Louise Hansen

Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina

Abstract Aims. We evaluated the feasibility, safety and efficacy of intra-myocardial injection of autologous mesenchymal stromal cells derived endothelial progenitor cell (MSC) in patients with stable coronary artery disease (CAD) and refractory angina in this first in man trial. Methods and results. A total of 31 patients with stable CAD, moderate to severe angina and no further revascularization options, were included. Bone marrow MSC were isolated and culture expanded for 6–8 weeks. It was feasible and safe to establish in-hospital culture expansion of autologous MSC and perform intra-myocardial injection of MSC. After six months follow-up myocardial perfusion was unaltered, but the patients increased exercise capacity (p < 0.001), reduction in CCS Class (p < 0.001), angina attacks (p < 0.001) and nitroglycerin consumption (p < 0.001), and improved Seattle Angina Questionnaire (SAQ) evaluations (p < 0.001). For all parameters there was a tendency towards improved outcome with increasing numbers of cells injected. In the MRI substudy: ejection fraction (p < 0.001), systolic wall thickness (p = 0.03) and wall thickening (p = 0.03) all improved. Conclusions. The study demonstrated that it was safe to treat patients with stable CAD with autologous culture expanded MSC. Moreover, MSC treated patients had significant improvement in left ventricular function and exercise capacity, in addition to an improvement in clinical symptoms and SAQ evaluations. Trial registration: ClinicalTrials.gov identifier: NCT00260338.

Changes in insulin sensitivity precede changes in body composition during 14 days of step reduction combined with overfeeding in healthy young men.

A lifestyle characterized by inactivity and a high-calorie diet is a known risk factor for impaired insulin sensitivity and development of Type 2 diabetes mellitus. To investigate possible links, nine young healthy men (24 ± 3 yr; body mass index of 21.6 ± 2.5 kg/m(2)) completed 14 days of step reduction (10,000 to 1,500 steps/day) and overfeeding (+50% kcal). Body composition (dual X-ray absorptiometry, MRI), aerobic fitness (maximal O(2) consumption), systemic inflammation and insulin sensitivity [oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp] were assessed before (day 0), during (days 3 and 7), and immediately after the intervention (day 14), with follow-up tests (day 30). Body weight had increased at days 7 and 14 (P < 0.05). The amount of visceral fat had increased at day 14 compared with day 0 (P < 0.05). The insulin response to the OGTT had increased at days 7 and 14 (P < 0.05). Insulin sensitivity, estimated using the Matsuda index, had decreased at days 3 and 7 (P < 0.01). At day 14, glucose infusion rates had decreased by ∼44% during the euglycemic clamps (P < 0.05). Also, plasma levels of leptin and adiponectin had increased (P < 0.05), whereas no changes were seen in inflammatory markers. At day 30, body weight and whole body adiposity were still elevated compared with day 0 (P < 0.05), whereas the insulin sensitivity as well as the insulin response to the OGTT did not differ from baseline. The glucose response to the OGTT was only affected at day 30, with a decrease compared with day 0. Our data show that insulin sensitivity was impaired after 3 days of inactivity and overfeeding. Impairments in insulin sensitivity occurred before changes in body composition, supporting the notion that the initial steps in impairment of insulin sensitivity may be linked directly to the effects of inactivity and a high calorie intake.

Identification of Weak Layers and Their Role for the Stability of Slopes at Finneidfjord, Northern Norway

The 1996 Finneidfjord landslide, which took four human lives in northern Norway, initiated along a weak layer in the fjord-marine sediments before developing retrogressively across the shoreline. The integration of results from sediment cores, free-fall cone penetrometer tests and high-resolution 3D seismic data indicates that the slide-prone layer is a regional bed likely sourced from clay-slide activity in the catchment of the fjord. The sediments in this regional layer are softer and more sensitive than the typical bioturbated, fjord-marine deposits, which explains their role in slope instability. In addition, biogenic gas in the stratified event bed may further affect its geotechnical properties. Similar, fine-grained, stratified beds with comparable origin and properties occur in other Norwegian fjords. They are presumably also present along coastlines of other previously glaciated margins, where they could contribute to mass movements.

Normal physical activity obliterates the deleterious effects of a high-caloric intake

A high-caloric intake combined with a sedentary lifestyle is an important player in the development of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine if the level of physical activity has impact on the metabolic effects of a high-caloric (+2,000 kcal/day) intake. Therefore, healthy individuals on a high-caloric intake were randomized to either 10,000 or 1,500 steps/day for 14 days. Step number, total energy expenditure, dietary records, neuropsychological tests, maximal oxygen uptake (Vo2max), whole body dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans, continuous glucose monitoring (CGM), and oral glucose tolerance tests (OGTT) with stable isotopes were performed before and after the intervention. Both study groups gained the same amount of body weight. However, the inactive group accumulated significantly more visceral fat compared with the active group. Following the 2-wk period, the inactive group also experienced a poorer glycemic control, increased endogenous glucose production, decreased hepatic insulin extraction, increased baseline plasma levels of total cholesterol and LDL, and a decreased cognitive function with regard to capacity of attention. In conclusion, we find evidence to support that habitual physical activity may prevent pathophysiological symptoms associated with diet-induced obesity.

Deltaic Infill of a Deglaciated Arctic Fjord, East Greenland: Sedimentary Facies and Sequence Stratigraphy

ABSTRACT The deltaic fill of a deglaciated side-entry fjord in western Jameson Land, East Greenland, shows the record of an interplay between regional and local controls, including climate and relative sea-level change, onshore and offshore topography, and sediment yield. A four-phase model is suggested for the delta development and fjord filling. At the deglaciation stage (phase 1), the newly flooded fjord floor primarily accumulated sediment from reworked glacial material. These deposits were relatively thin, and draped the uneven sea-floor topography. The subsequent onset of paraglacial delta sedimentation (phase 2) was characterized by a high meltwater runoff and extreme sediment yield, and corresponded to the highstand and gradual fall of relative sea level. A Gilbert-type delta with a short distributary plain formed at the head of the tributary fjord, which received a very high amount of fine-grained sediment. The stage of enhanced delta progradation (phase 3) was characterized by decreased sediment yield and runoff, and a rapid fall of relative sea level. Delta progradation was fast because of rapidly decreasing accommodation space, and a solitary river channel deeply incised the delta. The equilibrium stage (phase 4) spanned most of Holocene time and involved a lowered rate of relative sea-level fall. Seasonal runoff supplied limited amounts of sediment to the river mouth, and the delta front became increasingly reworked by wave action and longshore drift. The side-entry fjord, a small deglaciated valley invaded by the sea, was filled chiefly by highstand and regressive systems tracts, whereas relatively little sea-floor aggradation was associated with the transgressive systems tract. The stratigraphic pattern documented in this paper contrasts with the pattern usually reported from nonglaciated incised-valley systems, which are filled mainly by the transgressive systems tract, typically involving a retreating estuarine system. The pattern also differs from some large, gradually deglaciated fjord valleys containing thick, transgressive, glaciomarine deposits accumulated during glacier retreat. The study demonstrates the large variability of valley fills and illustrates the importance of topography, sediment supply, and climate as well as the style of deglaciation on the sediment filling of a fjord valley.

Comparison of mesenchymal stromal cells from young healthy donors and patients with severe chronic coronary artery disease

Abstract Background: It has been questioned whether bone marrow-derived mesenchymal stromal cells (MSCs) from patients with ischemic heart disease are suitable for use in regenerative stem cell therapy. We compared MSCs from patients with chronic coronary artery disease (CAD) and MSCs from young healthy donors with respect to phenotype, proliferation and endothelial differentiation capacity. Methods: MSCs from 16 young healthy donors and 15 elderly CAD patients were isolated, expanded by ex-vivo cultivation for two cell passages and characterized by flow cytometry, real time PCR and angiogenesis assay. Results: MSCs from healthy donors and CAD patients expressed the same surface markers and had similar proliferation capacity. In both groups VEGF-stimulation significantly increased the expression of the endothelial genes thrombospondin 1, Tie-2 and von Willebrand Factor and induced the capacity to form ring structures on extracellular matrix. Discussion: MSCs from young healthy donors and CAD patients proliferate equally well, express the same surface markers and increase in endothelial gene expression and ring structure formation capacity in the angiogenesis assay upon VEGF-stimulation. MSCs from CAD patients do not seem to be inferior to MSCs from young healthy donors thus indicating that autologous MSCs may be suitable for cell therapy in CAD patients.

Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes. Objective To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes. Design, Setting, and Participants Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non–insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34). Interventions All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months. Main Outcomes and Measures Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication. Results Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of −0.26% [95% CI, −0.52% to −0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group. Conclusions and Relevance Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings. Trial Registration clinicaltrials.gov Identifier: NCT02417012

Optimal labeling dose, labeling time, and magnetic resonance imaging detection limits of ultrasmall superparamagnetic iron-oxide nanoparticle labeled mesenchymal stromal cells.

Background. Regenerative therapy is an emerging treatment modality. To determine migration and retention of implanted cells, it is crucial to develop noninvasive tracking methods. The aim was to determine ex vivo magnetic resonance imaging (MRI) detection limits of ultrasmall superparamagnetic iron-oxide (USPIO) labeled mesenchymal stromal cells (MSCs). Materials and Methods. 248 gel-phantoms were constructed and scanned on a 1.5T MRI-scanner. Phantoms contained human MSCs preincubated with USPIO nanoparticles for 2, 6, or 21 hours using 5 or 10 μg USPIO/105 MSCs. In addition, porcine hearts were scanned after injection of USPIO labeled MSCs. Results. Using 21 h incubation time and 10 μg USPIO/105 MSCs, labeled cells were clearly separated from unlabeled cells on MRI using 250.000 (P < 0.001), 500.000 (P = 0.007), and 1.000.000 MSCs (P = 0.008). At lower incubation times and doses, neither labeled nor unlabeled cells could be separated. In porcine hearts labeled, but not unlabeled, MSCs were identified on MRI. Conclusions. As few as 250.000 MSCs can be detected on MRI using 21 h incubation time and 10 μg USPIO/105 MSCs. At lower incubation times and doses, several million cells are needed for MRI detection. USPIO labeled cells can be visualized by MRI in porcine myocardial tissue.

Physical Activity Enhances Metabolic Fitness Independently of Cardiorespiratory Fitness in Marathon Runners

High levels of cardiovascular fitness (CRF) and physical activity (PA) are associated with decreased mortality and risk to develop metabolic diseases. The independent contributions of CRF and PA to metabolic disease risk factors are unknown. We tested the hypothesis that runners who run consistently >50 km/wk and/or >2 marathons/yr for the last 5 years have superior metabolic fitness compared to matched sedentary subjects (CRF, age, gender, and BMI). Case-control recruitment of 31 pairs of runner-sedentary subjects identified 10 matched pairs with similar VO2max (mL/min/kg) (similar-VO2max). The similar-VO2max group was compared with a group of age, gender, and BMI matched pairs who had the largest difference in VO2max (different-VO2max). Primary outcomes that defined metabolic fitness including insulin response to an oral glucose tolerance test, fasting lipids, and fasting insulin were superior in runners versus sedentary controls despite similar VO2max. Furthermore, performance (velocity at VO2max, running economy), improved exercise metabolism (lactate threshold), and skeletal muscle levels of mitochondrial proteins were superior in runners versus sedentary controls with similar VO2max. In conclusion subjects with a high amount of PA have more positive metabolic health parameters independent of CRF. PA is thus a good marker against metabolic diseases.

Landscape and Coast Development of A Lowland Fjord Margin Following Deglaciation, East Greenland

The landscapes of western Jameson Land bordering Hall Bredning fjord comprise upper river basins, glacial landscapes, lower river basins and a near‐shore zone. The upper river basins are incised into bedrock and display no cover of young sediments whilst the glacial landscapes, located closer to the coast, are dominated by Pleistocene deposits and an irregular topography with hills and ridges. The lower river basins, dissecting the glacial landscapes, are connected to the upper river basins and contain well‐defined Holocene delta terraces. The near‐shore zone, which includes the present coast, displays a few raised shorelines. Geomorphological observations combined with stratigraphic work and 14C dates provide a chronological framework for the development of landscape and shoreline, as presented by a four‐stage reconstruction. The first stage covers the deglaciation of western Jameson Land at the Weichselian‐Holocene transition after a collapse of the main fjord glacier in Hall Bredning. The sea inundated the low‐lying areas on Jameson Land forming small side‐entry fjord basins that possibly follow the track of older valleys. This was followed by a second stage, the paraglacial period, when large meltwater production and sediment transport resulted in a fast infilling of the side‐entry fjord basins by deltas. These are now exposed in terraces in the lower river basins at 70–80 m a.s.l. During a third stage, the relaxation period, fluvial activity decreased and the land surface was increasingly occupied by a cover of tundra vegetation. A glacio‐isostatic rebound resulted in a relative sea level fall and fluvial incision. During stages two and three the coast was exposed to shallow marine processes that aided the alignment of the coast. Stages one to three presumably lasted for less than 2000 years. During stage four, the stable period, lasting for several thousand years till the present, there were minor adjustments of shoreline and landscape. The four‐step reconstruction describes the sedimentary response of a lowland fjord margin to dramatic changes in climate and sea level. The distribution of erosion and sedimentation during this development was mainly controlled by topography. The reconstruction of the latest environmental development of Jameson Land puts new light on Jameson Lands long and complex Quaternary stratigraphic record. The reconstruction may also be used as a model for the interpretation of deposits in similar areas elsewhere.