Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients

BACKGROUND: In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients. METHODS: Ten heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann–Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used. RESULTS: Three patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/10(6) cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11). CONCLUSIONS: The study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients

Punctuated equilibria and 1/f noise in a biological coevolution model with individual-based dynamics

We present a study by linear stability analysis and large-scale Monte Carlo simulations of a simple model of biological coevolution. Selection is provided through a reproduction probability that contains quenched, random interspecies interactions, while genetic variation is provided through a low mutation rate. Both selection and mutation act on individual organisms. Consistent with some current theories of macroevolutionary dynamics, the model displays intermittent, statistically self-similar behavior with punctuated equilibria. The probability density for the lifetimes of ecological communities is well approximated by a power law with exponent near -2, and the corresponding power spectral densities show 1/f noise (flicker noise) over several decades. The long-lived communities (quasi-steady states) consist of a relatively small number of mutualistically interacting species, and they are surrounded by a ``protection zone'' of closely related genotypes that have a very low probability of invading the resident community. The extent of the protection zone affects the stability of the community in a way analogous to the height of the free-energy barrier surrounding a metastable state in a physical system. Measures of biological diversity are on average stationary with no discernible trends, even over our very long simulation runs of approximately 3.4x10^7 generations.Comment: 20 pages RevTex. Minor revisions consistent with published versio

Self-optimization, community stability, and fluctuations in two individual-based models of biological coevolution

We compare and contrast the long-time dynamical properties of two individual-based models of biological coevolution. Selection occurs via multispecies, stochastic population dynamics with reproduction probabilities that depend nonlinearly on the population densities of all species resident in the community. New species are introduced through mutation. Both models are amenable to exact linear stability analysis, and we compare the analytic results with large-scale kinetic Monte Carlo simulations, obtaining the population size as a function of an average interspecies interaction strength. Over time, the models self-optimize through mutation and selection to approximately maximize a community fitness function, subject only to constraints internal to the particular model. If the interspecies interactions are randomly distributed on an interval including positive values, the system evolves toward self-sustaining, mutualistic communities. In contrast, for the predator-prey case the matrix of interactions is antisymmetric, and a nonzero population size must be sustained by an external resource. Time series of the diversity and population size for both models show approximate 1/f noise and power-law distributions for the lifetimes of communities and species. For the mutualistic model, these two lifetime distributions have the same exponent, while their exponents are different for the predator-prey model. The difference is probably due to greater resilience toward mass extinctions in the food-web like communities produced by the predator-prey model.Comment: 26 pages, 12 figures. Discussion of early-time dynamics added. J. Math. Biol., in pres

Spatial and temporal trends of mercury in freshwater fish in Fennoscandia (1965-2015)

Source at http://hdl.handle.net/11250/2467116Mercury (Hg) emissions to the atmosphere cause elevated Hg levels in fish, even in many remote regions of the world. Here we present an extensive database of more than 50 000 measurements of Hg in fish, including 2 775 individual water bodies in Fennoscandia (Norway, Sweden, Finland, Russian part of Kola Peninsula) sampled between 1965 and 2015. The data have been analysed for spatial patterns and temporal trends, on raw and weight-adjusted data. The database presents a useful reference for assessment of impacts of environmental policy on Hg in freshwater fish (i.e. Convention on Long-Range Transboundary Air Pollution and The Minamata Convention on Mercury)

Radiographs and low field MRI (0.2T) as predictors of efficacy in a weight loss trial in obese women with knee osteoarthritis

<p>Abstract</p> <p>Background</p> <p>To study the predictive value of baseline radiographs and low-field (0.2T) MRI scans for the symptomatic outcome of clinically significant weight loss in obese patients with knee osteoarthritis.</p> <p>Methods</p> <p>In this study we hypothesize that imaging variables assessed with radiographs and MRI scans pre-treatment can predict the symptomatic changes following a recommended clinically significant weight reduction Patients were recruited from the Department of Rheumatology, Frederiksberg Hospital, Denmark. Eligibility criteria were: age >18 years; primary osteoarthritis according to ACR; BMI > 28 kg/m2; motivation for weight loss. Subjects were randomly assigned to either intervention by low-energy diet (LED) for 8 weeks followed by another 24 weeks of dietary instruction or control-group. MRI scans and radiographs were scored for structural changes and these parameters were examined as independent predictors of changes in osteoarthritis symptoms after 32 weeks. The outcome assessor and statistician were blinded to group allocation.</p> <p>Results</p> <p>No significant correlations were found between imaging variables and changes in Western Ontario and McMaster Universities Index of Osteoarthritis (Spearman's test, r < 0.33 and P > 0.07).</p> <p>Only the LED group achieved a weight loss, with a mean difference of 16.3 kg (95%CI: 13.4-19.2;P < 0.0001) compared to the control group. The total WOMAC index showed a significant difference favouring LED, with a group mean difference of - 321.3 mm (95%CI: -577.5 to -65.1 mm; P = 0.01). No significant adverse events were reported.</p> <p>Conclusion</p> <p>Stage of joint destruction, assessed on either radiographs or low-field MRI (0.2T), does not preclude a symptoms relief following a clinically relevant weight loss in elderly obese female patients with knee osteoarthritis.</p

Improved environmental status : 50 years of declining fish mercury levels in boreal and subarctic Fennoscandia

Temporally (1965–2015) and spatially (55°–70°N) extensive records of total mercury (Hg) in freshwater fish showed consistent declines in boreal and subarctic Fennoscandia. The database contains 54 560 fish entries (n: pike > perch ≫ brown trout > roach ≈ Arctic charr) from 3132 lakes across Sweden, Finland, Norway, and Russian Murmansk area. 74% of the lakes did not meet the 0.5 ppm limit to protect human health. However, after 2000 only 25% of the lakes exceeded this level, indicating improved environmental status. In lakes where local pollution sources were identified, pike and perch Hg concentrations were significantly higher between 1965 and 1990 compared to values after 1995, likely an effect of implemented reduction measures. In lakes where Hg originated from long-range transboundary air pollution (LRTAP), consistent Hg declines (3–7‰ per year) were found for perch and pike in both boreal and subarctic Fennoscandia, suggesting common environmental controls. Hg in perch and pike in LRTAP lakes showed minimal declines with latitude, suggesting that drivers affected by temperature, such as growth dilution, counteracted Hg loading and food web exposure. We recommend that future fish Hg monitoring sampling design should include repeated sampling and collection of pollution history, water chemistry, fish age, and stable isotopes to enable evaluation of emission reduction policies

The Homeostatic Chemokine CCL21 Predicts Mortality and May Play a Pathogenic Role in Heart Failure

Background: CCL19 and CCL21, acting through CCR7, are termed homeostatic chemokines. Based on their role in concerting immunological responses and their proposed involvement in tissue remodeling, we hypothesized that these chemokines could play a pathogenic role in heart failure (HF). Methodology/Principal Findings: Our main findings were: (i) Serum levels of CCL19 and particularly CCL21 were markedly raised in patients with chronic HF (n = 150) as compared with healthy controls (n = 20). A CCL21 level above median was independently associated with all-cause mortality. (ii) In patients with HF following acute myocardial infarction (MI; n = 232), high versus low CCL21 levels 1 month post-MI were associated with cardiovascular mortality, even after adjustment for established risk factors. (iii). Explanted failing human LV tissue (n = 29) had markedly increased expression of CCL21 as compared with non-failing myocardium (n = 5). (iv) Our studies in CCR7−/− mice showed improved survival and attenuated increase in markers of myocardial dysfunction and wall stress in post-MI HF after 1 week, accompanied by increased myocardial expression of markers of regulatory T cells. (v) Six weeks post-MI, there was an increase in markers of myocardial dysfunction and wall stress in CCR7 deficient mice. Conclusions/Significance: High serum levels of CCL21 are independently associated with mortality in chronic and acute post-MI HF. Our findings in CCR7 deficient mice may suggest that CCL21 is not only a marker, but also a mediator of myocardial failure. However, while short term inhibition of CCR7 may be beneficial following MI, a total lack of CCR7 during long-term follow-up could be harmful.publishedVersio

Taurolidine-citrate lock solution (TauroLock) significantly reduces CVAD-associated grampositive infections in pediatric cancer patients

<p>Abstract</p> <p>Background</p> <p>Taurolidin/Citrate (TauroLock™), a lock solution with broad spectrum antimicrobial activity, may prevent bloodstream infection (BSI) due to coagulase-negative staphylococci (CoNS or 'MRSE' in case of methicillin-resistant isolates) in pediatric cancer patients with a long term central venous access device (CVAD, Port- or/Broviac-/Hickman-catheter type).</p> <p>Methods</p> <p>In a single center prospective 48-months cohort study we compared all patients receiving anticancer chemotherapy from April 2003 to March 2005 (group 1, heparin lock with 200 IU/ml sterile normal saline 0.9%; Canusal^®Wockhardt UK Ltd, Wrexham, Wales) and all patients from April 2005 to March 2007 (group 2; taurolidine 1.35%/Sodium Citrate 4%; TauroLock™, Tauropharm, Waldbüttelbrunn, Germany).</p> <p>Results</p> <p>In group 1 (heparin), 90 patients had 98 CVAD in use during the surveillance period. 14 of 30 (47%) BSI were 'primary Gram positive BSI due to CoNS (n = 4) or MRSE (n = 10)' [incidence density (ID); 2.30 per 1000 inpatient CVAD-utilization days].</p> <p>In group 2 (TauroLock™), 89 patients had 95 CVAD in use during the surveillance period. 3 of 25 (12%) BSI were caused by CoNS. (ID, 0.45). The difference in the ID between the two groups was statistically significant (P = 0.004).</p> <p>Conclusion</p> <p>The use of Taurolidin/Citrate (TauroLock™) significantly reduced the number and incidence density of primary catheter-associated BSI due to CoNS and MRSE in pediatric cancer patients.</p

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly