Amir H. Faraji

Nanoparticles in cellular drug delivery

This review highlights the properties of nanoparticles used in targeted drug delivery, including delivery to cells as well as organelle targets, some of the known pharmacokinetic properties of nanoparticles, and their typical modifications to allow for therapeutic delivery. Nanoparticles exploit biological pathways to achieve payload delivery to cellular and intracellular targets, including transport past the blood-brain barrier. As illustrative examples of their utility, the evaluation of targeted nanoparticles in the treatment of cancers and diseases of the central nervous system, such as glioblastoma multiforme, neurovascular disorders, and neurodegenerative diseases, is discussed.

Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer

As systemic therapies improve and patients live longer, concerns mount about the toxicity of whole‐brain radiation therapy (WBRT) for treatment of brain metastases. Development of delayed white matter abnormalities indicative of leukoencephalopathy have been correlated with cognitive dysfunction. This study assesses the risk of imaging‐defined leukoencephalopathy in patients whose management included WBRT in addition to stereotactic radiosurgery (SRS). This risk is compared to patients who only underwent SRS.

Hearing preservation up to 3 years after gamma knife radiosurgery for Gardner-Robertson class I patients with vestibular Schwannomas.

BACKGROUND Vestibular schwannoma patients with Gardner-Robertson (GR) class I hearing seek to maintain high-level hearing whenever possible. OBJECTIVE To evaluate hearing outcomes at 2 to 3 years in GR class I patients who underwent Gamma Knife radiosurgery (GKRS). METHODS Sixty-eight patients with GR class I hearing were identified between 2006 and 2009. Twenty-five patients had no subjective hearing loss (group A) and 43 patients reported subjective hearing loss (group B) before GKRS. The median tumor volume (1 cm) and tumor margin dose (12.5 Gy) were the same in both groups. RESULTS Serviceable hearing retention rates (GR grade I or II) were 100% for group A compared with 81% at 1 year, 60% at 2 years, and 57% at 3 years after GKRS for group B patients. Group A patients had significantly higher rates of hearing preservation in either GR class I (P < .001) or GR class II (P < .001). Patients with a pure tone average (PTA) <15 dB before GKRS had significantly higher rates of preservation of GR class I or II hearing. CONCLUSION At 2 to 3 years after GKRS, patients without subjective hearing loss or a PTA <15 dB had higher rates of grade I or II hearing preservation. Modification of the GR hearing classification into 2 groups of grade I hearing (group A, those with no subjective hearing loss and a PTA <15 dB; and group B, those with subjective hearing loss and a PTA >15 dB) may be useful to help predict hearing preservation rates at 2 to 3 years after GKRS.

Iontophoresis from a micropipet into a porous medium depends on the ζ-potential of the medium.

Iontophoresis uses electricity to deliver solutes into living tissue. Often, iontophoretic ejections from micropipets into brain tissue are confined to millisecond pulses for highly localized delivery, but longer pulses are common. As hippocampal tissue has a ζ-potential of approximately -22 mV, we hypothesized that, in the presence of the electric field resulting from the iontophoretic current, electroosmotic flow in the tissue would carry solutes considerably farther than diffusion alone. A steady state solution to this mass transport problem predicts a spherically symmetrical solute concentration profile with the characteristic distance of the profile depending on the ζ-potential of the medium, the current density at the tip, the tip size, and the solute electrophoretic mobility and diffusion coefficient. Of course, the ζ-potential of the tissue is defined by immobilized components of the extracellular matrix as well as cell-surface functional groups. As such, it cannot be changed at will. Therefore, the effect of the ζ-potential of the porous medium on ejections is examined using poly(acrylamide-co-acrylic acid) hydrogels with various magnitudes of ζ-potential, including that similar to hippocampal brain tissue. We demonstrated that nearly neutral fluorescent dextran (3 and 70 kD) solute penetration distance in the hydrogels and OHSCs depends on the magnitude of the applied current, solute properties, and, in the case of the hydrogels, the ζ-potential of the matrix. Steady state solute ejection profiles in gels and cultures of hippocampus can be predicted semiquantitatively.

Synthesis and Characterization of a Hydrogel with Controllable Electroosmosis: A Potential Brain Tissue Surrogate for Electrokinetic Transport

Electroosmosis is the bulk fluid flow initiated by application of an electric field to an electrolyte solution in contact with immobile objects with a nonzero ζ-potential such as the surface of a porous medium. Electroosmosis may be used to assist analytical separations. Several gel-based systems with varying electroosmotic mobilities have been made in this context. A method was recently developed to determine the ζ-potential of organotypic hippocampal slice cultures (OHSC) as a representative model for normal brain tissue. The ζ-potential of the tissue is significant. However, determining the role of the ζ-potential in solute transport in tissue in an electric field is difficult because the tissues ζ-potential cannot be altered. We hypothesized that mass transport properties, namely the ζ-potential and tortuosity, could be modulated by controlling the composition of a set of hydrogels. Thus, poly(acrylamide-co-acrylic acid) gels were prepared with three compositions (by monomer weight percent): acrylamide/acrylic acid 100/0, 90/10, and 75/25. The ζ-potentials of these gels at pH 7.4 are distinctly different, and in fact vary approximately linearly with the weight percent of acrylic acid. We discovered that the 25% acrylic acid gel is a respectable model for brain tissue, as its ζ-potential is comparable to the OHSC. This series of gels permits the experimental determination of the importance of electrokinetic properties in a particular experiment or protocol. Additionally, tortuosities were measured electrokinetically and by evaluating diffusion coefficients. Hydrogels with well-defined ζ-potential and tortuosity may find utility in biomaterials and analytical separations, and as a surrogate model for OHSC and living biological tissues.

Stereotactic Radiosurgery as Initial Surgical Management for Elderly Patients with Trigeminal Neuralgia

Background: Management of older patients with medically refractory trigeminal neuralgia (TN) is yet a matter of debate. Objective: We sought to determine the benefit of stereotactic radiosurgery (SRS) as the sole surgical management in older patients (≥70 years). Methods: One hundred and twenty-seven patients (≥70 years) with typical TN underwent SRS as initial surgical management. The median maximum dose for the first procedure was 80 Gy. Repeat SRS was performed in 46 patients who developed recurrent pain. Results: After the first SRS, the initial pain control was achieved in 91% of patients. Complete pain relief (Barrow Neurological Institute [BNI] score I) developed in 75 patients (59%) and was maintained in 59, 39, and 22% of patients at 1, 3, and 5 years. Following repeat SRS, the rate of complete pain relief was 79, 55, and 41% at 1, 3, and 5 years. The chance of BNI I preservation was greater after repeat SRS compared to initial SRS (hazards ratio: 2.02, p < 0.0001). The incidence of trigeminal sensory loss was 17% after initial SRS but increased to 39% after repeat SRS. Conclusions: SRS alone was used effectively in older TN patients to achieve pain control. Recurrent pain responded to retreatment but was associated with an increased risk of sensory dysfunction.

The Use of Nanotechnology to Improve the Neuroprotective Effects of Adenosine in Stroke and Spinal Cord Injury

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Multiple discrete aneurysmal subarachnoid hemorrhages during multimodality management of a hypothalamic glioma—Case report

Primary intracerebral tumors occasionally present with spontaeous intratumoral hemorrhage, or rarely, spontaneous subarachoid hemorrhage (SAH) [1]. SAH associated with primary brain umors usually results from extension of an intratumoral hemrrhage into the subarachnoid space. Tumors that spread within he distal vasculature (e.g. choriocarcinomas and atrial myxomas) re associated with aneurymsal subarachnoid hemorrhage [1]. owever, the association of a primary intracranial tumor and an djacent intracranial aneurysm is rare, except in the setting of ituitary adenomas. The authors describe a patient who suffered ultiple aneurysmal SAHs during the multimodality treatment f a hypothalamic glioma and concomitant arteriovenous malforation. We suspect that new aneurysm development may have een related to the combination of the peri-tumoral vascular nvironment with the application of anti-angiogenesis therapy, hemotherapy, and stereotactic radiosurgery.

Electrokinetic infusions into hydrogels and brain tissue: Control of direction and magnitude of solute delivery

BACKGROUND Delivering solutes to a particular region of the brain is currently achieved by iontophoresis for very small volumes and by diffusion from a microdialysis probe for larger volumes. There is a need to deliver solutes to particular areas with more control than is possible with existing methods. NEW METHOD Electrokinetic infusions of solutes were performed into hydrogels and organotypic hippocampal slice cultures. Application of an electrical current creates electroosmotic flow and electrophoresis of a dicationic fluorescent solute through organotypic hippocampal tissue cultures or larger hydrogels. Transport was recorded with fluorescence microscopy imaging in real-time. RESULTS Electrokinetic transport in brain tissue slice cultures and hydrogels occurs along an electrical current path and allows for anisotropic delivery over distances from several hundred micrometers to millimeters. Directional transport may be controlled by altering the current path. The applied electrical current linearly affects the measured solute fluorescence in our model system following infusions. COMPARISON WITH EXISTING METHODS Localized drug delivery involves iontophoresis, with diffusion primarily occurring beyond infusion capillaries under current protocols. Pressure-driven infusions for intraparenchymal targets have also been conducted. Superfusion across a tissue surface provides modest penetration, however is unable to impact deeper targets. In general, control over intraparenchymal drug delivery has been difficult to achieve. Electrokinetic transport provides an alternative to deliver solutes along an electrical current path in tissue. CONCLUSIONS Electrokinetic transport may be applied to living systems for molecular transport. It may be used to improve upon the control of solute delivery over that of pressure-driven transport.

Deep Brain Stimulation for Tourette Syndrome

It has historically been difficult to arrive at an accurate diagnostic criterion or devise optimal medical and pharmacological strategies for the treatment of Tourette syndrome (TS). The International Tourette Syndrome Deep Brain Stimulation (DBS) Public Database and Registry is a multinational collaborative effort designed to share data and improve the quality of outcomes research in the treatment of TS with DBS. , recently described by Martinez-Ramirez et al in JAMA Neurology. The registry accumulated data from 171 patients. Stimulation sites included the centromedian thalamic region (57.1%), anterior globus pallidus internus (GPi; 25.2%) and posterior GPi (15.3%). There was a 40% improvement in the YGTSS total score at 6-mo (P < .001) and 45% at 12-mo (P < .001) without statistical difference between the 3 targets. The registry results mirror those described in a systematic review and meta-analysis of DBS for TS that was published in 2016. These data nonetheless should encourage movement disorder groups to consider treating refractory TS with DBS. The development of standardized surgical criteria will be helpful for identifying appropriate patients for evaluation.