Value of dynamic contrast-enhanced MR imaging in diagnosing and classifying peripheral vascular malformations

OBJECTIVE: Our purpose was to evaluate prospectively whether MR imaging, including dynamic contrast-enhanced MR imaging, could be used to categorize peripheral vascular malformations and especially to identify venous malformations that do not need angiography for treatment. SUBJECTS AND METHODS: In this blinded prospective study, two observers independently correlated MR imaging findings of 27 patients having peripheral vascular malformations with those of diagnostic angiography and additional venography. MR diagnosis of the category, based on a combination of conventional and dynamic contrast-enhanced MR parameters, was compared with the angiographic diagnosis using gamma statistics. Sensitivity and specificity of conventional MR imaging and dynamic contrast-enhanced MR imaging in differentiating venous from nonvenous malformations were determined. RESULTS: Excellent agreement between the two observers in determining MR categories (gamma = 0.99) existed. Agreement between MR categories and angiographic categories was high for both observers (gamma = 0.97 and 0.92). Sensitivity of conventional MR imaging in differentiating venous and nonvenous malformations was 100%, whereas specificity was 24-33%. Specificity increased to 95% by adding dynamic contrast-enhanced MR imaging, but sensitivity decreased to 83%. CONCLUSION: Conventional and dynamic contrast-enhanced MR parameters can be used in combination to categorize vascular malformations. Dynamic contrast-enhanced MR imaging allows diagnosis of venous malformations with high specificity.     

Associations of maternal and fetal vitamin D status with childhood body composition and cardiovascular risk factors

Maternal vitamin D deficiency during pregnancy may have persistent adverse effects on childhood growth and development. We examined whether 25‐hydroxyvitamin D (25(OH)D) concentrations during pregnancy and at cord blood were associated with childhood body composition and cardiovascular outcomes. This study was embedded in a population‐based prospective cohort in Rotterdam, The Netherlands, among 4,903 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.4 weeks (95% range 18.5–23.4 weeks) and at birth (40.1 weeks [95% range 35.8–42.3 weeks]). 25(OH)D concentrations were categorized into severely deficient (<25.0 nmol/L); deficient (25.0 to 49.9 nmol/L); sufficient (50.0 to 74.9 nmol/L) and optimal (≥75.0 nmol/L). At 6 years, we measured childhood body mass index; fat and lean mass by Dual‐energy X‐ray Absorptiometry; blood pressure; and serum cholesterol, triglycerides, and insulin concentrations. Compared with children from mothers with optimal 25(OH)D concentrations (≥75.0 nmol/L), those of severely deficient vitamin D (<25.0 nmol/L) mothers had a 0.12 standard deviation score (SDS); (95% Confidence Interval (CI) [0.03, 0.21]) higher fat mass percentage and a 0.13 SDS (95% CI [?0.22, ?0.04]) lower lean mass percentage. These associations remained after adjustment for current child vitamin D status. Maternal and cord blood 25(OH)D concentrations were not associated with cardiovascular risk factors in childhood. In conclusion, severe maternal 25(OH)D deficiency (<25.0 nmol/L) during pregnancy is associated with an adverse childhood body composition profile, but we did not observe evidence for an association with childhood cardiovascular risk factors. Further studies are needed to replicate our findings, to examine the underlying mechanisms, the causality of the associations, and the potential for public health interventions.     

Development of a Food Group-Based Diet Score and Its Association with Bone Mineral Density in the Elderly: The Rotterdam Study

No diet score exists that summarizes the features of a diet that is optimal for bone mineral density (BMD) in the elderly. Our aims were (a) to develop a BMD-Diet Score reflecting a diet that may be beneficial for BMD based on the existing literature, and (b) to examine the association of the BMD-Diet Score and the Healthy Diet Indicator, a score based on guidelines of the World Health Organization, with BMD in Dutch elderly participating in a prospective cohort study, the Rotterdam Study (n = 5144). Baseline dietary intake, assessed using a food frequency questionnaire, was categorized into food groups. Food groups that were consistently associated with BMD in the literature were included in the BMD-Diet Score. BMD was measured repeatedly and was assessed using dual energy X-ray absorptiometry. The BMD-Diet Score considered intake of vegetables, fruits, fish, whole grains, legumes/beans and dairy products as “high-BMD” components and meat and confectionary as “low-BMD” components. After adjustment, the BMD-Diet Score was positively associated with BMD (β (95% confidence interval) = 0.009 (0.005, 0.012) g/cm² per standard deviation). This effect size was approximately three times as large as has been observed for the Healthy Diet Indicator. The food groups included in our BMD-Diet Score could be considered in the development of future dietary guidelines for healthy ageing.     

Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.     

Single-cell Raman and fluorescence microscopy reveal the association of lipid bodies with phagosomes in leukocytes

Cellular imaging techniques based on vibrational spectroscopy have become powerful tools in cell biology because the molecular composition of subcellular compartments can be visualized without the need for labeling. Using high-resolution, nonresonant confocal Raman microscopy on individual cells, we demonstrate here that lipid bodies (LBs) rich in arachidonate as revealed by their Raman spectra associate with latex bead-containing phagosomes in neutrophilic granulocytes. This finding was corroborated in macrophages and in PLB-985 cells, which can be induced to differentiate into neutrophil-like cells, by selective staining of LBs and visualization by confocal fluorescence microscopy. We further show that the accumulation of LBs near phagosomes is mediated at least in part by the flavohemoprotein gp91phox (in which "phox" is phagocyte oxidase), because different LB distributions around phagocytosed latex beads were observed in WT and gp91phox-deficient PLB-985 cells. gp91phox, which accumulates in the phagosomal membrane, is the catalytic subunit of the leukocyte NADPH oxidase, a critical enzyme in the innate immune response. Finally, time-lapse fluorescence microscopy experiments on neutrophils revealed that the LB-phagosome association is transient, similar to the "kiss-and-run" behavior displayed by endosomes involved in phagosome maturation. Because arachidonic acid (AA) has been shown to be involved in NADPH oxidase activation and phagosome maturation in neutrophils and macrophages, respectively, the findings reported here suggest that LBs may provide a reservoir of AA for local activation of these essential leukocyte functions.     

Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons

Heterotopic cardiac xenotransplantation from alpha1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons was performed to characterize immunological reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection. Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppressive therapy. Both histological and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection was observed. Three baboons were euthanized or died 16 to 56 days after transplantation. The other five grafts ceased beating between days 59 and 179 (median, 78 days). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL(+) endothelial cell death and procoagulant activation (increased expression of both tissue factor and von Willebrand factor and decreased expression of CD39). CD3(+) T-cell infiltration occurred in all grafts and weakly correlated with the development of TM. In conclusion, although the use of GalT-KO swine donors prevented hyperacute rejection and prolonged graft survival, slowly progressive humoral rejection--probably associated with non-Gal antibodies to the xenograft--and disordered thromboregulation represent major immunological barriers to long-term xenograft survival.