59 Publications

International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria).

Eur Respir J 2020 04 16;55(4). Epub 2020 Apr 16.

Sorbonne Université, Faculté de Médecine, INSERM UMR_S933, (APHP) Assistance Publique Hôpitaux de Paris and CHIC (Centre Hospitalier Intercommunal de Créteil), Paris, France.

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM.A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres.The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample.This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.
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http://dx.doi.org/10.1183/13993003.00725-2019DOI Listing
April 2020

Machine learning for intraoperative prediction of viability in ischemic small intestine.

Physiol Meas 2018 10 24;39(10):105011. Epub 2018 Oct 24.

Department of Clinical and Biomedical Engineering, Oslo University Hospital-Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway. Department of Physics, University of Oslo, Postboks 1048 Blindern, 0316 Oslo, Norway.

Objective: Evaluation of intestinal viability is essential in surgical decision-making in patients with acute intestinal ischemia. There has been no substantial change in the mortality rate (30%-93%) of patients with acute mesenteric ischemia (AMI) since the 1980s. As the accuracy from the first laparotomy alone is 50%, the gold standard is a second-look laparotomy, increasing the accuracy to 87%-89%. This study investigates the use of machine learning to classify intestinal viability and histological grading in pig jejunum, based on multivariate time-series of bioimpedance sensor data.

Approach: We have previously used a bioimpedance sensor system to acquire electrical parameters from perfused, ischemic and reperfused pig jejunum (7  +  15 pigs) over 1-16 h of ischemia and 1-8 h of reperfusion following selected durations of ischemia. In this study we compare the accuracy of using end-point bioimpedance measurements with a feedforward neural network (FNN), versus the accuracy when using a recurrent neural network with long short-term memory units (LSTM-RNN) with bioimpedance data history over different periods of time.

Main Results: Accuracies in the range of what has been reported clinically can be achieved using FNN's on a single bioimpedance measurement, and higher accuracies can be achieved when employing LSTM-RNN on a sequence of data history.

Significance: Intraoperative bioimpedance measurements on intestine of suspect viability combined with machine learning can increase the accuracy of intraoperative assessment of intestinal viability. Increased accuracy in intraoperative assessment of intestinal viability has the potential to reduce the high mortality and morbidity rate of the patients.
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http://dx.doi.org/10.1088/1361-6579/aae0eaDOI Listing
October 2018

Effects of marine n-3 fatty acid supplementation in renal transplantation: A randomized controlled trial.

Am J Transplant 2019 03 22;19(3):790-800. Epub 2018 Sep 22.

Department of Renal Medicine, Akershus University Hospital, Lørenskog, Norway.

Marine n-3 fatty acids (FAs) may exert beneficial effects on inflammation, fibrosis, and endothelial function, which could preserve renal graft function. In this randomized controlled trial, 132 Norwegian renal transplant recipients received either 2.6 g of marine n-3 FAs or olive oil (control) daily for 44 weeks, in addition to standard care. Thirty patients did not complete the trial. The primary endpoint was change (Δ) in measured glomerular filtration rate (mGFR) during follow-up. We found no significant difference in Δ mGFR between the marine n-3 FA group and controls (6.7 vs 3.8 mL/min per 1.73 m , P = .15). Significant beneficial effects from marine n-3 FA supplementation were, however, seen in secondary endpoints plasma triglycerides, plasma high-sensitivity C-reactive protein, and brachial artery flow-mediated dilation. In the per-protocol population, the renal graft indices percent interstitial fibrosis and Chronic Allograft Damage Index also were significantly lower in the marine n-3 FA group. The cumulative incidence of adverse events did not differ between the marine n-3 FA group (n = 218) and controls (n = 240). In conclusion, marine FA supplementation did not improve renal function compared with controls, but was safe, lowered plasma triglyceride and high-sensitivity C-reactive protein levels, and improved endothelial function (Clinical.Trials.gov identifier NCT01744067).
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http://dx.doi.org/10.1111/ajt.15080DOI Listing
March 2019

Ischemia/reperfusion injury in porcine intestine - Viability assessment.

World J Gastroenterol 2018 May;24(18):2009-2023

Department of Emergencies and Critical Care, Oslo University Hospital, Oslo 0424, Norway.

Aim: To investigate viability assessment of segmental small bowel ischemia/reperfusion in a porcine model.

Methods: In 15 pigs, five or six 30-cm segments of jejunum were simultaneously made ischemic by clamping the mesenteric arteries and veins for 1 to 16 h. Reperfusion was initiated after different intervals of ischemia (1-8 h) and subsequently monitored for 5-15 h. The intestinal segments were regularly photographed and assessed visually and by palpation. Intraluminal lactate and glycerol concentrations were measured by microdialysis, and samples were collected for light microscopy and transmission electron microscopy. The histological changes were described and graded.

Results: Using light microscopy, the jejunum was considered as viable until 6 h of ischemia, while with transmission electron microscopy the ischemic muscularis propria was considered viable until 5 h of ischemia. However, following ≥ 1 h of reperfusion, only segments that had been ischemic for ≤ 3 h appeared viable, suggesting a possible upper limit for viability in the porcine mesenteric occlusion model. Although intraluminal microdialysis allowed us to closely monitor the onset and duration of ischemia and the onset of reperfusion, we were unable to find sufficient level of association between tissue viability and metabolic markers to conclude that microdialysis is clinically relevant for viability assessment. Evaluation of color and motility appears to be poor indicators of intestinal viability.

Conclusion: Three hours of total ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in this porcine mesenteric ischemia model.
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http://dx.doi.org/10.3748/wjg.v24.i18.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949714PMC
May 2018

Negative effect of zoledronic acid on tendon-to-bone healing.

Acta Orthop 2018 Jun 1;89(3):360-366. Epub 2018 Mar 1.

b Institute of Clinical Medicine, Faculty of Medicine, University of Oslo (UIO).

Background and purpose - Outcome after ligament reconstruction or tendon repair depends on secure tendon-to-bone healing. Increased osteoclastic activity resulting in local bone loss may contribute to delayed healing of the tendon-bone interface. The objective of this study was to evaluate the effect of the bisphosphonate zoledronic acid (ZA) on tendon-to-bone healing. Methods - Wistar rats (n = 92) had their right Achilles tendon cut proximally, pulled through a bone tunnel in the distal tibia and sutured anteriorly. After 1 week animals were randomized to receive a single dose of ZA (0.1 mg/kg IV) or control. Healing was evaluated at 3 and 6 weeks by mechanical testing, dual-energy X-ray absorptiometry and histology including immunohistochemical staining of osteoclasts. Results - ZA treatment resulted in 19% (95% CI 5-33%) lower pullout strength and 43% (95% CI 14-72%) lower stiffness of the tendon-bone interface, compared with control (2-way ANOVA; p = 0.009, p = 0.007). Administration of ZA did not affect bone mineral density (BMD) or bone mineral content (BMC). Histological analyses did not reveal differences in callus formation or osteoclasts between the study groups. Interpretation - ZA reduced pullout strength and stiffness of the tendon-bone interface. The study does not provide support for ZA as adjuvant treatment in tendon-to-bone healing.
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http://dx.doi.org/10.1080/17453674.2018.1440189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055777PMC
June 2018

Kidney allograft subclinical rejection modulates systemic inflammation measured by C-reactive protein at 1 year after transplantation.

Clin Transplant 2018 03 30;32(3):e13196. Epub 2018 Jan 30.

Nephrology Department Hospital Universitari Vall d'Hebron and Universitat Autónoma de Barcelona, Barcelona, Spain.

Kidney allograft inflammation is associated with proinflammatory modifications of peripheral blood mononuclear cells, suggesting that renal inflammation contributes to systemic inflammation. Thus, the aim of this study was to evaluate the relationship between subclinical inflammation in surveillance biopsies performed at 1 year and systemic inflammation assessed by C-reactive protein (CRP) levels at the time of biopsy. We analyzed 544 surveillance biopsies performed at 1 year that were classified as normal (n = 368), borderline (n = 148), or subclinical rejection (SCR) (n = 28). CRP levels were divided into quartiles. Patients in 1st, 2nd, and 3rd quartile were classified as low CRP (n = 408) and patients in the 4th quartile as high CRP (n = 136). Univariate analysis showed that the proportion of patients with SCR was higher in the high CRP group (10.3% vs 3.4%, P = 0.0067). Multivariate analysis showed that independent predictors of high CRP were body mass index (odds ratio [OR] 1.072 and 95% confidence interval [CI] 1.027-1.119), a positive urine culture at the day of the biopsy (OR 2.760 and 95% CI 1.205-6.323), and the presence of SCR at 1-year surveillance biopsy (OR 7.260 and 95% CI 3.530-14.935). In summary, we describe that subclinical acute rejection constitutes an independent predictor of systemic inflammation as measured by CRP.
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http://dx.doi.org/10.1111/ctr.13196DOI Listing
March 2018

Development of Kidney Transplant Fibrosis Is Inversely Associated With Plasma Marine Fatty Acid Level.

J Ren Nutr 2018 03 14;28(2):118-124. Epub 2017 Nov 14.

Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Objective(s): We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys.

Design: The design of the study was single center cohort study.

Subjects: A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010.

Main Outcome Measure: Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors.

Results: Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized β-coefficient -1.12, standardized β-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation.

Conclusion: The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis.
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http://dx.doi.org/10.1053/j.jrn.2017.09.001DOI Listing
March 2018

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants.

Transpl Int 2017 Nov 27;30(11):1119-1131. Epub 2017 Jul 27.

Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC-C in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C levels are associated with subclinical inflammation in patients receiving reduced MMF dose.
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http://dx.doi.org/10.1111/tri.13002DOI Listing
November 2017

Inflammation in Early Kidney Allograft Surveillance Biopsies With and Without Associated Tubulointerstitial Chronic Damage as a Predictor of Fibrosis Progression and Development of De Novo Donor Specific Antibodies.

Transplantation 2017 06;101(6):1410-1415

1 Nephrology Department, Hospital Universitari Vall d'Hebron and Universitat Autonóma de Barcelona, Barcelona, Spain. 2 Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 3 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 4 Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Interstitial fibrosis and tubular atrophy (IFTA) associated with interstitial inflammation in nonscarred areas (IFTA+i) is associated with poorer graft outcome than inflammation without IFTA or IFTA without inflammation.

Methods: We evaluated if histological categories at week 6 could predict the development of interstitial fibrosis and de novo donor specific anti-HLA antibodies (dnDSA) at 1 year. Biopsies were classified according to Banff criteria as normal (i+t≤1 and ci+ct≤1), inflammation (i+t≥2 and ci+ct≤1), IFTA (i+t≤1 and ci+ct≥2) or IFTA+i (i+t≥2 and ci+ct≥2).

Results: We analyzed 598 standard immunological risk recipients. The histological diagnosis at 6 weeks was: normal (n = 206), inflammation (n = 29), IFTA (n = 255), and IFTA+i (n = 108). Moderate/severe interstitial fibrosis (ci≥2) at 1 year was observed in 4.2% of patients with prior (6 weeks) normal histology, in 3.4% with inflammation, in 13.8% with IFTA, and in 24.5% with IFTA+i (P = 0.0001). Fifty-three recipients (8.9%) had dnDSA at 1 year. Independent predictors of development of dnDSA at 1 year were: HLA-DR mismatches (odds ratio [OR], 1.95; 95% confidence interval [95% CI], 1.09-3.49), the presence of inflammation (OR, 5.49; 95% CI, 1.67-18.03) or IFTA+i (OR, 4.09; 95% CI, 1.67-10.0) in the 6-week surveillance biopsy.

Conclusions: Early subclinical inflammation in surveillance biopsies with or without tubulointerstitial chronic lesions is associated with an increased risk of dnDSA development.
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http://dx.doi.org/10.1097/TP.0000000000001216DOI Listing
June 2017

Total inflammation in early protocol kidney graft biopsies does not predict progression of fibrosis at one year post-transplant.

Clin Transplant 2016 07 18;30(7):802-9. Epub 2016 May 18.

Department of Pathology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.

Introduction: There is an uncertainty whether total inflammation in early protocol kidney graft biopsies is associated with fibrosis progression. We investigated whether total inflammation, both in fibrotic and non-fibrotic areas, at week 6 would predict fibrosis progression at one yr post-transplant.

Methods: We included 156 single adult ABO compatible kidney recipients with adequate week 6 and one yr transplant protocol biopsies (312 biopsies). Biopsies were scored according to the current Banff criteria. In addition, fibrosis and inflammation in fibrotic and non-fibrotic areas were scored in a 10-grade semi-quantitative eyeballing system from 0% to 100%.

Results: Fibrosis increased significantly from week 6 to one yr both by the 10-grade scoring system from 0.69 ± 1.07 to 1.45 ± 1.86, (mean ± SD), p < 0.001 and by Banff interstitial fibrosis (ci) scoring 0.81 ± 0.65 to 1.13 ± 0.87, p < 0.001. The 10-grade scoring system detected a larger proportion of fibrosis progressors than the Banff scoring 40.4% vs. 35.5%, p < 0.001. No significant positive association was found between inflammation at week 6 and progression of fibrosis in either of the scoring systems.

Conclusions: Total inflammation in kidney transplant biopsies at week 6 did not predict progression of fibrosis at one yr post-transplant.
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http://dx.doi.org/10.1111/ctr.12753DOI Listing
July 2016

Ichthyosis prematurity syndrome caused by a novel missense mutation in FATP4 gene-a case report from India.

Clin Case Rep 2016 01 1;4(1):87-9. Epub 2015 Dec 1.

Department of Pathology Oslo- University Hospital- Rikshospitalet Oslo Norway; Department of Dermatology Oslo- University Hospital- Rikshospitalet Oslo Norway.

Ichthyosis prematurity syndrome (IPS) is reported mainly from Scandinavia where most of the cases are homozygous or compound heterozygous for the nonsense mutation c.504C>A (p.Cys168*) in exon3 indicating a common ancestor for this mutation. The occurrence of IPS in an Indian patient suggests that it is more widespread than previously reported.
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http://dx.doi.org/10.1002/ccr3.462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706401PMC
January 2016

Autologous cell sources in therapeutic vasculogenesis: In vitro and in vivo comparison of endothelial colony-forming cells from peripheral blood and endothelial cells isolated from adipose tissue.

Cytotherapy 2016 Feb 3;18(2):242-52. Epub 2015 Dec 3.

Department of Immunology and Norwegian Center for Stem Cell Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

Background Aims: Autologous endothelial cells are promising alternative angiogenic cell sources in trials of therapeutic vasculogenesis, in the treatment of vascular diseases and in the field of tissue engineering. A population of endothelial cells (ECs) with long-term proliferative capability, endothelial colony-forming cells (ECFCs), can be isolated from human peripheral blood. ECFCs are considered an endothelial precursor population. They can be expanded in cell factories in sufficient numbers for clinical applications, but because the number of isolated primary ECs is low, the culture period required may be long. Another EC population that is easily available in the autologous setting and may be expanded in vitro through several population doublings are ECs from adipose tissue (AT-ECs).

Methods: Through extensive comparisons using whole-genome microarray analysis, morphology, phenotype and functional assays, we wanted to evaluate the potential of these EC populations for use in clinical neovascularization.

Results: Global gene expression profiling of ECFCs, AT-ECs and the classical EC population, human umbilical vein ECs, showed that the EC populations clustered as unique populations, but very close to each other. By cell surface phenotype and vasculogenic potential in vitro and in vivo, we also found the ECFCs to be extremely similar to AT-ECs.

Conclusions: These properties, together with easy access in the autologous setting, suggest that both AT-ECs and ECFCs may be useful in trials of therapeutic neovascularization. However, AT-ECs may be a more practical alternative for obtaining large quantities of autologous ECs.
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http://dx.doi.org/10.1016/j.jcyt.2015.10.009DOI Listing
February 2016

Tendon to bone tunnel healing--a study on the time-dependent changes in biomechanics, bone remodeling, and histology in a rat model.

J Orthop Res 2015 Feb 3;33(2):216-23. Epub 2014 Nov 3.

Department of Orthopaedic Surgery, Division of Surgery and Clinical Neuroscience, Oslo University Hospital, Kirkeveien 166, N-0450, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.

Tendons and ligaments attach to bone through a transitional connective tissue with complex biomechanical properties. This unique tissue is not regenerated during healing, and surgical reattachment therefore often fails. The present study was designed to evaluate tendon healing in a bone tunnel and to evaluate the utilized rat model. Wistar rats (n = 61) were operated with the Achilles tendon through a bone tunnel in the distal tibia. Healing was evaluated at 2, 3, 4, and 12 weeks by biomechanical testing, bone mineral density and histology. After 2 weeks median (interquartile range) pull-out force was 2.2 N (1.9). The pull-out force increased chronologically, by 12 weeks fivefold to 11.2 N (11.4). Energy absorption, stiffness, and bone mineral density increased similarly. The histological analyses showed inflammation at early stages with increasing callus by time. Our data showed a slow healing response the first 4 weeks followed by an accelerated healing period, favoring that most of the gain in mechanical strength occurred later than 4 weeks postoperatively. These findings support the concern of a vulnerable tendon bone tunnel interface in the early stages of healing.
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http://dx.doi.org/10.1002/jor.22756DOI Listing
February 2015

Quantitative proteomics at different depths in human articular cartilage reveals unique patterns of protein distribution.

Matrix Biol 2014 Nov 1;40:34-45. Epub 2014 Sep 1.

Department of Clinical Sciences Lund, Lund University, BMC-C12, 221 84 Lund, Sweden. Electronic address:

The articular cartilage of synovial joints ensures friction-free mobility and attenuates mechanical impact on the joint during movement. These functions are mediated by the complex network of extracellular molecules characteristic for articular cartilage. Zonal differences in the extracellular matrix (ECM) are well recognized. However, knowledge about the precise molecular composition in the different zones remains limited. In the present study, we investigated the distribution of ECM molecules along the surface-to-bone axis, using quantitative non-targeted as well as targeted proteomics.\ In a discovery approach, iTRAQ mass spectrometry was used to identify all extractable ECM proteins in the different layers of a human lateral tibial plateau full thickness cartilage sample. A targeted MRM mass spectrometry approach was then applied to verify these findings and to extend the analysis to four medial tibial plateau samples. In the lateral tibial plateau sample, the unique distribution patterns of 70 ECM proteins were identified, revealing groups of proteins with a preferential distribution to the superficial, intermediate or deep regions of articular cartilage. The detailed analysis of selected 29 proteins confirmed these findings and revealed similar distribution patterns in the four medial tibial plateau samples. The results of this study allow, for the first time, an overview of the zonal distribution of a broad range of cartilage ECM proteins and open up further investigations of the functional roles of matrix proteins in the different zones of articular cartilage in health and disease.
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http://dx.doi.org/10.1016/j.matbio.2014.08.013DOI Listing
November 2014

In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone.

Diabetologia 2014 Nov 22;57(11):2357-65. Epub 2014 Aug 22.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway,

Aims/hypothesis: In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone.

Methods: Estimated GFR (eGFR) was calculated in SPK (n = 25) and LDK (n = 17) recipients in a stable phase 3 months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy).

Results: SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1 years. Mean HbA1c levels during follow-up were 5.5 ± 0.4% (37 ± 5 mmol/mol) and 8.3 ± 1.5% (68 ± 16 mmol/mol) in the SPK and LDK group, respectively (p < 0.001). Compared with SPK recipients, LDK recipients had wider GBM (369 ± 109 nm vs 281 ± 57 nm; p = 0.008) and increased mesangial volume fraction (median 0.23 [range 0.13-0.59] vs 0.16 [0.10-0.41]; p = 0.007) at follow-up. Absolute eGFR change from baseline was -11 ± 21 and -23 ± 15 ml min(-1) 1.73 m(-2) (p = 0.060), whereas eGFR slope was -1.1 (95% CI -1.7, -0.5) and -2.6 (95% CI -3.1, -2.1) ml min(-1) 1.73 m(-2) per year in the SPK and LDK group, respectively (p = 0.001).

Conclusions/interpretation: In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone.
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http://dx.doi.org/10.1007/s00125-014-3353-2DOI Listing
November 2014

Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease.

Heart 2014 Nov 16;100(22):1793-8. Epub 2014 Jul 16.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Objective: To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry.

Methods: We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing.

Results: Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause.

Conclusions: We describe a novel familial Gb3-associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.
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http://dx.doi.org/10.1136/heartjnl-2014-305616DOI Listing
November 2014

Relationship between CTX-II and patient characteristics, patient-reported outcome, muscle strength, and rehabilitation in patients with a focal cartilage lesion of the knee: a prospective exploratory cohort study of 48 patients.

BMC Musculoskelet Disord 2014 Mar 24;15:99. Epub 2014 Mar 24.

Department of Orthopedic Surgery, Akershus University Hospital, Lørenskog, Norway.

Background: C-telopeptide fragments of type II collagen (CTX-II) are created during articular cartilage breakdown and CTX-II is considered useful as a biomarker of osteoarthritis. The primary objective of the present study was to explore the relationship between urinary CTX-II concentration and patient characteristics, patient-reported outcome, muscle strength, and rehabilitation in patients with isolated focal knee cartilage lesions. Furthermore, the secondary objective was to examine differences in urinary CTX-II concentration between patients with focal cartilage lesions and healthy controls.

Methods: 48 patients (mean age 33.4 years, standard deviation 9.0) with a focal full-thickness (International Cartilage Repair Society grade 3 or 4) cartilage lesion on the medial or lateral femoral condyle were included. After baseline assessments, the patients completed a 3-month rehabilitation program and 44 patients attended the 3 month follow-up. Baseline and follow-up assessments consisted of urinary CTX-II, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and isokinetic quadriceps and hamstring muscle strength measurements. CTX-II was also analysed in urine samples from 6 healthy individuals, serving as normal controls. Correlations were classified as very weak (correlation coefficient [r] < 0.20), weak (r = 0.20 - 0.39), moderate (r = 0.40 - 0.59), strong (r = 0.60 - 0.79), and very strong (r > 0.80).

Results: Except for age and quadriceps strength, no significant correlations were found between CTX-II concentrations and baseline characteristics, KOOS, or muscle strength. Except for age, all correlations were considered as weak or very weak. The patients with a focal cartilage lesion had significantly higher mean CTX-II concentration than the healthy control individuals both at baseline (p = 0.001) and at follow-up (p = 0.001). The mean CTX-II concentration tended to decrease during rehabilitation, but the reduction was not significant (p = 0.076).

Conclusions: The current exploratory study demonstrated that patients with a focal cartilage lesion of the knee had higher concentrations of urinary CTX-II than healthy individuals. In addition, CTX-II concentration tended to decrease during rehabilitation.

Trial Registration: ClinicalTrials.gov NCT00885729.
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http://dx.doi.org/10.1186/1471-2474-15-99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987845PMC
March 2014

Contrast-enhanced ultrasound identifies reduced overall and regional renal perfusion during global hypoxia in piglets.

Invest Radiol 2014 Aug;49(8):540-6

From the *Department of Radiology and Nuclear Medicine, †The Intervention Centre, ‡Department of Pathology, §Department of Pediatric Research, and ∥Department of Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Objective: It is well known from both clinical experience and animal research that renal hypoxia may lead to temporary or permanent renal failure, the severity being dependent largely on the duration and grade of the hypoxia. The medulla is more susceptible to hypoxic injury than the cortex because approximately 90% of the renal blood flow supplies the cortex. Various methods have been applied to evaluate renal perfusion in both experimental and clinical settings, including magnetic resonance imaging, computed tomography, laser Doppler, and contrast-enhanced ultrasound (CEUS).

Purpose: The aim of this study was to evaluate changes in overall and regional renal perfusion with CEUS in response to global hypoxia.

Material And Methods: Twelve newborn anesthetized piglets were exposed to general hypoxia with a fraction of inspired oxygen of 8% of 30 minutes duration. Resuscitation was performed with either 100% oxygen (n = 6) or air (21% oxygen) (n = 6) for 30 minutes followed by 7 hours of reoxygenation with air. Before, during, and after hypoxia, the left kidney was examined with CEUS using 0.2 mL IV of SonoVue followed by 2 mL saline flush. Five additional piglets served as controls. The kidney was examined using a 9-MHz linear transducer with low mechanical index (0.21) and pulse inversion contrast program. One region of interest was drawn in the renal cortex and 1 in the medulla to obtain the corresponding time intensity curves (TICs). From these curves, the peak intensity (PI), time to peak (TTP), upslope of the curve, area under the curve, and mean transit time (MTT) were recorded. Also, the renal arteriovenous transit time (AVTT) was registered. The resistance index (RI) was repeatedly measured in the renal artery. Contrast-enhanced ultrasound was repeated at regular intervals until the animals were sacrificed 8 hours after the hypoxic period.

Results: In the group of 12 piglets subjected to hypoxia, RI increased from 0.69 ± 0.08 at baseline to 0.99 ± 0.09 during hypoxia (P < 0.01), indicating severe general renal vasoconstriction. The AVTT increased from 2.6 ± 0.5 seconds at baseline to 6.7 ± 2.8 seconds during hypoxia (P < 0.001). The PI in the cortex decreased from a mean value of 38.6 ± 6.1 dB at baseline to 30.3 ± 9.7 dB during hypoxia (P < 0.05). In the medulla, only a minor, nonsignificant reduction in PI was observed during hypoxia. In the medulla, TTP and MTT increased from 6.4 ± 1.5 and 9.2 ± 1.7 seconds at baseline to 14.6 ± 8.4 seconds (P < 0.01) and 15.2 ± 5.6 seconds (P < 0.01), respectively, during hypoxia. In the cortex, no statistically significant changes in TTP or MTT were observed during hypoxia. A return to near-baseline values was observed for TTP, PI in both the medulla and cortex, as well as for RI and AVTT within 1 to 3 hours after hypoxia, and they remained relatively constant for the duration of the experiment.Less than 1 hour after the hypoxia, PI both in the cortex and the medulla was significantly higher in the group resuscitated with air than in the group resuscitated with 100% oxygen, 36.0 ± 4.3 versus 27.2 ± 2.2 dB (P < 0.05) and 33.3 ± 8.2 versus 21.1 ± 2.0 dB (P < 0.01), respectively.

Conclusion: Global hypoxia induced changes in overall and regional renal perfusion detectable with CEUS. Cortical and medullary flows were affected differently by hypoxia; a strong increase in medullary TTP and MTT was observed, indicating a reduction in medullary blood flow velocity. In the cortex, a significant reduction in PI was found, probably because of a reduction in cortical blood volume. A faster recovery of both medullary and cortical PI in the group resuscitated with air could indicate that air might be more beneficial for renal perfusion than hyperoxia during resuscitation after renal hypoxia.
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http://dx.doi.org/10.1097/RLI.0000000000000053DOI Listing
August 2014

Increased tartrate-resistant Acid phosphatase expression in osteoblasts and osteocytes in experimental osteoporosis in rats.

Calcif Tissue Int 2014 May 7;94(5):510-21. Epub 2014 Jan 7.

Department of Pathology, Oslo University Hospital, Rikshospitalet, Postbox 4950, Nydalen, 0424, Oslo, Norway,

Tartrate-resistant acid phosphatase (TRAP) is known as an osteoclast marker, but osteoblasts and osteocytes in the vicinity of bone remodeling sites also express TRAP. Cell culture studies suggest that osteoblasts endocytose osteoclastic TRAP for inactivation. To evaluate whether changes in osteoclast activity could alter TRAP expression in osteoblasts and/or osteocytes in vivo, we studied the ovariectomized and vitamin D-deficient rat (Ovx-D) and rats healing from rickets. Bone sections were analyzed for TRAP gene expression by in situ hybridization, TRAP protein by immunogold labeling, and TRAP enzyme activity using the fluorescent substrate ELF97. Osteoblasts and osteocytes close to intracortical remodeling sites and bone surfaces demonstrated TRAP, most prominently in cancellous bone and osteocytes. Intracellular TRAP was located to electron-dense vesicles with similar morphology in both cell types. Ovx-D increased osteoclast activity (p < 0.001) and ELF97⁺ osteocytes (p < 0.05) in cancellous bone, but no corresponding increase was observed in the osteocyte lacunar area. The level of TRAP⁺ vesicles in cortical osteoblasts (p < 0.01) in Ovx-D rats was also increased. Enhanced osteoclast activity was noted in healing rickets after 72 h (p < 0.05), but no differences in TRAP expression were detected in osteoblasts or osteocytes. Thus, increased osteoclast activity does not affect TRAP expression in osteoblasts and osteocytes, favoring the notion that increased TRAP in these cells is rather due to increased synthesis. Although the role of TRAP in osteoblasts and osteocytes remains elusive, we speculate that the function is related to the capability of the enzyme to regulate the phosphorylation of proteins known to be expressed by these cells.
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http://dx.doi.org/10.1007/s00223-013-9834-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148331PMC
May 2014

Effect of proline-rich synthetic peptide-coated titanium implants on bone healing in a rabbit model.

Int J Oral Maxillofac Implants 2013 Nov-Dec;28(6):e547-55

Purpose: Previous studies have demonstrated the capacity of a designed proline-rich synthetic peptide to stimulate osteoblast differentiation and biomineralization in vitro. Therefore, the aim of the present study was to evaluate the osseointegration capacity of titanium (Ti) implants coated with these peptides in a rabbit model.

Materials And Methods: Four calibrated defects were prepared in the tibiae of three New Zealand rabbits, and the defects were randomized into a test group (peptide-modified machined Ti implant) and a control group (unmodified machined Ti implant). The performance in vivo was investigated after 4 weeks of implantation by real-time reverse transcriptase polymerase chain reaction of bone and inflammatory markers, microcomputed tomographic analysis of mineralized bone, and histologic examination.

Results: The peptides adsorbed in agglomerates on Ti and underwent a change in secondary structure upon adsorption, which induced an increase in surface wettability. Gene expression markers indicated that peptide-coated Ti implants had significantly decreased mRNA levels of tartrate-resistant acid phosphatase. A trend toward increased osteocalcin in the peri-implant bone tissue was also seen. Bone morphometric and histologic parameters did not show significant differences, although the peptide group showed a higher percentage of new bone histologically.

Conclusions: Proline-rich peptides have potential as a biocompatible coating for promoting osseointegration of Ti implants by reducing bone resorption.
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http://dx.doi.org/10.11607/jomi.te35DOI Listing
April 2014

The skeletal phenotype of chondroadherin deficient mice.

PLoS One 2014 3;8(6):e63080. Epub 2013 Jun 3.

Sections of Molecular Skeletal Biology and Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3-6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the α1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063080PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670915PMC
January 2015

Quantitative proteomic analysis of eight cartilaginous tissues reveals characteristic differences as well as similarities between subgroups.

J Biol Chem 2012 Jun 9;287(23):18913-24. Epub 2012 Apr 9.

Department of Clinical Sciences Lund, Lund University, BMC-C12, 221 84 Lund, Sweden.

Human synovial joints display a characteristic anatomic distribution of arthritis, e.g. rheumatoid arthritis primarily affects the metacarpophalangeal and proximal finger joints, but rarely the distal finger joints, whereas osteoarthritis occurs in the distal and proximal finger joints. Pelvospondylitis has a selective localization to the spine and sacroiliac joints. Is this tropism due to differences between the cartilages at the molecular level? To substantiate this concept the present study provides a background detailed compositional analysis by relative quantification of extracellular matrix proteins in articular cartilages, meniscus, intervertebral disc, rib, and tracheal cartilages on samples from 5-6 different individuals using an optimized approach for proteomics. Tissue extraction followed by trypsin digestion and two-dimensional LC separations coupled to tandem mass spectrometry, relative quantification with isobaric labeling, iTRAQ(TM), was used to compare the relative abundance of about 150 proteins. There were clear differences in protein patterns between different kinds of cartilages. Matrilin-1 and epiphycan were specific for rib and trachea, whereas asporin was particularly abundant in the meniscus. Interestingly, lubricin was prominent in the intervertebral disc, especially in the nucleus pulposus. Fibromodulin and lumican showed distributions that were mirror images of one other. Analyses of the insoluble residues from guanidine extraction revealed that a fraction of several proteins remained unextracted, e.g. asporin, CILP, and COMP, indicating cross-linking. Distinct differences in protein patterns may relate to different tissue mechanical properties, and to the intriguing tropism in different patterns of joint pathology.
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http://dx.doi.org/10.1074/jbc.M111.298968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365926PMC
June 2012

Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function.

Cell Transplant 2012 8;21(8):1697-709. Epub 2012 Mar 8.

Department of Cardiology, Oslo University Hospital, Oslo, Norway.

Cell therapy is a promising treatment modality to improve heart function in acute myocardial infarction. However, the mechanisms of action and the most suitable cell type have not been finally determined. We performed a study to compare the effects of mesenchymal stem cells (MSCs) harvested from different tissues on LV function and explore their effects on tissue structure by morphometry and histological staining for species and lineage relationship. MSCs from skeletal muscle (SM-MSCs) and adipose tissue (ADSCs) were injected in the myocardium of nude rats 1 week after myocardial infarction. After 4 weeks of observation, LVEF was significantly improved in the SM-MSCs group (39.1%) and in the ADSC group (39.6%), compared to the placebo group (31.0%, p < 0.001 for difference in change between groups). Infarct size was smaller after cell therapy (16.3% for SM-MSCs, 15.8% for ADSCs vs. 26.0% for placebo, p < 0.001), and the amount of highly vascularized granulation tissue in the border zone was significantly increased in both groups receiving MSCs (18.3% for SM-MSCs, 22.6% for ADSCs vs. 13.1% for placebo, p = 0.001). By in situ hybridization, moderate engraftment of transplanted cells was found, but no transdifferentiation to cardiomyocytes, endothelial cells, or smooth muscle cells was observed. We conclude that MSC injections lead to improved LVEF after AMI in rats predominantly by reduction of infarct size. After 4 weeks, we observed modulation of scar formation with significant increase in granulation tissue. Transdifferentiation of MSCs to cardiomyocytes or vascular cells did not contribute significantly in this process. MSCs from skeletal muscle and adipose tissue had similar effects.
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http://dx.doi.org/10.3727/096368911X627462DOI Listing
April 2013

Cartilage repair in the rabbit knee: mosaic plasty resulted in higher degree of tissue filling but affected subchondral bone more than microfracture technique: a blinded, randomized, controlled, long-term follow-up trial in 88 knees.

Knee Surg Sports Traumatol Arthrosc 2012 Feb 3;20(2):197-209. Epub 2011 Sep 3.

Martina Hansens Hospital, Box 23, 1306 Bærum, Norway.

Purpose: Discrepancies and variances in outcome following different surgical techniques for cartilage repair are poorly understood. Successful repair relies on proper tissue filling without initiating degenerative processes in the cartilage-bone unit. Consequently, the objective of the current study was to compare two available techniques for cartilage repair, i.e., microfracture technique and mosaic plasty, regarding tissue filling and subchondral bone changes in an experimental model.

Methods: A 4-mm pure chondral defect was created in the medial femoral condyle of both knees in New Zealand rabbits, aged 22 weeks. A stereomicroscope was used to optimize the preparation of the defects. In one knee (randomized), the defect was treated with microfracture technique whereas in the other with mosaic plasty. The animals were killed at 12, 24 and 36 weeks after surgery. Defect filling, new bone formation above the level of the tidemark and the density of subchondral mineralized tissue were estimated by histomorphometry.

Results: Mosaic plasty resulted in a significantly 34% higher degree of tissue filling than microfracture technique at 36 weeks, SD of mean difference being 34%. Mosaic plasty resulted in significantly more new bone formation and reduced subchondral mineralized tissue density compared to microfracture technique. The differences between the two techniques were apparent mainly at the long-term follow-up.

Conclusion: Tissue filling is a limiting factor regarding microfracture technique when compared to mosaic plasty, whereas mosaic plasty resulted in more bone changes than microfracture technique-the implications of the latter remain to be settled. This study underlines the difficulty in predicting outcome in the single case with any of these two techniques, particularly in a long-term perspective.
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http://dx.doi.org/10.1007/s00167-011-1596-8DOI Listing
February 2012

Liver X receptor protects against liver injury in sepsis caused by rodent cecal ligation and puncture.

Surg Infect (Larchmt) 2011 Aug 4;12(4):283-9. Epub 2011 Aug 4.

Institute for Surgical Research, Oslo University Hospital Rikshospitalet HF, Oslo, Norway.

Background: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP).

Methods: Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for morphologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma.

Results: Expression of the LXRα gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRα- and LXRαβ-deficient mice compared with wild-type and LXRβ-deficient mice, indicating a role for LXRα in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model.

Conclusions: Collectively, these results argue in favor of a role for LXRα in protection against liver injury in experimental sepsis induced by CLP.
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http://dx.doi.org/10.1089/sur.2010.066DOI Listing
August 2011

Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype.

J Bone Miner Res 2011 Aug;26(8):1793-801

Section of Endocrinology, Department of Medicine, Rikshospitalet University Hospital, Oslo, Norway.

Genome-wide gene expressions in bone biopsies from patients with postmenopausal osteoporosis and healthy controls were profiled, to identify osteoporosis candidate genes. All osteoporotic patients (n = 27) in an unbiased cohort of Norwegian women presented with bone mineral density (BMD) T-scores of less than -2.5 SD and one or more confirmed low-energy fracture(s). A validation group (n = 18) had clinical and laboratory parameters intermediate to the control (n = 39) and osteoporosis groups. RNA from iliac crest bone biopsies were analyzed by Affymetrix microarrays and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Differentially expressed genes in osteoporosis versus control groups were identified using the Bayesian ANOVA for microarrays (BAMarray) method, whereas the R-package Limma (Linear Models for Microarray Data) was used to determine whether these transcripts were explained by disease, age, body mass index (BMI), or combinations thereof. Laboratory tests showed normal ranges for the cohort. A total of 609 transcripts were differentially expressed in osteoporotic patients relative to controls; 256 transcripts were confirmed for disease when controlling for age or BMI. Most of the osteoporosis susceptibility genes (80%) also were confirmed to be regulated in the same direction in the validation group. Furthermore, 217 of 256 transcripts were correlated with BMD (adjusted for age and BMI) at various skeletal sites (|r| > 0.2, p < .05). Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups. Our results identify potential osteoporosis susceptibility candidate genes adjusted for confounding factors (ie, age and BMI) with or without a significant correlation with BMD.
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http://dx.doi.org/10.1002/jbmr.396DOI Listing
August 2011

Healing of long-term frozen orthotopic bone allografts is not affected by MHC differences between donor and recipient.

Clin Orthop Relat Res 2011 May 3;469(5):1479-86. Epub 2011 Feb 3.

Department of Orthopaedics, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway.

Background: The use of bone grafting in orthopaedic surgery has increased dramatically in recent years. However, the degree to which immune responses are important for the survival of the allograft is not fully understood. In particular it remains unclear whether differences in the major histocompatibility complex (MHC) influence incorporation of bone allografts and their subsequent biologic performance.

Questions/purposes: Therefore, we asked whether isolated mismatch for MHC antigens of deep frozen bone allografts in the long-term causes (1) immune reactions, and whether these reactions have any effect on (2) morphologic features of the graft, (3) radiographic graft healing, and (4) graft strength.

Methods: We used an established orthotopic tibial segment transplantation technique that allows determination of mechanical strength, histologic evaluation, and immune responses. Tibial segments that had been deep-frozen at -80°C for 1 year were transplanted into 24 PVG (RT1 (c)) rats from either 12 syngeneic donors or 12 MHC congenic donors PVG.1U (RT1 (u)). We determined immune responses using an indirect Coombs reaction and determined graft healing radiographically and mechanically after 6 months.

Results: We detected no alloantibody production to graft MHC-I antigens, and found no differences between syngeneic and MHC mismatched grafts in terms of remodeling with host bone, graft healing, and mechanical strength.

Conclusions: Mismatches for MHC antigens do not seem to play a decisive role in healing of long-term, deep-frozen bone allografts.
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http://dx.doi.org/10.1007/s11999-011-1796-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069278PMC
May 2011

[Osteoarthritis].

Tidsskr Nor Laegeforen 2010 Nov;130(21):2136-40

Ortopedisk avdeling, Oslo universitetssykehus, Ullevål, 0407 Oslo, Norway.

Background: Osteoarthritis is among the most common causes of functional disability and severe pain, and the prevalence of arthritic symptoms among adults is more than 50%. The article discusses epidemiology, pathology and treatment options.

Material And Methods: The review is based on a non-systematic search in PubMed and the authors' experience with treating this patient group.

Results: Osteoarthritis is a degenerative disease which leads to loss of joint functioning. Symptoms usually present in the hip, hands and knees. Women are affected more often than men and the prevalence increases with increasing age. Some families have an increased prevalence of osteoarthritis, but the genetic etiology is not clear. Mechanic conditions such as overweight and heavy physical work explain some of the pathogenesis, but non-mechanical factors are probably involved as well. Loss of weight is likely to have a preventive effect, and surgical correction of mechanic conditions such as hip dysplasia and varus deformity can prevent development of osteoarthritis. Treatment of symptomatic osteoarthritis includes educating the patient and continues with stretching, physical exercise, weight reduction, technical aids (supporting braces, walking sticks) and analgesics. Subsequent options are treatment with paracetamol, NSAIDs and possibly opiates and finally insertion of an artificial joint. Many patients with disabling osteoarthritis function much better and have markedly less pain with an artificial joint.

Interpretation: Current treatment options alleviate but do not cure arthritic symptoms; preventive actions should be instigated when possible. Treatment of osteoarthritis involves many medical specialties and treatment modalities.
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http://dx.doi.org/10.4045/tidsskr.09.1054DOI Listing
November 2010

Intraarticular location predicts cartilage filling and subchondral bone changes in a chondral defect.

Acta Orthop 2010 Oct;81(5):619-27

Martina Hansens Hospital, Bærum, Norway.

Background And Purpose: The natural history of, and predictive factors for outcome of cartilage restoration in chondral defects are poorly understood. We investigated the natural history of cartilage filling subchondral bone changes, comparing defects at two locations in the rabbit knee.

Animals And Methods: In New Zealand rabbits aged 22 weeks, a 4-mm pure chondral defect (ICRS grade 3b) was created in the patella of one knee and in the medial femoral condyle of the other. A stereo microscope was used to optimize the preparation of the defects. The animals were killed 12, 24, and 36 weeks after surgery. Defect filling and the density of subchondral mineralized tissue was estimated using Analysis Pro software on micrographed histological sections.

Results: The mean filling of the patellar defects was more than twice that of the medial femoral condylar defects at 24 and 36 weeks of follow-up. There was a statistically significant increase in filling from 24 to 36 weeks after surgery at both locations. The density of subchondral mineralized tissue beneath the defects subsided with time in the patellas, in contrast to the density in the medial femoral condyles, which remained unchanged.

Interpretation: The intraarticular location is a predictive factor for spontaneous filling and subchondral bone changes of chondral defects corresponding to ICRS grade 3b. Disregarding location, the spontaneous filling increased with long-term follow-up. This should be considered when evaluating aspects of cartilage restoration.
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http://dx.doi.org/10.3109/17453674.2010.524593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214753PMC
October 2010

Chondrogenesis in a hyaluronic acid scaffold: comparison between chondrocytes and MSC from bone marrow and adipose tissue.

Knee Surg Sports Traumatol Arthrosc 2010 Oct 18;18(10):1407-16. Epub 2009 Dec 18.

Institutes of Immunology and Pathology, Rikshospitalet University Hospital, 0027 Oslo, Norway.

Treatment of focal lesions of the articular cartilage of the knee using chondrocytes in a hyaluronic acid (HA) scaffold is already being investigated in clinical trials. An alternative may be to use mesenchymal stem cells (MSC). We have compared articular chondrocytes with MSC from human bone marrow (BM) and adipose tissue (AT), all cultured in HA scaffolds, for their ability to express genes and synthesize proteins associated with chondrogenesis. The cells were expanded in monolayer cultures. After seeding into the scaffold, the chondrocytes were maintained in medium, while the two MSC populations were given a chondrogenic differentiation medium. Chondrogenesis was assessed by real-time RT-PCR for chondrocyte-associated genes, by immunohistochemistry and by ELISA for collagens in the supernatant. Redifferentiation of the dedifferentiated chondrocytes in the HA scaffold was shown by a modest increase in type II collagen mRNA (COL2A1) and reduction in COL1A1. BM-MSC expressed 600-fold higher levels of COL2A1 than chondrocytes after 3 weeks in the scaffold. The levels of aggrecan (AGC1) and COL1A1 were similar for chondrocyte and BM-MSC scaffold cultures, while COL10A1 was higher in the BM-MSC. AT-MSC expressed levels of COL2A1 and COL1A1 similar to chondrocytes, but less AGC1 and COL10A1. Surprisingly, little collagen II protein was observed in the scaffold. Instead, collagen II was found in the culture medium. Chondrogenesis in HA scaffolds was more efficient using BM-MSC than AT-MSC or chondrocytes. Some of the secreted collagen II escaped entrapment in the extracellular space and was detected in the culture medium.
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http://dx.doi.org/10.1007/s00167-009-1017-4DOI Listing
October 2010