Background-There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.

The blood-brain-barrier (BBB), a network of tight junctions that impedes large molecule transport, limits the usefulness of systemic chemotherapeutic delivery for the treatment of malignant gliomas and other neurological diseases. Here, we present a tool for BBB disruption that uses bursts of sub-microsecond bipolar pulses to enhance the transfer of large molecules to the brain. Blunt needle electrodes were advanced into the motor cortex of anesthetized adult rats, and a series of 90-900 bursts were delivered with voltage-to-distance ratios of 250 or 2000 V/cm, a total programmed energized time of 100 µs, and a repetition rate of 1 Hz. BBB disruption was assessed via a gadolinium-Evans blue albumin tracer, and all experimental conditions were found to cause BBB disruption immediately following treatment without inducing local or distal muscle contractions. The lowest energy condition, 300 bursts consisting of 850 ns bipolar pulses, resulted in signifi cant BBB disruption (0.51 cm 3 ), without displaying necrotic or apoptotic damage to neurological tissue. INNOVATIONTh e Vascular Enabled Integrated Nanosecond pulse (VEIN pulse) platform is a new technology for reversibly opening the blood-brain-barrier (BBB) to facilitate the treatment of brain cancer. Our experiments reveal that the delivery of bipolar sub-microsecond pulses eliminates the electrically induced movement associated with longer duration unipolar pulses used in irreversible electroporation and electrochemotherapy treatments. Th erefore, it may be possible in the future to perform these procedures while patients are under conscious sedation and assess cognitive function as the therapy is being delivered. Th e sub-lethal nature of these bursts indicates that this modality may be useful for treating other neurological disorders, such as Parkinson's disease and epilepsy, in which certain therapeutics show eff ectiveness in in vitro models of disease, but fail to reach their therapeutic target in vivo. Generation of these waveforms is possible using solid-state electronics, enabling the creation of compact systems that can easily be scaled for human clinical applications.

Cytoplasmic vacuolation of sensory neurons has been reported to occur within the dorsal root ganglia in studies investigating various neuropathic conditions including the effects of neurotoxic chemicals. In this study, we investigated this lesion in adult (98-119 days old) male Long-Evans rats, after multiple exposures to two organophosphates (tri-ortho-tolyl phosphate [TOTP] and chlorpyrifos) and the modifying effects of concurrent corticosterone. Tri-ortho-tolyl phosphate was administered by gavage (75, 150, or 300 mg/kg) every other day between days 14 and 28 and between days 49 and 63, chlorpyrifos (60 mg/kg) was administered subcutaneously on days 7 and 42, and corticosterone was provided in the drinking water throughout the study at a concentration of 400 microg/mL. Although relatively uncommon, there was an increase in frequency of cytoplasmic vacuoles seen in treatment groups having multiple exposures to TOTP. They were characterized as peripherally located, single-limiting membrane-bound structures in the neuronal perikarya. There was no associated cell death, even when vacuoles were large. This is the initial report of an association of this change following exposure to neurotoxic organophosphates.

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