Edited by Norma AllewellP-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancer; it plays important roles in determining the pharmacokinetics of many drugs. Understanding the structural basis of P-gp, substrate polyspecificity has been hampered by its intrinsic flexibility, which is facilitated by a 75-residue linker that connects the two halves of P-gp. Here we constructed a mutant murine P-gp with a shortened linker to facilitate structural determination. Despite dramatic reduction in rhodamine 123 and calcein-AM transport, the linker-shortened mutant P-gp possesses basal ATPase activity and binds ATP only in its N-terminal nucleotide-binding domain. Nine independently determined structures of wild type, the linker mutant, and a methylated P-gp at up to 3.3 Å resolution display significant movements of individual transmembrane domain helices, which correlated with the opening and closing motion of the two halves of P-gp. The open-andclose motion alters the surface topology of P-gp within the drugbinding pocket, providing a mechanistic explanation for the polyspecificity of P-gp in substrate interactions.The association of multidrug resistance (MDR) 3 in cancer treatment with expression of human ABC transporters on the cell surface has raised the possibility that overcoming MDR might be achieved by inhibiting these transporters (1). One transporter in particular, the human P-glycoprotein (P-gp), has been well characterized; it is able to confer MDR by transporting numerous structurally unrelated drugs at the expense of hydrolyzing ATP (2, 3). In addition, P-gp plays important roles in drug distribution in normal physiology and is an essential component of many physiological barriers (4, 5).Long-standing efforts have been devoted to understanding the mechanism of P-gp function by various experimental approaches. Among them, structural studies of P-gp from various organisms have been reported (6 -8). In particular, a number of structures for the mouse P-gp (mP-gp) were obtained (8 -10). However, the diffraction limits of "near-native," inhibitor-bound, and nanobody-associated mP-gp crystals were relatively low, mostly near 4 Å resolution. The methylated protein gave higher resolution structures (11), but the impact of reductive methylation on the structure and function of P-gp was not addressed. The low resolution diffraction of P-gp crystals has been attributed in part to the intrinsic flexibility of the molecule (12-14).Mouse P-gp is a 1276-residue polypeptide and bears 87% sequence identity to human P-gp; it consists of two homologous halves connected by a flexible linker of ϳ75 residues. Each half is made of a transmembrane domain (TMD) implicated in drug recognition and transport and a nucleotide-binding domain (NBD). Each NBD is able to bind and hydrolyze ATP (15, 16), which is, however, dependent on the other NBD being functional (17,18). The two NBDs of P-gp are highly homologous, each featuring a consensus nucleotide-binding site with full-fledged Walker...

This article explains possible reasons outlined by FACETS for the health disparities in epilepsy surgery that exist in patients of a certain race, socioeconomic status, and language proficiency.

CLINICAL PEARL Fibrocartilaginous embolism myelopathy is a stroke syndrome, characterized by rapidly progressive paraplegia (hours to 2-3 days) following an episode of back pain (mostly after a minor trauma).1 CSF studies are normal and MRI shows T2 hyperintensity in the spinal cord with associated swelling, diffusion restriction, and often presence of Schmorl's nodes at the level of injury.1 CASE REPORT A 25-year-old man with no significant past medical history and an active lifestyle presented to the hospital with a complaint of bilateral lower extremity numbness and weakness. Three days prior, the patient slipped while getting out of his truck and fell into a split position. Immediately afterwards he felt a sudden pain in his left groin with associated paraesthesia and weakness initially in his left thigh. Within several hours, the weakness and paraesthesia spread over the entire left leg and 24 hours later to the right leg. He also felt his bladder was full and lost control of his flatulence.The patient was a well-developed man in mild distress with normal vital signs. On neurologic examination, mental status and cranial nerves were normal. Manual motor testing of his upper extremities was unremarkable. Testing of his lower extremities revealed increased tone bilaterally. In the right lower extremity his iliopsoas was 4/5, hamstrings were 4ϩ/5, quadriceps were 4ϩ/5, tibialis anterior was 5/5, and gastrocnemius was 5/5. In the left lower extremity, his iliopsoas was 1/5, hamstrings were 4Ϫ/5, quadriceps were 4Ϫ/5, tibialis anterior was 4/5, and gastrocnemius was 4ϩ/5. Muscle bulk was normal. Rectal sphincter tone was diminished. He had no adventitial movements. Deep tendon reflexes were 2ϩ/4 in the upper extremities and 4ϩ/4 in the lower extremities bilaterally, with several beats of ankle clonus and bilateral extensor response in the toes. Sensory examination revealed intact vibration, proprioception, and pain and temperature sensation in the upper extremities bilaterally. There was an L1 sensory level involving pinprick and temperature testing. Proprioception and vibration were intact. Light touch elicited dysesthesias in the left lower extremity. Coordination was intact. The patient was able to sit up with assistance but was not able to bear any weight on his legs.The patient was admitted to a telemetry unit and had a thoracolumbar spine MRI, which showed a hyperintense T2 signal in the central and left posterior aspect of the cord from T9 through T11, slightly greater in the craniocaudal dimension. There were Schmorl's nodes at the inferior T10, superior T11, inferior T11, and superior T12 end plates (figure). Axial and sagittal MRI T1 pre-and post-gadolinium images did not show any evidence of enhancement at the level corresponding to the T2 hyperintensity. A lumbar puncture revealed an opening pressure of 29 cm of water with CSF analysis showing leukocytes 2/L, erythrocytes 4/L, glucose 63 mg/dL, and protein 44 mg/dL. CSF Lyme antibody was negative. CSF myelin basic protein was elevated at 307 ng/mL. CS...

Academic Neurology Departments must confront the challenges of developing a diverse workforce, reducing inequity and discrimination within academia, and providing neurologic care for an increasingly diverse society. A neurology diversity officer should have a specific role and associated title within a neurology department as well as a mandate to focus their efforts on issues of equity, diversity and inclusion that affect staff, trainees and faculty. This role is expansive and works across departmental missions but it has many challenges related to structural intolerance and cultural gaps. In this review, we describe the many challenges that diversity officers face and how they might confront them. We delineate the role and duties of the neurology diversity officer and provide a guide to departmental leaders on how to assess qualifications and evaluate progress. Finally, we describe the elements necessary for success. A neurology diversity officer should have the financial, administrative and emotional support of leadership in order for them to carry out their mission and to truly have a positive influence.