Omar Zurkiya

MagA Is Sufficient for Producing Magnetic Nanoparticles in Mammalian Cells, Making it an MRI Reporter

Magnetic resonance imaging (MRI) is routinely used to obtain anatomical images that have greatly advanced biomedical research and clinical health care today, but the full potential of MRI in providing functional, physiological, and molecular information is only beginning to emerge. In this work, we sought to provide a gene expression marker for MRI based on bacterial magnetosomes, tiny magnets produced by naturally occurring magnetotactic bacteria. Specifically, magA, a gene in magnetotactic bacteria known to be involved with iron transport, is expressed in a commonly used human cell line, 293FT, resulting in the production of magnetic, iron‐oxide nanoparticles by these cells and leading to increased transverse relaxivity. MRI shows that these particles can be formed in vivo utilizing endogenous iron and can be used to visualize cells positive for magA. These results demonstrate that magA alone is sufficient to produce magnetic nanoparticles and that it is an appropriate candidate for an MRI reporter gene. Magn Reson Med 59:1225–1231, 2008.

Evaluation of Corpus Callosum Anisotropy in Young Adults With Fetal Alcohol Syndrome According to Diffusion Tensor Imaging

BACKGROUND Fetal alcohol syndrome (FAS) and associated disorders resulting from maternal alcohol use during gestation are among the most common developmental disorders. However, they are rarely diagnosed and not fully understood in terms of their behavioral and neurocognitive phenotype. Prenatal exposure leads to alterations in facial morphology, growth, and neurocognition. The nature and extent of teratogenic effects on the brain and the relationship between such effects and observed behaviors remain in debate because there are no established markers for the neurological effects of exposure. In this study, we examined the impact of prenatal alcohol exposure on white-matter integrity in the corpus callosum by using diffusion tensor imaging (DTI) and herein describe the relationship between such effects and observed physical and behavioral outcomes. METHODS DTI was used to evaluate diffusion anisotropy in the genu and splenium of corpus callosum in 16 low-income, primarily African-American volunteers. Volunteers were recruited from a cohort of young adults who had received neuropsychological evaluations during adolescence. Nine had been prenatally exposed to alcohol and had characteristics of FAS, and seven were nonexposed controls. RESULTS Significant difference in the means for diffusion fractional anisotropy (t = 2.26, df = 9, p <0.002) and apparent diffusion coefficient (t = 2.14, df = 14, p < 0.008) were observed in the corpus callosum of alcohol-exposed youth compared with nonexposed youth. No significant differences were found in intracranial volume between these groups. CONCLUSIONS Our results illustrate that DTI can be used in evaluating the integrity of corpus callosum in alcohol-exposed individuals. If future studies support these findings, diffusion anisotropy, represented by fractional anisotropy, has the potential to be used as a clinical marker in the diagnosis of FAS.

Rational Design of Protein-based MRI Contrast Agents

We describe the rational design of a novel class of magnetic resonance imaging (MRI) contrast agents with engineered proteins (CAi.CD2, i = 1, 2,..., 9) chelated with gadolinium. The design of protein-based contrast agents involves creating high-coordination Gd(3+) binding sites in a stable host protein using amino acid residues and water molecules as metal coordinating ligands. Designed proteins show strong selectivity for Gd(3+) over physiological metal ions such as Ca(2+), Zn(2+), and Mg(2+). These agents exhibit a 20-fold increase in longitudinal and transverse relaxation rate values over the conventional small-molecule contrast agents, e.g., Gd-DTPA (diethylene triamine pentaacetic acid), used clinically. Furthermore, they exhibit much stronger contrast enhancement and much longer blood retention time than Gd-DTPA in mice. With good biocompatibility and potential functionalities, these protein contrast agents may be used as molecular imaging probes to target disease markers, thereby extending applications of MRI.

Off-resonance saturation as a means of generating contrast with superparamagnetic nanoparticles

This work demonstrates an alternative approach, termed off‐resonance saturation (ORS), for generating contrast that is sensitive to superparamagnetic particles. This method leads to a calculated contrast that increases with superparamagnetic nanoparticle concentration. Experimental data demonstrate that in the presence of superparamagnetic particles, an off‐resonance effect exists that is distinct from the magnetization transfer (MT) effect and is highly dependent on diffusion. Data show that the dependence on water diffusion becomes most significant at rates of 0.5 × 10–9 m2/s and slower. We investigated the dependence of the off‐resonance effect on off‐resonance frequency and particle concentration. The data suggest a useful frequency offset range of 500 Hz < |Δω| < 1500 Hz at 3T. This approach may be especially useful in organs and diseases in which diffusion may be altered by pathologies. Magn Reson Med, 2006.

Treatment of multiple system atrophy using intravenous immunoglobulin

BackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.MethodsThis was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment.ResultsNine subjects were enrolled, and seven (2 women and 5 men, age range 55–64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment.ConclusionsTreatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

Digital diffraction analysis enables low-cost molecular diagnostics on a smartphone

Significance Smartphones and wearable electronics have advanced tremendously over the last several years but fall short of allowing their use for molecular diagnostics. We herein report a generic approach to enable molecular diagnostics on smartphones. The method utilizes molecular-specific microbeads to generate unique diffraction patterns of “blurry beads” which can be recorded and deconvoluted by digital processing. We applied the system to resolve individual precancerous and cancerous cells as well as to detect cancer-associated DNA targets. Because the system is compact, easy to operate, and readily integrated with the standard, portable smartphone, this approach could enable medical diagnostics in geographically and/or socioeconomically limited settings with pathology bottlenecks. The widespread distribution of smartphones, with their integrated sensors and communication capabilities, makes them an ideal platform for point-of-care (POC) diagnosis, especially in resource-limited settings. Molecular diagnostics, however, have been difficult to implement in smartphones. We herein report a diffraction-based approach that enables molecular and cellular diagnostics. The D3 (digital diffraction diagnosis) system uses microbeads to generate unique diffraction patterns which can be acquired by smartphones and processed by a remote server. We applied the D3 platform to screen for precancerous or cancerous cells in cervical specimens and to detect human papillomavirus (HPV) DNA. The D3 assay generated readouts within 45 min and showed excellent agreement with gold-standard pathology or HPV testing, respectively. This approach could have favorable global health applications where medical access is limited or when pathology bottlenecks challenge prompt diagnostic readouts.

Beyond Hepatocellular Carcinoma and Colorectal Metastasis: The Expanding Applications of Radioembolization

As a relatively safe outpatient procedure, radioembolization can potentially be used to treat any type of tumor within the liver, primary or metastatic. The safety and effectiveness of radioembolization in the treatment of hepatocellular carcinoma (HCC) and metastatic colorectal cancer (mCRC) has led many groups to explore its application in other malignancies. Moreover, other organs, such as the lungs and kidneys, have been explored as targets for therapy. Although the most data for radioembolization is related to HCC and mCRC, there is increasing experience and data regarding metastatic disease to the liver for other primary tumors. We review the current state of liver-directed therapy with radioembolization outside of HCC and mCRC, including metastatic neuroendocrine, breast, and melanoma, as well as limited experiences with other primary malignancies. Applications of radioembolization related to these other cancers and new trends and future directions will be discussed. With increasing use and availability of radioembolization, it promises to serve an expanding role in the repertoire of tools available for treating and managing oncologic disease.

Angiographic Evaluation and Management of Nonvariceal Gastrointestinal Hemorrhage.

OBJECTIVE The purpose of this article is to review the roles of angiography, embolization, and various ancillary techniques in evaluating and managing gastrointestinal hemorrhage. CONCLUSION Nonvariceal gastrointestinal hemorrhage typically resolves spontaneously or responds to medical or endoscopic management. Refractory hemorrhage may require angiography and transcatheter intervention. Noninvasive imaging evaluation may be useful for characterizing the bleeding source and confirming the presence of active hemorrhage before angiography. If a bleeding source is angiographically identified, superselective catheterization with embolization is typically effective in controlling hemorrhage while minimizing complications.

Safety and Efficacy of Catheter-Directed Therapies as a Supplement to Surgical Decompression in Venous Thoracic Outlet Syndrome

OBJECTIVE The purpose of this study is to evaluate the role of endovascular therapy in the management of venous thoracic outlet syndrome (TOS), with an emphasis on its role after surgical decompression. MATERIALS AND METHODS This single-center retrospective review identified all patients who underwent conventional contrast-enhanced venography as a component of the imaging evaluation of clinically suspected venous TOS from January 2004 through September 2015. Eighty-one patients were identified, with a mean (± SD) age of 33 ± 12 years, of whom 59% (48/81) were women. After imaging confirmation of venous TOS, a standardized treatment protocol combining surgical and endovascular intervention was used for management. RESULTS Of the 81 patients included in the study, 73 (90%) had angiographic evidence of venous TOS; 41 of these 73 patients (56%) underwent endovascular venous intervention (e.g., thrombolysis or angioplasty before surgical) decompression. A total of 67 patients (67/73; 92%) with venous TOS underwent surgical decompression, with 56 of these (56/73; 77%) undergoing postoperative venography. Of these 56 patients who underwent postoperative venography, 48 (86%) required venoplasty, four had normal-appearing subclavian veins (7%) and had no intervention, and four of 48 (8%) had chronic total venous occlusions that could not be recanalized. Only four of the 48 of the patients (8%) who underwent postdecompression venoplasty required subsequent repeat venography and intervention for management of persistent or recurrent symptoms, whereas all others (44/48; 92%) remained symptom free on clinical follow-up. No complications were identified that were related to the endovascular interventions. CONCLUSION Combining venography and endovascular venous intervention with surgical decompression in managing patients with clinically suspected venous TOS is safe and effective. Postdecompression venoplasty appears to be highly effective, with a low rate of symptom recurrence.