FIT & STRONG! PLUS: DESCRIPTIVE DEMOGRAPHIC AND RISK CHARACTERISTICS IN A COMPARATIVE EFFECTIVENESS TRIAL FOR OLDER AFRICAN-AMERICAN ADULTS WITH OSTEOARTHRITIS.

OBJECTIVES: The prevalence of osteoarthritis (OA) has increased in the US. We report on a comparative effectiveness trial that compares Fit & Strong!, an existing evidence-based physical activity (PA) program, to Fit & Strong! Plus, which combines the Fit & Strong! intervention with a weight management intervention. METHODS: Participants included 413 overweight/obese (BMI 25-50 kg/m2) adults with lower extremity (LE) OA. The majority of the sample was African-American and female. Both interventions met 3 times weekly for 8 weeks. Primary measures included diet and weight. RESULTS: The baseline mean BMI for all participants was 34.8 kg/m², percentage of calories from fat was high, and self-reported PA was low. DISCUSSION: This sample of overweight/obese African-American adults had lifestyle patterns at baseline that were less than healthful, and there were differences between self-report and performance-based measures as a function of age.

The KTx360°-study: a multicenter, multisectoral, multimodal, telemedicine-based follow-up care model to improve care and reduce health-care costs after kidney transplantation in children and adults.

BACKGROUND: Follow-up care after kidney transplantation is performed in transplant centers as well as in local nephrologist's practices in Germany. However, organized integrated care of these different sectors of the German health care system is missing. This organizational deficit as well as non-adherence of kidney recipients and longterm cardiovascular complications are major reasons for an impaired patient and graft survival. METHODS: The KTx360° study is supported by a grant from the Federal Joint Committee of the Federal Republic of Germany. The study will include 448 (39 children) incident patients of all ages with KTx after study start in May 2017 and 963 (83 children) prevalent patients with KTx between 2010 and 2016. The collaboration between transplant centers and nephrologists in private local practices will be supported by internet-based case-files and scheduled virtual visits (patient consultation via video conferencing). At specified points of the care process patients will receive cardiovascular and adherence assessments and respective interventions. Care will be coordinated by an additional case management. The goals of the study will be evaluated by an independent institute using claims data from the statutory health insurances and data collected from patients and their caregivers during study participation. To model longitudinal changes after transplantation and differences in changes and levels of immunosuppresive therapy after transplantation between study participants and historical data as well as data from control patients who do not participate in KTx360°, adjusted regression analyses, such as mixed models with repeated measures, will be used. Relevant confounders will be controlled in all analyses. DISCUSSION: The study aims to prolong patient and graft survival, to reduce avoidable hospitalizations, co-morbidities and health care costs, and to enhance quality of life of patients after kidney transplantation. TRIAL REGISTRATION: ISRCTN29416382 (retrospectively registered on 05.05.2017).

The steroid metabolite 16(ß)-OH-androstenedione generated by CYP21A2 serves as a substrate for CYP19A1.

The 21-hydroxylase (CYP21A2) is a steroidogenic enzyme crucial for the synthesis of mineralo- and glucocorticoids. It is described to convert progesterone as well as 17-OH-progesterone, through a hydroxylation at position C21, into 11-deoxycorticosterone (DOC) and 11-deoxycortisol (RSS), respectively. In this study we unraveled CYP21A2 to have a broader steroid substrate spectrum than assumed. Utilizing a reconstituted in vitro system, consisting of purified human CYP21A2 and human cytochrome P450 reductase (CPR) we demonstrated that CYP21A2 is capable to metabolize DOC, RSS, androstenedione (A4) and testosterone (T). In addition, the conversion of A4 rendered a product whose structure was elucidated through NMR spectroscopy, showing a hydroxylation at position C16-beta. The androgenic properties of this steroid metabolite, 16(ß)-OH-androstenedione (16bOHA4), were investigated and compared with A4. Both steroid metabolites were shown to be weak agonists for the human androgen receptor. Moreover, the interaction of 16bOHA4 with the aromatase (CYP19A1) was compared to that of A4, indicating that the C16 hydroxyl group does not influence the binding with CYP19A1. In contrast, the elucidation of the kinetic parameters showed an increased Km and decreased kcat value resulting in a 2-fold decreased catalytic efficiency compared to A4. These findings were in accordance with our docking studies, revealing a similar binding conformation and distance to the heme iron of both steroids. Furthermore, the product of 16bOHA4, presumably 16-hydroxy-estrone (16bOHE1), was investigated with regard to its estrogenic activity, which was negligible compared to estradiol and estrone. Finally, 16bOHA4 was found to be present in a patient with 11-hydroxylase deficiency and in a patient with an endocrine tumor. Taken together, this study provides novel information on the steroid hormone biosynthesis and presents a new method to detect further potential relevant novel steroid metabolites.

[Rehabilitation after kidney transplantation: Old problems and new structures]. / Rehabilitation nach Nierentransplantation: Alte Probleme und neue Strukturen.

Kidney transplantation is currently the best therapeutic option for patients with end stage renal disease. Alternative treatment with hemo- or peritoneal dialysis is associated with higher comorbidities, higher morbidity/mortality, and reduced quality of life. Thus, a major aim in posttransplant care is to develop strategies to increase transplant survival and reduce known risk factors and comorbidities. In this overview, we propose a concept to include rehabilitation clinics in all aspects of the transplant process. This concept includes pretransplant care on the waiting list to prepare the patient for the transplant, the direct postoperative treatment phase, and repeated and risk adapted stays in rehabilitation clinics during long-term follow-up to address specific and individual problems.

CXCL13 as a new biomarker of systemic lupus erythematosus and lupus nephritis - from bench to bedside?

Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 (CXCL13) to the autoimmune disease systemic lupus erythematosus (SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE.

Pathogenetic role of glomerular CXCL13 expression in lupus nephritis.

Podocytes maintain the structure and function of the glomerular filtration barrier. However, podocytes have recently been implicated in the innate immune response, and their function as non-haematopoietic antigen-presenting cells was highlighted. We have shown previously that excessive expression of the chemokine CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, we found that CXCL13 is elevated significantly in the serum of patients with SLE-nephritis. In this study, we were able to show for the first time that (i) CXCL13 is expressed locally in glomeruli in a model for SLE-nephritis in mice and that (ii) incubation of human podocytes with CXCL13 induces receptor stimulation of CXCR5 with activation of signalling pathways, resulting in (iii) secretion of proinflammatory cytokines and chemokines in culture supernatant. This cytokine/chemokine cocktail can lead to (iv) a neutrophil respiratory burst in isolated human granulocytes. Taken together, our results provide further evidence that CXCL13 is involved in the pathogenesis of glomerulonephritis and that podocytes can play an active role in local proinflammatory immune responses. Thus, CXCL13 could be a direct target for the therapy of glomerulonephritis in general and for SLE-nephritis in particular.

CXCL13 as a novel marker for diagnosis and disease monitoring in pediatric PTLD.

Posttransplant lymphoproliferative disease (PTLD) is a severe complication of immunosuppressive treatment in organ-grafted children. Early diagnosis of PTLD is hampered by both unspecific clinical symptoms and lack of easy accessible markers. The homeostatic chemokine CXCL13, which plays a crucial role in B-cell homing and lymphoid organ development, is expressed in some lymphomatous diseases. This study aims to investigate whether serum CXCL13 (sCXCL13) levels correlate with occurrence and regression of PTLD in pediatric solid-organ graft recipients. Serum samples from PTLD patients (n = 21), patients with Epstein-Barr virus (EBV) reactivation (n = 18), and healthy age-matched controls (n = 19) were tested for CXCL13 using a commercially available ELISA kit. sCXCL13 levels were significantly higher in PTLD patients than in healthy children. PTLD patients had also higher sCXCL13 values than pediatric solid-organ recipients with EBV reactivation. An increase in sCXCL13 levels was observed from EBV reactivation to PTLD diagnosis in most cases. Elevated sCXCL13 levels were detected up to 2 years prior to PTLD diagnosis and correlated well with response to cytoreductive treatment in individual patients. sCXCL13, thus, may be a readily available surrogate marker for the diagnosis of PTLD and for monitoring of response to treatment in patients with initially elevated sCXCL13 levels.

Elevation of serum CXCL13 in SLE as well as in sepsis.

Recent studies have demonstrated that CXCL13 serum levels correlate significantly with systemic lupus erythematosus (SLE) disease activity. However, experimental studies show that CXCL13 production can also be induced by bacterial exposure as well as in response to inflammatory cytokines. This report asks whether CXCL13 serum levels are elevated in patients with evidence of bacterial infections and whether there is a correlation with the C-reactive protein (CRP) levels or the severity of illness in critically ill patients. CXCL13 levels were compared in 39 patients with active SLE (without concomitant infection), 40 non-SLE patients with sepsis, and 40 healthy controls by enzyme-linked immunosorbent assay (ELISA) methodology. We also tested storage conditions and freeze-thaw cycles for stability of CXCL13 in serum samples. Our studies demonstrated that the median CXCL13 serum levels were significantly elevated in patients with SLE [median 83 pg/ml (interquartile range 38-366)] or sepsis [359 pg/ml (151-459)] compared with healthy controls [32 pg/ml (27-41), p < 0.001]. The CXCL13 serum levels correlated with disease activity in SLE (CXCL13 vs. SLEDAI r = 0.65, p < 0.001), but were not associated with severity of illness score in critically ill patients (CXCL13 vs. SOFA r = -0.15, p = 0.35). However, CXCL13 serum levels were clearly associated with CRP levels in both sepsis (r = 0.45, p = 0.003) and SLE (r = 0.39, p = 0.02). In conclusion, CXCL13 is a stable serum marker for disease activity in SLE patients, but concomitant infections can also lead to increased CXCL13 levels.

Lowering anti-dsDNA antibodies--what's new?

Antibodies to dsDNA are specific to SLE and are pathogenic, both due to their ability to deposit in tissues through a variety of mechanisms, and to their ability, when present in immune complexes, to activate inflammatory cells. The relationship of serum anti-dsDNA antibody levels to disease activity is a complex one and the factors that determine whether or not such antibodies will be pathogenic in an individual SLE patient are incompletely understood. Although anti-dsDNA antibodies can be made by naïve B cells and B cells belonging to the B1 and marginal zone subsets, pathogenic anti-dsDNA antibodies have the hallmarks of germinal center development and exposure to T cell help, including accumulation of somatic mutations and class switching to the IgG isotype. Epitope spreading may result in aquisition of cross-reactivities with multiple target organ antigens and aquisition of a memory phenotype will allow these B cells to acquire antigen presentation functions that amplify the autoreactive response. In the early stages of disease, or after remission induction protocols, autoreactive B cells may be susceptible to treatments that target T cell costimulation or that deplete or tolerize naïve and mature B cells. Therapeutic approaches targeting innate immune responses or regulatory T cells are starting to be tested in pre-clinical models. In later disease stages, memory and plasma cell accumulation may render patients more resistant to this type of therapeutic approach. Deposition of anti-dsDNA antibodies in target tissues can stimulate an inflammatory cascade that leads to tissue damage. A number of murine models have now been developed that show that interruption of this cascade can prevent or reverse such damage. This type of approach may be beneficial for individuals with established disease. As we learn more about the specific defects that cause SLE, it may become possible to individualize therapy based on patient specific biologic markers.

Oats and soy in lipid-lowering diets for women with hypercholesterolemia: is there synergy?

OBJECTIVES: To study possible synergistic effects of oats and soy on reducing total and low-density lipoprotein cholesterol (LDL-C) concentrations in human beings and the efficacy and feasibility of including these adjustments to a National Cholesterol Education Program Step I diet. SUBJECT/SETTING: One hundred twenty-seven postmenopausal women with moderate hypercholesterolemia were recruited from a large Midwestern workforce and senior centers in the surrounding community. Intervention and clinical visits were conducted in these same facilities. DESIGN: After a 3-week lead-in period on the Step I diet, participants were randomly assigned to 1 of 4 dietary treatments for an additional 6 weeks: an oats/milk group, a wheat/soy group, an oats/soy group, and a wheat/milk group. Clinical measurements included blood draws, body weight and height, blood pressure, and medical history data. Three-day food records were collected at baseline and Weeks 3 and 9 of the intervention. Randomization was stratified based on the status of hormone replacement therapy and was blocked with sizes 4 or 8 for group assignment. RESULTS: After 3 weeks on the Step I diet, total cholesterol, LDL-C, and triglyceride levels; total fat and saturated fat intake, dietary cholesterol intake, Keys score, and body mass index were all reduced. Following an additional 6 weeks on the Step I diet plus intervention, total cholesterol and LDL-C were further reduced for both the oats/soy group and oats/milk group. There were no significant further changes in total cholesterol, LDL-C, or high-density lipoprotein cholesterol levels in the wheat/soy and wheat/milk groups. Body mass index remained stable in all groups from Week 3 to Week 9. APPLICATIONS: Nonpharmacologic dietary interventions like the Step I diet are feasible in a community setting and can produce rapid and significant lipid-lowering benefits. Daily consumption of 2 servings of oats can contribute to further lipid alterations in this population although soy intake at this dose may not. Palatability and convenience are important considerations in achieving dietary adherence.

Brain-tumor cell kinetics correlated with survival.

In a review of 38 glioblastoma patients for whom fresh tissue kinetic data were available before any therapy was instituted, no correlation between the labeling index and survival time could be statistically determined. This relationship seems entirely consistent with the published theoretical determinants of tumor behavior: that is, altered ability for growth arrest and differentiation, constantly evolving mutant sublines, genetic instability, and an ever-changing metabolic and vascular environment.

Effect of dexamethasone on vascular function in RIF-1 tumors.

The present series of experiments was conducted to determine the effect of dexamethasone on vascular function and cell proliferation in s.c. RIF-1 tumors. 125I-BSA, 51Cr-EDTA dilution techniques were used to evaluate dexamethasone induced changes in tumor plasma water, capillary permeability, and extracellular water volumes, while 59Fe and 51Cr labeled erythrocyte techniques were used to assess changes in tumor exchangeable erythrocyte volumes. 86RbCl distribution studies were also conducted to evaluate vascular perfusion in RIF-1 tumors after dexamethasone treatment. In this corticosteroid receptor containing tumor model, dexamethasone had profound effects on all of the measured parameters of vascular function. Reduced tumor cell proliferation after dexamethasone treatments was accompanied by reduced capillary permeability, reduced interstitial water volumes, increased plasma volumes, and reduced vascular perfusion. Serial studies after dexamethasone treatments indicated that increases in vascular perfusion preceded proliferative recovery. Intervals of maximal [3H]thymidine labeling after dexamethasone were characterized by transient increases in capillary permeability, interstitial water volumes, and tumor erythrocyte exchange with the general circulation. At intervals of maximal cell proliferation (36-48 h after dex) 86RbCl distribution in tumors was about 3 times that seen in untreated controls. The results seem to indicate that, as in edematous normal tissues, dexamethasone can have profound effects on vascular function and water compartmentalization in RIF-1 tumors.

1H-NMR relaxation times and water compartmentalization in experimental tumor models.

The present studies were conducted with RIF-1, M5076 and Panc02 subcutaneous tumor models to assess the relationship between tissue-free water compartmentalization and observed tissue T1 and T2 changes at 10 MHz. Observed T1 was shown to correlate directly with total extracellular water and interstitial water volumes. T1 and T2 were also inversely related to intracellular water volumes. T1 and T2 decreases after dexamethasone treatment were, however, most closely correlated with changes in tumor extracellular water and not changes in cell or total water volumes. Studies to assess Gd-DTPA-dimeg dose dependent T1 and T2 modification in model serum protein solutions indicated that although the Gd concentration that reduced T2 by 50% was about 2.5 fold greater than that required to reduce T1 equally, the of the concentration dependent T1 and T2 modifications were similar. In studies with tumor models, the injected dose of Gd-DTPA-dimeg that reduced T1 by 50% was inversely correlated with tumor extracellular water volumes. The slopes for dose dependent T1 modification in all tumors were similar and similar to that observed for model protein solutions. Gd-DTPA-dimeg had a different effect on observed T2 values for the 3 tumor models. Exponential slopes were about twice that observed for T2 modification of serum protein solutions, and Gd-DTPA-dimeg doses that reduced observed tumor T2 ranged from 9 to 50 times that necessary to similarly reduce T1. The results from these studies indicate that the observed T1, for these tumors, was dominated by relaxation of water protons in interstitial water but that the observed T2 was most strongly influenced by proton relaxation in water compartments that were unavailable to the Gd labeled probe.

The measurement of extracellular water volumes in tissues by gadolinium modification of 1H-NMR spin lattice (T1) relaxation.

The present studies were conducted in RIF-1, M5076 and Panc02 murine tumor models to compare extracellular water measurements made by 51Cr-EDTA dilution techniques and a new method which exploits the concentration dependent modification of 1H-NMR proton relaxation by Gadolinium-DTPA-dimethyl glucamine (Gd-DTPA-dimeg) in plasma and tissues. The time dependent changes in T1 modification in tissue and plasma were determined at various intervals after i.v. injection of 0.1 ml of 100 mM Gd-DTPA-dimeg and Gd concentrations determined from standard curves of Gd concentration dependent T1 modification of mouse plasma. Comparison of tissue and plasma Gd concentrations permitted the calculation of Gd-DTPA-dimeg distribution volumes. In unperturbed RIF-1, M5076 and Panc02 tumors, Gd-DTPA-dimeg distribution volumes determined by the T1 modification technique were similar to extracellular water spaces determined by 51Cr-EDTA dilution assays. In mouse liver, the 51Cr-EDTA assay resulted in artifactually high extracellular water space estimates due to internalization of the probe; Gd-DTPA-dimeg distribution volumes determined in liver with both the 153Gd-DTPA-dimeg and by the T1 modification method were approximately 150 ul/gram. The Gd-DTPA-dimeg T1 modification method also provided good approximations of changes in extracellular water volumes in RIF-1 tumors after dexamethasone and cyclophosphamide treatments. These results indicate that Gd-DTPA-dimeg modification of proton relaxation may be extremely useful for monitoring changes in tumor water dynamics during cancer therapy.

Menstrual variation of normal breast NMR relaxation parameters.

Nuclear magnetic resonance (NMR) offers great promise in noninvasively distinguishing normal, benign, and malignant tissues in the breast. However, well-documented changes that occur in breast tissues during the normal menstrual cycle suggest that lesion detectability will depend on knowledge of the variations in NMR parameters that occur as a consequence of these changes. Correct selection of optimal NMR pulse sequences and interpulse times, based on spin density and T1 and T2 values, to maximize tissue contrast and lesion detectability, will likewise depend on our understanding of variations in NMR parameters of normal breast tissues. The purpose of this study is to determine the range and variability of NMR parameters (spin density, T1 and T2) associated with changes in normal breast tissues during the menstrual cycle, as measured by NMR imaging. Initial findings suggest that there are measurable differences between breast tissues as a function of time in the menstrual cycle.

Fluorine nuclear magnetic resonance: calibration and system optimization.

Fluorine-19 magnetic resonance imaging (MRI) offers advantages for imaging organs and tissues. 19F is readily synthesized into a variety of compounds and offers the potential for in-vivo imaging as a complement to hydrogen MRI. The purpose of this work was to determine the minimum detection sensitivity for a fluorinated compound (CF3-CO2H) as a function of pulse sequence, interpulse times (TE, TI, and TR), gradient values and the number of data averages. CF3-CO2H was chosen because it has a single spectral line and exhibits a minimal frequency shift under the experimental conditions used for this experiment. A resistance MR scanner operating at a resonance frequency of 6.255 MHz was used for imaging both fluorine (.156 T) and hydrogen (.147 T). Critical factors determining the minimum detection sensitivity included system signal-to-noise ratio (S/N), acquisition time, relaxation times (T1, T2), and sample volume. Samples were measured over the range of 0.05 M to 20.0 M and showed a linear relationship between signal strength and concentration. The minimum detection sensitivity was 0.1 M. Use of higher static fields and optimized coils as well as improved system signal-to-noise ratios will improve detection sensitivity. We conclude that imaging of fluorine on low-field system is feasible, although it is necessary to optimize many parameters to maximize detection sensitivity.

NMR study of in vivo RIF-1 tumors. Analysis of perchloric acid extracts and identification of 1H, 31P and 13C resonances.

Perchloric acid extracts of radiation-induced fibrosarcoma (RIF-1) tumors grown in mice have been analyzed by multinuclear NMR spectroscopy and by various chromatographic methods. This analysis has permitted the unambiguous assignment of the 31P resonances observed in vivo to specific phosphorus-containing metabolites. The region of the in vivo spectra generally assigned to sugar phosphates has been found in RIF-1 tumors to contain primarily phosphorylethanolamine and phosphorylcholine rather than glycolytic intermediates. Phosphocreatine was observed in extracts of these tumor cells grown in culture as well as in the in vivo spectra, indicating that at least some of the phosphocreatine observed in vivo arises from the tumor itself and not from normal tissues. In the 31P-NMR spectra of the perchloric acid extract, resonances originating from purine and pyrimidine nucleoside di- and triphosphate were resolved. HPLC analyses of the nucleotide pool indicate that adenine derivatives were the most abundant components, but other nucleotides were present in significant amounts. The 1H and 13C resonance assignments of the majority of metabolites present in RIF-1 extracts have also been made. Of particular importance is the ability to observe lactate, the levels of which may provide a noninvasive measure of glycolysis in these cells in both the in vitro states. In addition, the aminosulfonic acid, taurine, was found in high levels in the tumor extracts.

Receptor-mediated antiproliferative effects of corticosteroids in Lewis lung tumors.

Dextran-coated charcoal competitive binding assays and Scatchard analysis revealed the presence of high-affinity, low capacity binding sites for dexamethasone in cytosol preparations from Lewis lung tumors. In vitro studies with live cells indicated approximately 9000 nuclear binding sites/cell for the ligand-receptor complex. In vivo inhibition of cell proliferation by dexamethasone, methylprednisolone and triamcinolone acetonide was found to be dose-dependent. Changes in the [3H]-TdR labeling index, mitotic index and saturable cytosol receptor sites after dexamethasone treatment in vivo suggested a dose-dependent G1 progression delay which, after cessation of dexamethasone treatments, was apparently reversible. Resumption of cell-cycle progression was characterized by synchronous progression through S-phase and correlated temporally with receptor site desaturation. In vivo studies indicated that the effectiveness of vincristine given after dexamethasone was highly sequence-dependent, with the most effective sequence interval being coincident with the interval of maximal S-phase cellularity. Other studies indicated sequential chemotherapy with dexamethasone, vincristine and 5-Fu could be effectively employed, following primary tumor excision, to increase animal survival.