StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.

The pathological accumulation of cholesterol is a signature feature of Niemann-Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease.

Antifungal liposomes: Lipid saturation and cholesterol concentration impact interaction with fungal and mammalian cells.

Liposomes are lipid-based nanoparticles that have been used to deliver encapsulated drugs for a variety of applications, including treatment of life-threatening fungal infections. By understanding the effect of composition on liposome interactions with both fungal and mammalian cells, new effective antifungal liposomes can be developed. In this study, we investigated the impact of lipid saturation and cholesterol content on fungal and mammalian cell interactions with liposomes. We used three phospholipids with different saturation levels (saturated hydrogenated soy phosphatidylcholine (HSPC), mono-unsaturated 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), and di-unsaturated 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC)) and cholesterol concentrations ranging from 15% to 40% (w/w) in our liposome formulations. Using flow cytometry, >80% of Candida albicans SC5314 cells were found to interact with all liposome formulations developed, while >50% of clinical isolates tested exhibited interaction with these liposomes. In contrast, POPC-containing formulations exhibited low levels of interaction with murine fibroblasts and human umbilical vein endothelial cells (<30%), while HSPC and PLPC formulations had >50% and >80% interaction, respectively. Further, PLPC formulations caused a significant decrease in mammalian cell viability. Formulations that resulted in low levels of mammalian cell interaction, minimal cytotoxicity, and high levels of fungal cell interaction were then used to encapsulate the antifungal drug, amphotericin B. These liposomes eradicated planktonic C. albicans at drug concentrations lower than free drug, potentially due to the high levels of liposome-C. albicans interaction. Overall, this study provides new insights into the design of liposome formulations towards the development of new antifungal therapeutics.

Imaging modalities in mild traumatic brain injury and sports concussion.

Mild traumatic brain injury is a significant public health issue that has been gaining considerable attention over the past few years. After injury, a large percentage of patients experience postconcussive symptoms that affect work and school performance and that carry significant medicolegal implications. Conventional imaging modalities (computed tomography and magnetic resonance imaging) are insensitive to microstructural changes and underestimate the degree of diffuse axonal injury and metabolic changes. Newer imaging techniques have attempted to better diagnose and characterize diffuse axonal injury and the metabolic and functional aspects of traumatic brain injury. The following review article summarizes the currently available imaging studies and describes the novel and more investigational techniques available for mild traumatic brain injury. A suggested algorithm is offered.

Piriformis syndrome versus radiculopathy following lumbar artificial disc replacement.

STUDY DESIGN: Case series. OBJECTIVE: To describe the presentation, diagnostic challenges, and treatment of five patients with piriformis syndrome after lumbar artificial disc replacement. SUMMARY OF BACKGROUND DATA: Until recently, spinal fusion was considered the standard for surgical treatment of severe lumbar degenerative disc disease. However, artificial disc replacement now offers an alternative solution. Piriformis syndrome results from entrapment of the sciatic nerve at the greater sciatic notch, with symptoms of pain and numbness radiating from the buttock to the foot, mimicking radiculopathy. METHODS: In this case series, we report five patients who developed piriformis at our institution after artificial disc replacement. RESULTS: Five patients, aged 35 to 46 years, developed some or all of the following symptoms in the affected leg after artificial disc replacement: posterior leg and buttock pain, calf weakness, and toe and ball of foot numbness and tingling. The onset of symptoms ranged from 6 days to 8 months postoperative, and became debilitating over time. Each patient was diagnosed with piriformis syndrome through physical examination. Three of the patients received a piriformis injection and reported 50% to 100% pain relief lasting 1 to 3 weeks. The patients subsequently underwent physical therapy that provided relief of their piriformis syndrome-related pain and enabled them to resume their normal activities. CONCLUSION: Piriformis syndrome has not previously been described in the literature as a sequela of lumbar artificial disc replacement. Our case series indicates that this complication may be underdiagnosed. Careful consideration after artificial disc replacement is required if the patient presents with buttock, leg or foot pain, and/or numbness. It is important for physicians to recognize the symptoms of piriformis syndrome and to differentiate piriformis syndrome from nerve root compression and irritation or referred pain from spinal structures. Although controversial, the proper diagnosis of piriformis syndrome may have prevented some of these patients from undergoing unnecessary surgical procedures.

The diagnostic validity of hip provocation maneuvers to detect intra-articular hip pathology.

OBJECTIVE: To determine which hip provocation maneuvers best predict the presence of an intra-articular hip pathology. DESIGN: Prospective diagnostic study. SETTING: Musculoskeletal clinic at a university-based multispecialty group practice. PARTICIPANTS: Fifty subjects referred for intra-articular hip injection under fluoroscopic guidance. INTERVENTIONS: Subjects were examined with 4 pain provocation maneuvers before and after anesthetic intra-articular hip injection administered under fluoroscopic guidance. MAIN OUTCOME MEASUREMENTS: Presence of intra-articular hip pain generator was confirmed by > or =80% improvement on visual analog scale after intra-articular hip injection. RESULTS: The most sensitive tests were flexion abduction external rotation (FABER) test and internal rotation over pressure (IROP) maneuver. For the FABER test, sensitivity was 0.82 (95% CI 0.57-0.96); sensitivity for the IROP maneuver was 0.91 (95% CI 0.68-0.99). The most specific test was the Stinchfield maneuver, with specificity at 0.32 (95% CI 0.14-0.55). FABER and IROP had the highest positive predictive value, with 0.46 (95% CI 0.28-0.65) and 0.47 (95% CI 0.29-0.64), respectively. IROP had the highest negative predictive value at 0.71 (95% CI 0.25-0.98). CONCLUSIONS: IROP and FABER may be worthwhile components of the clinical evaluation of hip pain to determine intra-articular hip pathology. These tests are nonspecific and therefore not necessarily negative in the absence of intra-articular hip pathology. These hip provocation maneuvers are a useful part of an evaluation that includes history, further examination findings, and other diagnostic studies.

Treating and precepting with RESPECT: a relational model addressing race, ethnicity, and culture in medical training.

BACKGROUND: In 2000 a diverse group of clinicians/educators at an inner-city safety-net hospital identified relational skills to reduce disparities at the point of care. DESCRIPTION: The resulting interviewing and precepting model helps build trust with patients as well as with learners. RESPECT adds attention to the relational dimension, addressing documented disparities in respect, empathy, power-sharing, and trust while incorporating prior cross-cultural models. Specific behavioral descriptions for each component make RESPECT a concrete, practical, integrated model for teaching patient care. CONCLUSIONS: Precepting with RESPECT fosters a safe climate for residents to partner with faculty, address challenges with patients at risk, and improve outcomes.

The effects of epidural betamethasone on blood glucose in patients with diabetes mellitus.

OBJECTIVE: To determine the effects of lumbosacral transforaminal and caudal epidural betamethasone injections on blood glucose levels in diabetic subjects. The hypothesis is that epidural steroid injections result in transient elevation of blood glucose levels in diabetic subjects. DESIGN: This is a prospective, observational cohort. Twelve diabetic subjects (6 non-insulin-dependent and 6 insulin-dependent) receiving lumbosacral or caudal epidural betamethasone injections for neurogenic claudication or radicular pain were studied. Spinal level and approach were decided based on symptoms, pathology, and magnetic resonance imaging findings. Subjects recorded their finger stick blood glucose levels twice daily for 3 days before the injection, the day of the injection, and 3 days after the injection. SETTING: A tertiary, university-based, spine center. PARTICIPANTS: Inclusion criteria included diabetic subjects (age 18 years) with the ability and willingness to monitor and report their blood glucose. Exclusion criteria included epidural steroid injections (ESIs) within the previous 2 months or peripheral corticosteroid injections within the previous 2 weeks. Nineteen subjects initially enrolled, and 12 successfully completed the study. INTERVENTIONS: After informed consent was obtained, subjects underwent fluoroscopically guided lumbosacral transforaminal ESIs (TFESIs) or caudal ESIs, using contrast to confirm targeted needle placement and to rule out vascular uptake. MAIN OUTCOME MEASURES: Subjects recorded morning and evening blood glucose (mg/dL) via glucometer. RESULTS: There was a 106 mg/dL average elevation in blood glucose level on the evening of the injection day. The blood glucose elevation remained statistically significant for 3 days after the injection (P < .002). Blood glucose remained elevated through postinjection day 2, though these elevations were not statistically significant. CONCLUSIONS: Lumbosacral transforaminal and caudal epidural betamethasone injections are associated with statistically significant elevations in blood glucose levels in diabetic subjects. This effect peaked on the day of the injection and lasted approximately 2 days.

Confirmation of needle placement within the piriformis muscle of a cadaveric specimen using anatomic landmarks and fluoroscopic guidance.

Of patients presenting to pain clinics, complaints are of low back or buttock pain with or without radicular leg symptoms is one of the most common. Piriformis syndrome may be a contributor in up to 8% of these patients. The mainstay of treatment is conservative management with physical therapy, anti-inflammatory medications, muscle relaxants, and correction of biomechanical abnormalities. However, in recalcitrant cases, a piriformis injection of anesthetic and/or corticosteroids may be considered. Because of its small size, proximity to neurovascular structures, and deep location, the piriformis muscle is often injected with the use of commuted tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), fluoroscopy, electrical stimulators, or electromyography (EMG). Numerous techniques have been proposed using one or a combination of the above modalities. However, application of these techniques is limited by unavailability of CT, MRI, and EMG equipment as well as a paucity of trained physicians in US-guided procedures in many pain treatment centers throughout the United States. Fluoroscopy, however, is more widely available in this setting. This study utilized a cadaveric specimen to confirm proper needle placement for piriformis or peri-sciatic injection utilizing the previously documented landmarks for fluoroscopic guidance as described by Betts. An anteroposterior of the pelvis with inclusion of the acetabular region of the hip and the inferior aspect of the sacroiliac joint was obtained. The most superior-lateral aspect of the acetabulum and the inferior aspect of the sacroiliac joint were identified. A marker was placed one-third of the distance from the acetabular location to the inferior sacroiliac joint, indicating the target location. A 22-gauge, 3.5-inch spinal needle was directed through the gluteal muscles to the target location using intermittent fluoroscopic guidance. The posterior ileum was contacted and the needle was withdrawn 1 -2 mm. This approach found the needle within the piriformis muscle belly 2 -3 cm lateral to sciatic nerve. The present study was the first study, to our knowledge, that has confirmed the intramuscular position of the needle within the piriformis muscle of a cadaveric specimen using these anatomic landmarks and fluoroscopic guidance.

Evidence-informed management of chronic low back pain with adjunctive analgesics.

The management of chronic low back pain (CLBP) has proven very challenging in North America, as evidenced by its mounting socioeconomic burden. Choosing among available nonsurgical therapies can be overwhelming for many stakeholders, including patients, health providers, policy makers, and third-party payers. Although all parties share a common goal and wish to use limited health-care resources to support interventions most likely to result in clinically meaningful improvements, there is often uncertainty about the most appropriate intervention for a particular patient. To help understand and evaluate the various commonly used nonsurgical approaches to CLBP, the North American Spine Society has sponsored this special focus issue of The Spine Journal, titled Evidence-Informed Management of Chronic Low Back Pain Without Surgery. Articles in this special focus issue were contributed by leading spine practitioners and researchers, who were invited to summarize the best available evidence for a particular intervention and encouraged to make this information accessible to nonexperts. Each of the articles contains five sections (description, theory, evidence of efficacy, harms, and summary) with common subheadings to facilitate comparison across the 24 different interventions profiled in this special focus issue, blending narrative and systematic review methodology as deemed appropriate by the authors. It is hoped that articles in this special focus issue will be informative and aid in decision making for the many stakeholders evaluating nonsurgical interventions for CLBP.