Modeling Dynamic Contrast-Enhanced MRI Data with a Constrained Local AIF

Purpose

This study aims to develop a constrained local arterial input function (cL-AIF) to improve quantitative analysis of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) data by accounting for the contrast-agent bolus amplitude error in the voxel-specific AIF.

Procedures

Bayesian probability theory-based parameter estimation and model selection were used to compare tracer kinetic modeling employing either the measured remote-AIF (R-AIF, i.e., the traditional approach) or an inferred cL-AIF against both in silico DCE-MRI data and clinical, cervical cancer DCE-MRI data.

Results

When the data model included the cL-AIF, tracer kinetic parameters were correctly estimated from in silico data under contrast-to-noise conditions typical of clinical DCE-MRI experiments. Considering the clinical cervical cancer data, Bayesian model selection was performed for all tumor voxels of the 16 patients (35,602 voxels in total). Among those voxels, a tracer kinetic model that employed the voxel-specific cL-AIF was preferred (i.e., had a higher posterior probability) in 80 % of the voxels compared to the direct use of a single R-AIF. Maps of spatial variation in voxel-specific AIF bolus amplitude and arrival time for heterogeneous tissues, such as cervical cancer, are accessible with the cL-AIF approach.

Conclusions

The cL-AIF method, which estimates unique local-AIF amplitude and arrival time for each voxel within the tissue of interest, provides better modeling of DCE-MRI data than the use of a single, measured R-AIF. The Bayesian-based data analysis described herein affords estimates of uncertainties for each model parameter, via posterior probability density functions, and voxel-wise comparison across methods/models, via model selection in data modeling.

     

The role of sex in health-related quality of life after cardiac surgery: a prospective study

BACKGROUND: To assess health-related quality of life (HRQOL) in patients after cardiac surgery with emphasis on sex differences. DESIGN AND METHODS: Between September 2004 and September 2005, 534 patients (413 males and 121 females) were consecutively included. HRQOL was measured by the short-form 36 (SF-36) before surgery with follow-up 6 and 12 months after surgery. RESULTS: Five hundred and twenty-one patients were alive after 12 months, 462 (89%) and 465 (89.4%) responded after 6 and 12 months, respectively. Female patients had less favorable scores than male patients on most subscales of the SF-36 both before and after surgery. Both male and female patients improved substantially after surgery, but female patients reported significantly less improvement on two of eight subscales of the SF-36; role emotional and bodily pain. CONCLUSION: The study demonstrates that there are sex differences concerning HRQOL both before and after cardiac surgery. A clear overall improvement in HRQOL over the first year after cardiac surgery, more specifically during the first 6 months for both sexes was found.     

Transgenic Overexpression of Interleukin-1β Induces Persistent Lymphangiogenesis But Not Angiogenesis in Mouse Airways

These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1β mice that conditionally overexpress IL-1β in Clara cells to determine whether IL-1β can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1β production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1β, and lymphotoxin-β), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1β overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1β induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1β–induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1β/CXCR2^−/− mice had the usual IL-1β-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1β, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1β overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.IL-1β is a key inflammatory cytokine found in many pathologic conditions and is responsible for triggering multiple downstream inflammatory pathways.¹ Inhibiting IL-1 signaling by neutralizing antibodies or by blocking IL1R1 receptors is effective in treating inflammation in numerous pathologic conditions.² However, IL-1β can be a two-edged sword. Depending on the context, IL-1β is responsible for deleterious effects by amplifying inflammation and also for protective effects, for example, by activating the immune system during infection.³IL-1β has a main role in the remodeling of many tissues, including the airways and lungs. Overexpression of IL-1β in adult mouse airways and lungs results in pulmonary inflammation and the recruitment of inflammatory cells, including neutrophils, enlargement of distal airspaces, and the induction of mucous metaplasia and airway fibrosis.⁴ In neonatal mice, overexpression of IL-1β results in the disruption of lung development characteristic of bronchopulmonary dysplasia,^5,6 and this effect is mediated in part by integrins.^7,8 Furthermore, in addition to its known effects on remodeling of many tissue types, IL-1β has been reported to induce angiogenesis in several experimental models and in human diseases, including the eye, arthritic joints, and tumors, mediated in part by recruitment of leukocytes that release other inflammatory mediators.^9–14Blood vessels and lymphatics of airways show a wide repertoire of responses to different inflammatory stimuli. Various patterns of blood vessel enlargement and angiogenic sprouting are found in mice with chronic airway inflammation.^15–17 For the most part, the cellular and molecular mediators that drive vascular changes are still poorly understood, but numerous cytokines and chemokines, including IL-1β, are up-regulated in Mycoplasma pulmonis infection.^17–20 M. pulmonis-infected mice also show profound lymphangiogenesis, mediated by vascular endothelial growth factor receptor (VEGFR)-3 signaling.²¹ Because IL-1β can activate NF-κB pathways to up-regulate vascular endothelial growth factor (VEGF)-C and -D, ligands for VEGFR-3,^22,23 IL-1β could also be a candidate for driving lymphangiogenesis. IL-1β is also known to up-regulate VEGF-C in vitro, a VEGFR-3 ligand that can drive lymphangiogenesis.²⁴ However, it has been difficult to dissect the effects of individual cytokines in bacterial infection, and the effects of IL-1β alone in airways have not been examined.With this background, we took advantage of bi-transgenic (CCSP/IL-1β) mice in which IL-1β is overexpressed in airways by the rat Clara cell secretory protein (CCSP) promoter in a doxycycline (Dox)-inducible fashion.⁴ This model permitted us to study the effects of overexpression of IL-1β alone on lymphangiogenesis and angiogenesis.The goal of this study was to determine whether selective overexpression of IL-1β in adult mouse airways would induce growth or remodeling of blood vessels or lymphatic vessels and to determine the involved cells and molecules. We also sought to learn if vessel remodeling persisted after IL-1β was turned off and if VEGFR-3 signaling drove the lymphangiogenesis. To approach these issues, we stained blood vessels and lymphatics immunohistochemically in whole mounts of tracheas from CCSP/IL-1β mice treated with Dox. We also used immunohistochemistry to identify airway cells that stained for IL1R1. Because IL-1β induced leukocyte influx, including abundant neutrophils, we tested whether neutrophils were essential for the effects of IL-1β on lymphatic vessels by examining lymphangiogenesis in CXCR2^−/− mice crossed to CCSP/IL-1β mice.We found that overexpression of IL-1β in mouse airways produced neutrophil and macrophage influx, expression of inflammatory cytokines and chemokines, and long-lasting lymphangiogenesis, but not angiogenesis. IL1R1 receptors were abundant on epithelial basal cells and neuroendocrine cells, but not on lymphatics. Inactivation of VEGFR-3 ligands by soluble VEGFR-3 (VEGF-C/D Trap) from an adeno-associated viral (AAV) vector completely blocked the lymphangiogenesis, indicative of the necessity of VEGFR-3 ligands, VEGF-C and/or VEGF-D. VEGF-C immunoreactivity was present in some recruited macrophages, but the lymphangiogenesis did not require the influx of neutrophils.     

Reliability and validity of a new classification of MIH based on severity

To describe a new molar-incisor hypomineralization (MIH) severity scoring system (MIH-SSS) that focuses on the defects’ severity and to assess the sy     

Relationship between stimulated prolactin release from GH cells and cyclic AMP degradation and formation

We have studied the relationship between the prolaction (PRL) release induced by thyroliberin (TRH) and theophylline and the formation and inactivation of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) in cultured rat-pituitary cells (GH3 cells). TRH, which stimulated prolactin release, increased cyclic AMP formation and stimulated transiently both the low- and high-Km cyclic phosphodiesterases. The maximal effect on the phosphodiesterase was observed at 30 mM TRH. The stimulatory effect of TRH on the activity of the cyclic AMP phosphodiesterases was duplicated by incubation of the cells with cyclic AMP (2-10 mM). In washed particulate GH3 cell fractions, TRH increased the adenylyl cyclase activity up to 180%. Treatment of GH3 cells with theophylline stimulated the release of PRL and inhibited cyclic AMP degradation probably leading to the measured increase in cellular concentrations of the nucleotide. The effects of TRH and theophylline on cellular cyclic AMP concentrations and on PRL release were additive. There was a positive correlation between PRL release and cellular cyclic AMP concentration (r = 0.97). The elevations observed in cellular cyclic AMP concentration after TRH treatment are due to increased formation which in turn leads to phosphodiesterase activation. Therefore, cyclic AMP formation appears to be an intermediary step in the stimulus-secretion coupling caused by the tripeptide.