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ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Tissue Pathology Study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository.MethodsRECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Casual inference methods will be employed to investigate associations between risk factors and pathologic outcomes.DiscussionRECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.Clinicaltrials.govnumber:NCT05292274

The objective of this study was to characterize femur morphology in healthy infants and young children. Anterior-posterior (AP) radiographs of the femur from children age 0-3 years with no history of bone disease were obtained from two children's hospitals and one medical examiner's office. Femur morphological measures (bone length, minimum diaphysis diameter, growth plate width, and femur radius of curvature) and sectional structural measures were determined. Measures were described and compared based on subject age and mass. Relationships between measures and age and mass were evaluated. The 169 AP femur radiographs were obtained from 99 children (59.6% males, median age = 12.0 months, IQR = 0-27.5 months, median body weight = 10.0 kg, IQR = 4.4-15.6 kg). Femur length (r

Post-mortem computed tomography (PMCT) is now performed routinely in some medical examiner's offices, and the images are typically interpreted by forensic pathologists. In this study, the question of whether pathologists appropriately identify significant PMCT findings and incorporate them into the death investigation report and the cause and manner of death (COD and MOD) statements was addressed. We retrospectively reviewed 200 cases where PMCT was performed. The cases were divided into four categories: (1) full autopsy without radiology consultation (n = 77), (2) external exam without radiology consultation (n = 79), (3) full autopsy with radiology consultation (n = 26), (4) external exam with radiology consultation (n = 18). A radiologist (not the consult radiologist) read the PMCT images, and a pathologist (not the case pathologist) reviewed the case pathologist's post-mortem examination report in tandem to determine any PMCT findings omitted from the report. Omitted findings were classified into error types according to a modified Goldman classification including Major 1: Unrecognized fatal injury or pathology that would change COD and/or MOD, and Major 2: Unrecognized fatal injury or pathology that would not change COD and/or MOD. A total of 13 Major errors were identified (6.5%), and none definitively changed the MOD. All four Major-1 errors which could change the COD were found in Category 2. Of 9 Major-2 errors, 2 occurred in Category 1, 6 occurred in Category 2, and 1 occurred in Category 4. In conclusion, forensic pathologists who routinely utilize computed tomography (CT) interpret CT images well enough to reliably certify the COD and MOD.

Study objective Extraglottic airway devices are frequently used during cardiac arrest resuscitations and for failed intubation attempts. Recent literature suggests that many extraglottic airway devices are misplaced. The aim of this study is to create a classification system for extraglottic airway device misplacement and describe its frequency in a cohort of decedents who died with an extraglottic airway device in situ. Methods We assembled a cohort of all decedents who died with an extraglottic airway device in situ and underwent postmortem computed tomographic (CT) imaging at the state medical examiner's office during a 6-year period, using retrospective data. An expert panel developed a novel extraglottic airway device misplacement classification system. We then applied the schema in reviewing postmortem CT for extraglottic airway device position and potential complications. Results We identified 341 eligible decedents. The median age was 47.0 years (interquartile range 32 to 59 years). Out-of-hospital personnel placed extraglottic airway devices in 265 patients (77.7%) who subsequently died out of hospital; the remainder died inhospital. The classification system consisted of 6 components: depth, size, rotation, device kinking, mechanical blockage of ventilation opening, and injury. Under the system, extraglottic airway devices were found to be misplaced in 49 cases (14.4%), including 5 (1.5%) that resulted in severe injuries. Conclusion We created a novel extraglottic airway device misplacement classification system. Misplacement occurred in greater than 14% of cases. Severe traumatic complications occurred rarely. Quality improvement activities should include review of extraglottic airway device placement when CT images are available and use the classification system to describe misplacements.

The 2019 novel coronavirus disease (COVID-19) has spread worldwide, infiltrating, infecting, and devastating communities in all locations of varying demographics. An overwhelming majority of published literature on the pathologic findings associated with COVID-19 is either from living clinical cohorts or from autopsy findings of those who died in a medical care setting, which can confound pure disease pathology. A relatively low initial infection rate paired with a high biosafety level enabled the New Mexico Office of the Medical Investigator to conduct full autopsy examinations on suspected COVID-19-related deaths. Full autopsy examination on the first 20 severe acute respiratory syndrome coronavirus 2-positive decedents revealed that some extent of diffuse alveolar damage in every death due to COVID-19 played some role. The average decedent was middle-aged, male, American Indian, and overweight with comorbidities that included diabetes, ethanolism, and atherosclerotic and/or hypertensive cardiovascular disease. Macroscopic thrombotic events were seen in 35% of cases consisting of pulmonary thromboemboli and coronary artery thrombi. In 2 cases, severe bacterial coinfections were seen in the lungs. Those determined to die with but not of severe acute respiratory syndrome coronavirus 2 infection had unremarkable lung findings.

Compared to intubation with a cuffed endotracheal tube, extraglottic airway devices (EGDs), such as laryngeal mask airways, are considered less definitive ventilation conduit devices and are therefore often exchanged via endotracheal intubation (ETI) prior to obtaining CT images. With more widespread use and growing comfort among providers, reports have now described use of EGDs for up to 24 h including cases for which clinicians obtained CT scans with an EGD in situ. The term EGD encompasses a wide variety of devices with more complex structure and CT appearance compared to ETI. All EGDs are typically placed without direct visualization and require less training and time for insertion compared to ETI. While blind insertion generally results in functional positioning, numerous studies have reported misplacements of EGDs identified by CT in the emergency department or post-mortem. A CT-based classification system has recently been suggested to categorize these misplacements in six dimensions: depth, size, rotation, device kinking, mechanical blockage of the ventilation opening(s), and injury from EGD placement. Identifying the type of EGD and its correct placement is critically important both to provide prompt feedback to clinicians and prevent inappropriate medicolegal problems. In this review, we introduce the main types of EGDs, demonstrate their appearance on CT images, and describe examples of misplacements.

Compared to intubation with a cuffed endotracheal tube, extraglottic airway devices (EGDs), such as laryngeal mask airways, are considered less definitive ventilation conduit devices and are therefore often exchanged via endotracheal intubation (ETI) prior to obtaining CT images. With more widespread use and growing comfort among providers, reports have now described use of EGDs for up to 24 h including cases for which clinicians obtained CT scans with an EGD in situ. The term EGD encompasses a wide variety of devices with more complex structure and CT appearance compared to ETI. All EGDs are typically placed without direct visualization and require less training and time for insertion compared to ETI. While blind insertion generally results in functional positioning, numerous studies have reported misplacements of EGDs identified by CT in the emergency department or post-mortem. A CT-based classification system has recently been suggested to categorize these misplacements in six dimensions: depth, size, rotation, device kinking, mechanical blockage of the ventilation opening(s), and injury from EGD placement. Identifying the type of EGD and its correct placement is critically important both to provide prompt feedback to clinicians and prevent inappropriate medicolegal problems. In this review, we introduce the main types of EGDs, demonstrate their appearance on CT images, and describe examples of misplacements.

Highlights • Postmortem computed tomography shows characteristic findings in COVID-19 decedents. • Triage with this imaging can alert the forensic pathologist to COVID-19 infection. • This can improve the workflow and safety of those involved with the examination., Objective Computed tomography has significant utility as a diagnostic tool for coronavirus disease 2019 (COVID-19) in the clinical setting. COVID-19 deaths are sometimes examined by forensic pathologists, often in the setting of an unknown diagnosis. We assessed the utility of postmortem computed tomography (PMCT) for use as a triage tool for these autopsy examinations. Materials and methods We reviewed PMCT findings in 14 and histopathology in 11 decedents who were positive for COVID-19. Results The predominant imaging findings were bilateral mixed densities, in either a diffuse or peripheral distribution, with traction bronchiectasis, and/or crazy paving. In particular, traction bronchiectasis, ill-defined rounded consolidations, and reverse halo sign are useful when distinguishing from other postmortem changes. Conclusion We conclude that triage with a PMCT may aid the forensic pathologist in diagnosing possible COVID-19 infection prior to autopsy examination.

The successful integration of next-generation imaging technologies (full body X-ray, CT, and MRI) into the practice of death investigation requires their successful physical incorporation into the autopsy laboratory. A careful analysis of the physical movement of decedents and personnel through the facility is a critical planning step. Other key considerations include the installation and operating requirements of the imaging equipment (including space, clearance, and utilities) and safety requirements (such as shielding and biosafety). Collaboration between laboratory design professionals and medicolegal death investigative personnel can ensure a laboratory design that optimizes function, efficiency, and safety for using imaging technology.

Macrophages line the walls of microvasculature, extending processes into the blood flow to capture intruders, including nanoparticles. Here, using mesoporous silica or silicon particles, we show the interplay between macrophages and nanomaterial from initial uptake to intracellular trafficking along microtubules, to intercellular trafficking of material to neighboring cells. Transfer of materials between cells includes robust transfer of nanoparticles and cargo from macrophages to cancer cells in cytoplasmic bridges, coined tunneling nanotubes (TNT), and in thick, adherent connections with elaborate points of connection between cells. Both direct administration of nanoparticles and adoptive transfer of nanoparticle-loaded splenocytes in mice results in abundant localization of nanomaterials within macrophages 24 hours post injection. The relevance of macrophages as natural targets of nanomaterials and as significant regulators of the tumor microenvironment arises as an overlooked key-consideration when designing nano therapeutics for optimal drug delivery and therapeutic benefit.

Due to the excellent sensitivity of Magnetic Resonance (MR) imaging to subtle differences in soft tissues, MR enables non-invasive anatomical imaging with superior soft tissue contrast relative to X-ray Computed Tomography (CT). However, relative to the X-ray modalities, the utility of MR in the post-mortem setting is currently less well-defined. MR is significantly different from the X-ray modalities, in terms of the underlying principles of image formation, the equipment and expertise necessary to acquire the images, and the appearance of the images themselves. Because MR is sensitive to subtle differences in soft tissues, factors unique to the post-mortem setting, particularly variations in body temperature, tend to have a greater effect on MR imaging relative to the X-ray modalities. Fortunately, MR is inherently flexible and adaptable; there are many types of MR protocols, each with user-controlled parameters that can be adjusted to achieve the best imaging of a specific pathology or anatomic structure, at a given temperature or post-mortem interval (PMI). Optimizing, validating, and standardizing post-mortem MR (PMMR) protocols represents a challenging yet achievable long-term goal. For those interested in developing a better understanding of how to optimize PMMR image quality, this review is intended to provide some guidance, from a technical (but non-mathematical) perspective. A practical explanation of basic pulse sequences and MR relaxation times, and their relationship to tissue contrast, is provided. Strategies for optimizing PMMR for forensic imaging applications, suitable for users with varying levels of expertise, are discussed in the context of current progress in this area.

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines., Nanoparticle applications are limited by insufficient understanding of physiochemical properties on in vivo disposition. Here, the authors explore the influence of size, surface chemistry and administration on the biodisposition of mesoporous silica nanoparticles using image-based pharmacokinetics.

Background Treating burns effectively requires accurately assessing the percentage of the total body surface area (%TBSA) affected by burns. Current methods for estimating %TBSA, such as Lund and Browder (L&B) tables, rely on historic body statistics. An increasingly obese population has been blamed for increasing errors in %TBSA estimates. However, this assumption has not been experimentally validated. We hypothesized that errors in %TBSA estimates using L&B were due to differences in the physical proportions of today's children compared with children in the early 1940s when the chart was developed and that these differences would appear as body mass index (BMI)-associated systematic errors in the L&B values versus actual body surface areas. Materials and methods We measured the TBSA of human pediatric cadavers using computed tomography scans. Subjects ranged from 9 mo to 15 y in age. We chose outliers of the BMI distribution (from the 31st percentile at the low through the 99th percentile at the high). We examined surface area proportions corresponding to L&B regions. Results Measured regional proportions based on computed tomography scans were in reasonable agreement with L&B, even with subjects in the tails of the BMI range. The largest deviation was 3.4%, significantly less than the error seen in real-world %TBSA estimates. Conclusions While today's population is more obese than those studied by L&B, their body region proportions scale surprisingly well. The primary error in %TBSA estimation is not due to changing physical proportions of today's children and may instead lie in the application of the L&B table.

This paper presents the outcome of the first international forensic radiology and imaging research summit, organized by the International Society of Forensic Radiology and Imaging, the International Association of Forensic Radiographers, the National Institute of Justice of the United States of America, and the Netherlands Forensic Institute. During this meeting, an international and multidisciplinary panel of forensic scientists discussed the current state of science in forensic radiology, and drafted a research agenda to further advance the field. Four groups for further research focus were identified: big data and statistics, identification and biological profiling, multimodal imaging, and visualization and presentation. This paper describes each of these research topics and thereby hopes to contribute to the development of this exciting new field of forensic medical science.

As new magnetic nanoparticle-based technologies are developed and new target cells are identified, there is a critical need to understand the features important for magnetic isolation of specific cells in fluids, an increasingly important tool in disease research and diagnosis. To investigate magnetic cell collection, cell-sized spherical microparticles, coated with superparamagnetic nanoparticles, were suspended in (1) glycerine-water solutions, chosen to approximate the range of viscosities of bone marrow, and (2) water in which 3, 5, 10 and 100% of the total suspended microspheres are coated with magnetic nanoparticles, to model collection of rare magnetic nanoparticle-coated cells from a mixture of cells in a fluid. The magnetic microspheres were collected on a magnetic needle, and we demonstrate that the collection efficiency versus time can be modeled using a simple, heuristically-derived function, with three physically-significant parameters. The function enables experimentally-obtained collection efficiencies to be scaled to extract the effective drag of the suspending medium. The results of this analysis demonstrate that the effective drag scales linearly with fluid viscosity, as expected. Surprisingly, increasing the number of non-magnetic microspheres in the suspending fluid results increases the collection of magnetic microspheres, corresponding to a decrease in the effective drag of the medium.

Cystic fibrosis (CF) is an inherited childhood-onset life-shortening disease. It is characterized by increased respiratory production, leading to airway obstruction, chronic lung infection and inflammatory reactions. The most common bacteria causing persisting infections in people with CF isPseudomonas aeruginosa. Superparamagnetic Fe3O4iron oxide nanoparticles (NPs) conjugated to the antibiotic (tobramycin), guided by a gradient of the magnetic field or subjected to an oscillating magnetic field, show promise in improving the drug delivery across the mucus andP. aeruginosabiofilm to the bacteria. The question remains whether tobramycin needs to be released from the NPs after the penetration of the mucus barrier in order to act upon the pathogenic bacteria. We used a zero-length 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) crosslinking agent to couple tobramycin, via its amine groups, to the carboxyl groups on Fe3O4NPs capped with citric acid. The therapeutic efficiency of Fe3O4NPs attached to the drug versus that of the free drug was investigated inP. aeruginosaculture.

Magnetic nanocrystals have been investigated extensively in the past several years for several potential applications, such as information technology, MRI contrast agents, and for drug conjugation and delivery. A specific property of interest in biomedicine is magnetic hyperthermia—an increase in temperature resulting from the thermal energy released by magnetic nanocrystals in an external alternating magnetic field. Iron oxide nanocrystals of various sizes and morphologies were synthesized and tested for specific losses (heating power) using frequencies of 111.1 kHz and 629.2 kHz, and corresponding magnetic field strengths of 9 and 25 mT. Polymorphous nanocrystals as well as spherical nanocrystals and nanowires in paramagnetic to ferromagnetic size range exhibited good heating power. A remarkable 30 °C temperature increase was observed in a nanowire sample at 111 kHz and magnetic field of 25 mT (19.6 kA/m), which is very close to the typical values of 100 kHz and 20 mT used in medical treatments.

Both magnetic relaxometry and magnetic resonance imaging (MRI) can be used to detect and locate targeted magnetic nanoparticles, noninvasively and without ionizing radiation. Magnetic relaxometry offers advantages in terms of its specificity (only nanoparticles are detected) and the linear dependence of the relaxometry signal on the number of nanoparticles present. In this study, detection of single-core iron oxide nanoparticles by superconducting quantum interference device (SQUID)-detected magnetic relaxometry and standard 4.7 T MRI are compared. The nanoparticles were conjugated to a Her2 monoclonal antibody and targeted to Her2-expressing MCF7/Her2-18 (breast cancer cells); binding of the nanoparticles to the cells was assessed by magnetic relaxometry and iron assay. The same nanoparticle-labeled cells, serially diluted, were used to assess the detection limits and MR relaxivities. The detection limit of magnetic relaxometry was 125 000 nanoparticle-labeled cells at 3 cm from the SQUID sensors. T(2)-weighted MRI yielded a detection limit of 15 600 cells in a 150 µl volume, with r(1) = 1.1 mm(-1) s(-1) and r(2) = 166 mm(-1) s(-1). Her2-targeted nanoparticles were directly injected into xenograft MCF7/Her2-18 tumors in nude mice, and magnetic relaxometry imaging and 4.7 T MRI were performed, enabling direct comparison of the two techniques. Co-registration of relaxometry images and MRI of mice resulted in good agreement. A method for obtaining accurate quantification of microgram quantities of iron in the tumors and liver by relaxometry was also demonstrated. These results demonstrate the potential of SQUID-detected magnetic relaxometry imaging for the specific detection of breast cancer and the monitoring of magnetic nanoparticle-based therapies.

We use dynamic susceptometry measurements to extract semiempirical temperature-dependent, 255–400 K, magnetic parameters that determine the behavior of single-core nanoparticles useful for SQUID relaxometry in biomedical applications. Volume susceptibility measurements were made in 5 K degree steps at nine frequencies in the 0.1–1000 Hz range, with a 0.2 mT amplitude probe field. The saturation magnetization (Ms) and anisotropy energy density (K) derived from the fitting of theoretical susceptibility to the measurements both increase with decreasing temperature; good agreement between the parameter values derived separately from the real and imaginary components is obtained. Characterization of the Neel relaxation time indicates that the conventional prefactor, 0.1 ns, is an upper limit, strongly correlated with the anisotropy energy density. This prefactor decreases substantially for lower temperatures as K increases. We find, using the values of the parameters determined from the real part of the susceptibility measurements at 300 K, that SQUID relaxometry measurements of relaxation and excitation curves on the same sample are well described.

Optimizing the sensitivity of SQUID (superconducting quantum interference device)-relaxometry for detecting cell-targeted magnetic nanoparticles for in vivo diagnostics requires nanoparticles with a narrow particle size distribution to ensure that the Néel relaxation times fall within the measurement timescale (50 ms - 2 s, in this work). To determine the optimum particle size, single-core magnetite nanoparticles (with nominal average diameters 20, 25, 30, and 35 nm) were characterized by SQUID-relaxometry, transmission electron microscopy (TEM), SQUID-susceptometry, dynamic light scattering, and zeta potential analysis. The SQUID-relaxometry signal (detected magnetic moment/kg) from both the 25 nm and 30 nm particles was an improvement over previously-studied multi-core particles. However, the detected moments were an order of magnitude lower than predicted based on a simple model that takes into account the measured size distributions (but neglects dipolar interactions and polydispersity of the anisotropy energy density), indicating that improved control of several different nanoparticle properties (size, shape, coating thickness) will be required to achieve the highest detection sensitivity. Antibody conjugation and cell incubation experiments show that single-core particles enable a higher detected moment per cell, but also demonstrate the need for improved surface treatments to mitigate aggregation and improve specificity.

Acute leukemia is a hematopoietic malignancy for which the accurate measurement of minimal residual disease is critical to determining prognosis and treatment. Although bone marrow aspiration and light microscopy remain the current standard of care for detecting residual disease, these approaches cannot reliably discriminate less than 5% lymphoblast cells. To improve the detection of leukemia cells in the marrow, we developed a novel apparatus that utilizes antibodies conjugated to superparamagnetic iron oxide nanoparticles (SPION) and directed against the acute leukemia antigen CD34, coupled with a “magnetic needle” biopsy. Leukemia cell lines expressing high or minimal CD34 were incubated with anti-CD34–conjugated SPIONs. Three separate approaches including microscopy, superconducting quantum interference device magnetometry, and in vitro magnetic needle extraction were then used to assess cell sampling. We found that CD34-conjugated nanoparticles preferentially bind high CD34-expressing cell lines. Furthermore, the magnetic needle enabled identification of both cell line and patient leukemia cells diluted into normal blood at concentrations below those normally found in remission marrow samples. Finally, the magnetic needle enhanced the percentage of lymphoblasts detectable by light microscopy by 10-fold in samples of fresh bone marrow aspirate approximating minimal residual disease. These data suggest that bone marrow biopsy using antigen-targeted magnetic nanoparticles and a magnetic needle for the evaluation of minimal residual disease in CD34-positive acute leukemias can significantly enhance sensitivity compared with the current standard of care. [Cancer Res 2009;69(21):8310–6]

Magnetite nanoparticles (Chemicell SiMAG-TCL) were characterized by SQUID-relaxometry, susceptometry, and TEM. The magnetization detected by SQUID-relaxometry was 0.33% of that detected by susceptometry, indicating that the sensitivity of SQUID-relaxometry could be significantly increased through improved control of nanoparticle size. The relaxometry data were analyzed by the moment superposition model (MSM) to determine the distribution of nanoparticle moments. Analysis of the binding of CD34-conjugated nanoparticles to U937 leukemia cells revealed 60,000 nanoparticles per cell, which were collected from whole blood using a prototype magnetic biopsy needle, with a capture efficiency of >65% from a 750 µl sample volume in 1 minute.

The purpose of this study is to investigate the potential of magnetic nanoparticles for enhancing drug delivery using a low oscillating magnetic field (OMF) strength. We investigated the ability of magnetic nanoparticles to cause disruption of a viscous biopolymer barrier to drug delivery and the potential to induce triggered release of drug conjugated to the surfaces of these particles. Various magnetic nanoparticles were screened for thermal response under a 295-kHz OMF with an amplitude of 3.1 kA/m. Based on thermal activity of particles screened, we selected the nanoparticles that displayed desired characteristics for evaluation in a simplified model of an extracellular barrier to drug delivery, using lambda DNA/HindIII. Results indicate that nanoparticles could be used to induce DNA breakage to enhance local diffusion of drugs, despite low temperatures of heating. Additional studies showed increased diffusion of quantum dots in this model by single-particle tracking methods. Bimane was conjugated to the surface of magnetic nanoparticles. Fluorescence and transmission electron microscope images of the conjugated nanoparticles indicated little change in the overall appearance of the nanoparticles. A release study showed greater drug release using OMF, while maintaining low bulk heating of the samples (T = 30 degrees C). This study indicates that lower magnetic field strengths may be successfully utilized for drug delivery applications as a method for drug delivery transport enhancement and drug release switches.

Microcoil probes enclosing sample volumes of 1.2, 3.3, 7.0, and 81 nanoliters are constructed as nuclear magnetic resonance (NMR) detectors for operation in a 1 tesla permanent magnet. The probes for the three smallest volumes utilize a novel auxiliary tuning inductor for which the design criteria are given. The signal-to-noise ratio (SNR) and line width of water samples are measured. Based on the measured DC resistance of the microcoils, together with the calculated radio frequency (RF) resistance of the tuning inductor, the SNR is calculated and shown to agree with the measured values. The details of the calculations indicate that the auxiliary inductor does not degrade the NMR probe performance. The diameter of the wire used to construct the microcoils is shown to affect the signal line widths.

Superparamagnetic nanoparticles can be attached in great numbers to pathogenic cells using specific antibodies so that the magnetically-labeled cells themselves become superparamagnets. The cells can then be manipulated and drawn out of biological fluids, as in a biopsy, very selectively using a magnetic needle. We examine the origins and uncertainties in the forces exerted on magnetic nanoparticles by static magnetic fields, leading to a model for trajectories and collection times of dilute superparamagnetic cells in biological fluids. We discuss the design and application of such magnetic needles and the theory of collection times. We compare the mathematical model to measurements in a variety of media including blood. For more information on this article, see medicalphysicsweb.org.

MR images of laboratory rat lungs that resolve the thin membranes that separate lung lobes are presented. It appears that the capabilities of in vivo small-animal pulmonary MRI may rival those of in vivo small-animal X-ray CT. Free induction decay (FID)-projection imaging was employed with particular attention to the choice of acquisition time. For a given nominal resolution, one obtains optimal point discrimination when the acquisition time Tacq normalized by the signal decay time constant T is approximately 0.8–0.9, although a better signal-to-noise ratio (SNR) is obtained when this quotient is 1.6. Currently available equipment should be able to even exceed the results presented herein. Magn Reson Med 57:1058–1064, 2007. © 2007 Wiley-Liss, Inc.

In breast cancer, certain types of circulating immune cells respond to long-range chemical signals from tumors by leaving the blood stream to actively infiltrate tumor tissue. The aim of this study was to evaluate whether immune cells could be used to deliver therapeutic nanoparticles into breast tumors in mice. Mononuclear splenocytes (MS) were harvested from donor mice, labeled with Indium-111, injected intravenously into immune-competent recipient mice (3 tumor-bearing and 3 control), and imaged longitudinally by SPECT/CT. For comparison, the biodistribution of bonemarrow derived macrophages (BMDM) in one pair of mice was also imaged. Quantitative analysis of the SPECT images demonstrates that, after 24 hours, the concentration of MS detected in mammary tumors is more than 3-fold higher than the concentration detected in normal mammary glands. The ratio of MS concentration in mammary tissue to MS concentration in non-target tissues (muscle, lung, heart, liver, spleen, and kidney) was enhanced in tumor-bearing mice (compared to controls), with statistical significance achieved for mammary/muscle (p

Pseudomonas aeruginosa bacterium is a deadly pathogen, leading to respiratory failure in cystic fibrosis and nosocomial pneumonia, and responsible for high mortality rates in these diseases. P. aeruginosa has inherent as well as acquired resistance to many drug classes. In this paper, we investigate the effectiveness of two classes; aminoglycoside (tobramycin) and fluoroquinolone (ciprofloxacin) administered alone, as well as conjugated to iron oxide (magnetite) nanoparticles. P. aeruginosa possesses the ability to quickly alter its genetics to impart resistance to the presence of new, unrecognized treatments. As a response to this impending public health threat, we have synthesized and characterized magnetite nanoparticles capped with biodegradable short-chain carboxylic acid derivatives conjugated to common antibiotic drugs. The functionalized nanoparticles may carry the drug past the mucus and biofilm layers to target the bacterial colonies via magnetic gradient-guided transport. Additionally, the magnetic ferrofluid may be used under application of an oscillating magnetic field to raise the local temperature, causing biofilm disruption, slowed growth, and mechanical disruption. These abilities of the ferrofluid would also treat multi-drug resistant strains, which appear to be increasing in many nosocomial as well as acquired opportunistic infections. In this in vitro model, we show that the iron oxide alone can also inhibit bacterial growth and biofilm formation.

The first application of a recent theory linking nuclear magnetic resonance spin-lattice relaxation rates to interstitial atom motion in disordered systems is presented. Laboratory and rotating frame relaxation rate data taken as a function of temperature for 1H moving in quasicrystalline Ti45Zr38Ni17H163 are fitted with the new theory, yielding a hydrogen site energy distribution of Gaussian shape and width 47±5 meV. The energy barriers for hydrogen motion show a Gaussian distribution of width 50±5 meV, and the difference between the means of the distributions is 0.42±0.01 eV. This is the first time relaxation rates have been analysed to provide information on both hydrogen site energy and barrier energy distributions simultaneously. The data are also fitted using an approach popular for disordered systems: the integration of the Bloembergen, Purcell, and Pound relaxation theory over a distribution of activation energies. The relative merits of this traditional approach and the recent theory in fitting the relaxation data, and also in fitting measurements of the static and magic angle spinning linewidths, are discussed. Although the traditional approach can fit all the data self-consistently, the theory's unsupported assumptions are undermined by the new approach.

Nuclear magnetic resonance spin-lattice relaxation rates for 1H in quasicrystalline Ti45Zr38Ni17H x are presented as a function of temperature and hydrogen concentration x. The temperature dependence demonstrates that the relaxation is via interaction with conduction electrons. The relaxation rate is extremely sensitive to hydrogen content, with the rate changing by a factor of as much as two for samples that differ in x

Three samples of ${\mathrm{YD}}_{x},$ with x ranging from 2.9 to nearly 3.0, were studied with deuterium nuclear magnetic resonance to gain insight into the locations of the D atoms in the lattice and their motions. Line shapes at low temperatures (200--330 K) show substantial disorder at some of the deuterium sites. Near 355 K, the spectrum sharpens to yield three uniaxial Pake patterns, reflecting a motional averaging process. However, the three measured intensities do not match the ratios expected from the neutron-determined, ${\mathrm{HoD}}_{3}$-like structure. This is strong evidence that the structure and space group of ${\mathrm{YD}}_{3}$ are different than reported, or that the current model needs adjustment. At still higher temperatures near 400 K, the Pake doublet features broaden, and a single sharp resonance develops, signalling a diffusive motion that carries all D atoms over all sites. The temperature at which line shape changes occur depends on the number of deuterium vacancies, $3\ensuremath{-}x.$ The changes occur at lower temperatures in the most defective sample, indicating the role of D-atom vacancies in the motional processes. The longitudinal relaxation rate ${T}_{1}^{\ensuremath{-}1}$ displays two regimes, being nearly temperature independent below 300 K and strongly thermally activated above. The relaxation rate depends on the number of deuterium vacancies, $3\ensuremath{-}x,$ varying an order of magnitude over the range of stoichiometries studied and suggesting that D-atom diffusion is involved. Also, the activation energy describing ${T}_{1}^{\ensuremath{-}1} (\ensuremath{\simeq}{k}_{B}\ifmmode\times\else\texttimes\fi{}5500 \mathrm{K})$ approximately matches that for diffusion. An unusual ${\ensuremath{\omega}}_{0}^{\ensuremath{-}0.7}$ frequency dependence of ${T}_{1}^{\ensuremath{-}1}$ is observed. A relaxation mechanism is proposed in which diffusion is the rate-determining step and in which frequency dependence arises from a field-dependent radius of the relaxation zones.

Organ transplantation is a life-saving procedure and the preferred method of treatment for a growing number of disease states. The advent of new immunosuppressants and improved care has led to great advances in both patient and graft survival. However, acute T-cell-mediated graft rejection occurs in a significant quantity of recipients and remains a life-threatening condition. Acute rejection is associated with decrease in long-term graft survival, demonstrating a need to carefully monitor transplant patients. Current diagnostic criteria for transplant rejection rely on invasive tissue biopsies or relatively nonspecific clinical features. A noninvasive way is needed to detect, localize, and monitor transplant rejection. Capitalizing on advances in targeted contrast agents and magnetic-based detection technology, we developed anti-CD3 antibody-tagged nanoparticles. T cells were found to bind preferentially to antibody-tagged nanoparticles, as identified through light microscopy, transmission electron microscopy, and confocal microscopy. Using mouse skin graft models, we were also able to demonstrate in vivo vascular delivery of T-cell targeted nanoparticles. We conclude that targeting lymphocytes with magnetic nanoparticles is conducive to developing a novel, noninvasive strategy for identifying transplant rejection.

Vascular disruption agents (VDAs) have been shown to selectively destroy established tumor vasculature, which results in the ischemic death of up to 99% of tumor cells. The weakness of VDA monotherapy is that it often leaves a rim of surviving tumor cells which can then regrow and spread. The overall goal of this study (addressed in Task 2) was to enhance VDA therapy by inducing hyperthermia, targeted to the neovascular endothelium, through the use of superparamagnetic iron oxide nanoparticles (SPIONs), in order to halt, or significantly slow down tumor growth. Therefore, the first aim of this study (Task 1) was to maximize the delivery of SPIONs to the tumor rim, through a combination of neovascular targeting and increased vascular permeability induced by the VDA. Covalent coupling of primary amines on VEGFR-2 antibodies to carboxyl groups on the SPIONs activated by EDC/Sulfo-NHS resulted in stable particles that showed specific binding to endothelial cells in vitro. Current in vivo results suggest a modest enhancement of SPION delivery to the tumor rim when VEGFR-2 targeting of PEG-coated particles and 15 min pre-administration of DMXAA (a VDA) are employed. The results suggest that the combination of targeting the neovasculature and increasing vascular permeability through the action of the VDA is an effective SPION delivery strategy; however, statistically-significant nanoparticle quantitation (by mass spectrometry) was not realized, due to high endogenous iron levels in tumor tissue. In vitro testing of SPION heating in the presence of an alternating magnetic field demonstrated that heating is optimized using 20 nm SPIONs. Reformulation of the poorly soluble DMXAA (using bicarbonate buffer to replace DMSO) was shown to improve long-term survival of the mice after DMXAA administration, which will enable in vivo longitudinal measurements of therapeutic efficacy to be carried out in a future study.

Magic-angle-spinning ~MAS! deuterium NMR of YD x , x;2, yields spectrally resolved lines for D atoms in tetrahedral (T) and octahedral (O) interstitial sites. Compared to MAS line narrowing of metal hydrides, the deuterides line narrow with only modest, readily attainable spinning speeds. This is the first application of NMR to resolve inequivalent sites in these systems. For YD x at 200 K we find only T sites occupied for x

The 35 Cl nuclear quadrupole resonance (NQR) spectrum of the (thiourea) 3 -CCl 4 inclusion compound has been determined at several temperatures in the range 5-20 K. The ratio of intensities of the two resonances was found to be 1:1, indicating that the tetrahedral CCl - molecule sites in the trigonal thiourea channel with the molecular and site 2-fold axes coinciding. NQR frequency-swept spin-echo measurements of the (thiourea) 3 -3CCl 3 Br inclusion compound reveal broad resonances at 40.995 and 40.690 MHz at 9.9 K, with a 1:2 ratio of intensities. The ∼300-kHz separation and the temperature dependence of the resonance frequencies are the same as that observed in the thiourea-CCl - compound, indicating that the two compounds are isomorphic at low temperatures

The first organometallic syntheses of the ternary phosphides M II M IV P 2 (M II  Zn, Cd; M IV  Ge, Sn) are described. Reactions between the precursors {M II [P(SiMe 3 ) 2 ] 2 } 2 and M IV X 4 (X  OMe, Cl) afford the intermediates [M II M IV P 2 (X) x (SiMe 3 ) x ] with x = 0.3–0.8, which are converted to amorphous M II M IV P 2 compounds by annealing at 250–350°C in vacuo . The amorphous compounds crystallize to the corresponding chalcopyrite phases at low temperatures, providing the lowest synthesis temperatures yet reported by any synthetic method: ZnGep 2 , 700–800°C; CdGeP 2 , 500–650°C; ZnSnP 2 , 350–600°C; CdSnP 2 , 250–450°C. The solid-state MAS 31 P NMR spectrum of the amorphous CdGeP 2 contains a single feature centered at − 104 ppm relative to H 3 PO 4 (full width at half maximum, 160 ppm). Spin-echo experiments on a nonspinning sample determine that T 2 = 350 μs. These data are indistinguishable from data for glassy CdGeP 2 obtained from conventional melt quenching, suggesting that the amorphous CdGeP 2 phases prepared by the two techniques have very similar or identical structures. Analogies between the new organometallic syntheses and the sol-gel process for oxides are discussed.

The magic-angle spinning 31 P NMR spectrum of Cd 3 P 2 is reported. Three lines with intensities nearly 1:1:2 are observed, as expected from the X-ray determined crystal structure. In light of this agreement and the reported identical crystal structures, the 31 P NMR of Zn 3 P 2 is re-examined. At room temperature, a doublet of equal intensities is observed and has been explained previously as an accidental overlap. This interpretation is confirmed by the observation that the overlap is removed at low temperatures. In addition, an unexpected overall frequency shift with temperature is observed and attributed to a Knight-shift-type mechanism.

Proton spin-lattice relaxation data {ital R}{sub 1} (1/{ital T}{sub 1}) are reported for the solid solution Nb{sub 0.5}V{sub 0.5}H{sub 0.36}. In the region of the previously reported anomaly ({ital T}{gt}700 K), a strong frequency dependence is observed by extending the measurements to a high frequency, 341 MHz. The correlation time {tau}{sub {ital c}} is determined and is found to decrease with increasing temperature. The mean-square magnetic-field fluctuation {ital M}{sub 2} responsible for the relaxation is also determined. Surprisingly, {ital M}{sub 2} increases rapidly with increasing temperature, suggesting an excited state with a large spin interaction, such as molecular hydrogen.

The development of microbiological biofilms greatly reduces the efficacy of antibiotic therapies and is a serious problem in chronic infection and for implantable medical devices. We investigated the potential of superparamagnetic nanoparticles to increase transport through in vitro models of alginate biofilms. An in vitro alginate biofilm model was developed to mimic the composition of in vivo samples of P. aeruginosa infections. Transport through this model biofilm was performed using both bulk diffusion methods and single particle tracking techniques in the presence and absence of an external magnetic field. Bulk diffusion of nanoparticles through the biofilm was significantly enhanced in the presence of a magnetic field, both visually and quantitatively. Nanoparticle trajectories also showed transport increases were significantly higher when magnetic fields were applied. We also showed that surface chemistry (cationic, anioni, or neutral) of the nanoparticles significantly influenced transport rates. Finally, nanoparticle size also influenced the transport rates and variability of transport rates through the biofilm. In these first studies using magnetic nanoparticles in bacterial biofilms, we demonstrate that transport enhancement can be achieved and further studies are warranted.

A new method is presented for quantitative mapping of ventilation-to-perfusion ratios (V(A)/Q) in the lung: MRI of the (19)F longitudinal relaxation time (T(1)) of an inert fluorinated gas at thermal polarization. The method takes advantage of the dependence of the (19)F T(1) on the local SF(6) partial pressure, which depends on the local value of V(A)/Q. In contrast to hyperpolarized noble gases, with very long T(1)s, the T(1) of SF(6) in mammal lungs is 0.8-1.3 ms. Thus, rapid signal averaging overcomes the low thermal equilibrium polarization. T(1) imaging of a phantom consisting of four different SF(6)/air mixtures with known T(1) values validates the modified Look-Locker T(1) imaging sequence. To demonstrate the method in vivo, partial obstruction of the left bronchus was attempted in three rats; 3D free induction decay (FID)-projection T(1) images (2 mm isotropic resolution) revealed obstructed ventilation in two of the animals. In those images, approximately 1700 lung voxels contained sufficient SF(6) for analysis and T(1) was determined in each voxel with a standard error of 8-10%. For comparison, independent V(A)/Q images of the same animals were obtained using a previously described SF(6) MRI technique, and good agreement between the two techniques was obtained. Relative to the previous technique the resolution achieved using the T(1) method is lower (for similar V(A)/Q precision and imaging time); however, the T(1) method offers the potential advantages of eliminating the need for image coregistration and allowing patients with impaired lung function to breathe a 70% O(2) gas mixture during the entire imaging procedure.