Albuminuria, Reduced Kidney Function, and the Risk of ST - and non-ST-segment-elevation myocardial infarction.

Background Chronic kidney disease is a recognized independent risk factor for cardiovascular disease, but whether the risks of ST-segment-elevation myocardial infarction ( STEMI ) and non-ST-segment-elevation myocardial infarction ( NSTEMI ) differ in the chronic kidney disease population is unknown. Methods and Results Using administrative data from Ontario, Canada, we examined patients ≥66 years of age with an outpatient estimated glomerular filtration rate ( eGFR ) and albuminuria measure for incident myocardial infarction from 2002 to 2015. Adjusted Fine and Gray subdistribution hazard models accounting for the competing risk of death were used. In 248 438 patients with 1.2 million person-years of follow-up, STEMI , NSTEMI , and death occurred in 1436 (0.58%), 4431 (1.78%), and 30 015 (12.08%) patients, respectively. The highest level of albumin-to-creatinine ratio (>30 mg/mmol) was associated with a 2-fold higher adjusted risk of both STEMI and NSTEMI among patients with eGFR ≥60 mL/(min·1.73 m2) compared to albumin-to-creatinine ratio <3 mg/mmol. The lowest level of eGFR (<30 mL/[min·1.73 m2]) was not associated with higher STEMI risk but with a 4-fold higher risk of NSTEMI compared to those with eGFR ≥60 mL/(min·1.73 m2). The lowest eGFR (<30 mL/[min·1.73 m2]) and highest albumin-to-creatinine ratio (>30 mg/mmol) were associated with a greater than 4-fold higher risk of both STEMI and NSTEMI (subdistribution hazard models [95% confidence interval] 4.53 [3.30-6.21] and 4.42 [3.67-5.32], respectively) compared to albumin-to-creatinine ratio <3 mg/mmol and eGFR ≥60 mL/(min·1.73 m2). Conclusions Elevations in albuminuria are associated with a higher risk of both NSTEMI and STEMI , regardless of kidney function, whereas reduced kidney function alone is associated with a higher NSTEMI risk.

Origins of R2* orientation dependence in gray and white matter.

Estimates of the apparent transverse relaxation rate (R2*) can be used to quantify important properties of biological tissue. Surprisingly, the mechanism of R2* dependence on tissue orientation is not well understood. The primary goal of this paper was to characterize orientation dependence of R2* in gray and white matter and relate it to independent measurements of two other susceptibility based parameters: the local Larmor frequency shift (fL) and quantitative volume magnetic susceptibility (Δχ). Through this comparative analysis we calculated scaling relations quantifying R2' (reversible contribution to the transverse relaxation rate from local field inhomogeneities) in a voxel given measurements of the local Larmor frequency shift. R2' is a measure of both perturber geometry and density and is related to tissue microstructure. Additionally, two methods (the Generalized Lorentzian model and iterative dipole inversion) for calculating Δχ were compared in gray and white matter. The value of Δχ derived from fitting the Generalized Lorentzian model was then connected to the observed R2* orientation dependence using image-registered optical density measurements from histochemical staining. Our results demonstrate that the R2* and fL of white and cortical gray matter are well described by a sinusoidal dependence on the orientation of the tissue and a linear dependence on the volume fraction of myelin in the tissue. In deep brain gray matter structures, where there is no obvious symmetry axis, R2* and fL have no orientation dependence but retain a linear dependence on tissue iron concentration and hence Δχ.

Temporal changes in monocyte and macrophage subsets and microglial macrophages following spinal cord injury in the Lys-Egfp-ki mouse model.

The role of hematogenous (hMΦ) and microglial (mMΦ) macrophages following spinal cord injury (SCI) remains unclear as they are not distinguished easily from each other in the lesion area. We have recently described the temporal and spatial response to SCI of each MΦ population using the lys-EGFP-ki mouse that enables EGFP(+) hMΦ to be distinguished from EGFP(-) mMΦ at the lesion site. In the present study, we characterized the response of monocyte and hMΦ subsets and mMΦ to SCI. We describe, for the first time, the responses of circulating classical (pro-inflammatory) and non-classical monocyte subsets to SCI. Additionally, we show the presence of classical and non-classical hMΦ at the SCI lesion. Importantly, we demonstrate that the 'classical pro-inflammatory' hMΦ respond in the acute (1d, 3d) stages of SCI while the 'non-classical' hMΦ respond in the sub-acute (7d, 14d) phase of SCI. At later time points (6weeks post injury) classical hMΦ return to the injury site. Our study offers new insight into the cellular inflammatory response that occurs after SCI and suggests that the timing and targets of anti-inflammatory therapies may be crucial to maximize neuroprotection at the acute and more chronic stages of SCI.

Tracking and evaluation of dendritic cell migration by cellular magnetic resonance imaging.

Cellular magnetic resonance imaging (MRI) is a means by which cells labeled ex vivo with a contrast agent can be detected and tracked over time in vivo. This technology provides a noninvasive method with which to assess cell-based therapies in vivo. Dendritic cell (DC)-based vaccines are a promising cancer immunotherapy, but its success is highly dependent on the injected DC migrating to a secondary lymphoid organ such as a nearby lymph node. There the DC can interact with T cells to elicit a tumor-specific immune response. It is important to verify DC migration in vivo using a noninvasive imaging modality, such as cellular MRI, so that important information regarding the anatomical location and persistence of the injected DC in a targeted lymph node can be provided. An understanding of DC biology is critical in ascertaining how to label DC with sufficient contrast agent to render them detectable by MRI. While iron oxide nanoparticles provide the best sensitivity for detection of DC in vivo, a clinical grade iron oxide agent is not currently available. A clinical grade (19) Fluorine-based perfluorcarbon nanoemulsion is available but is less sensitive, and its utility to detect DC migration in humans remains to be demonstrated using clinical scanners presently available. The ability to quantitatively track DC migration in vivo can provide important information as to whether different DC maturation and activation protocols result in improved DC migration efficiency which will determine the vaccine's immunogenicity and ultimately the tumor immunotherapy's outcome in humans.

Cellular magnetic resonance imaging of monocyte-derived dendritic cell migration from healthy donors and cancer patients as assessed in a scid mouse model.

BACKGROUND AIMS. The use of dendritic cells (DC) as an adjuvant in cell-based immunotherapeutic cancer vaccines is a growing field of interest. A reliable and non-invasive method to track the fate of autologous DC following their administration to patients is required in order to confirm that clinically sufficient numbers are reaching the lymph node (LN). We demonstrate that an immunocompromised mouse model can be used to conduct translational studies employing cellular magnetic resonance imaging (MRI). Such studies can provide clinically relevant information regarding the migration potential of clinical-grade DC used in cancer immunotherapies. METHODS. Human monocyte-derived dendritic cells (mo-DC) were generated from negatively selected monocytes obtained from either healthy donors or cancer patients. DC were labeled with superparamagnetic iron oxide (SPIO) nanoparticles in order to track them in vivo in a CB17scid mouse model using cellular MRI. SPIO did not have any adverse effects on DC phenotype or function, independent of donor type. Cellular MRI readily detected migration of SPIO-loaded DC in CB17scid mice. No differences in migration were observed between DC obtained from healthy donors and those obtained from donors undergoing autologous stem cell transplant for cancer therapy. CONCLUSIONS. Cellular MRI provided semi-quantitative image data that corresponded with data obtained by digital morphometry, validating cellular MRI's potential to assess DC migration in DC-based cancer immunotherapy clinical trials.

Labelling dendritic cells with SPIO has implications for their subsequent in vivo migration as assessed with cellular MRI.

An optimized non-invasive imaging modality capable of tracking and quantifying in vivo DC migration in patients would provide clinicians with valuable information regarding therapeutic DC-based vaccine outcomes. Superparamagnetic iron oxide (SPIO) nanoparticles were used to label bone marrow-derived DC. In vivo DC migration was tracked and quantified non-invasively using cellular magnetic resonance imaging (MRI) in a mouse model. Labelling DC with SPIO reflects the kinetics of DC migration in vivo but appears to reduce overall DC migration, in part due to nanoparticle size. Magnetic separation of SPIO-labelled (SPIO(+)) DC from unlabelled (SPIO(-)) DC prior to injection improves SPIO(+) DC migration to the lymph node. Corresponding MR image data better correlate with the presence of DC in vivo; an improved immunological response is also seen. Cellular MRI is a viable, non-invasive imaging tool that can routinely track DC migration in vivo. Consideration should be given to optimizing MRI contrast agent-labelling of clinical-grade DC in order to accurately correlate DC fate to immunological outcomes in patients.

In vivo cellular MRI of dendritic cell migration using micrometer-sized iron oxide (MPIO) particles.

PURPOSE: This study seeks to assess the use of labeling with micron-sized iron oxide (MPIO) particles for the detection and quantification of the migration of dendritic cells (DCs) using cellular magnetic resonance imaging (MRI). PROCEDURES: DCs were labeled with red fluorescent MPIO particles for detection by cellular MRI and a green fluorescent membrane dye (PKH67) for histological detection. MPIO-labeled DCs or unlabeled control DCs were injected into mice footpads at two doses (0.1 × 10(6) and 1 × 10(6)). Images were acquired at 3 Tesla before DC injection and 2, 3, and 7 days post-DC injection. RESULTS: Labeling DCs with MPIO particles did not affect viability, but it did alter markers of DC activation and maturation. MRI and fluorescence microscopy allowed for the detection of MPIO-labeled DCs within the draining popliteal nodes after their injection into the footpad. CONCLUSIONS: This paper presents the first report of the successful use of fluorescent MPIO particles to label and track DC migration.