Role of Functional neurosurgery in Improving Patient Outcomes in Epilepsy, Movement Disorders, and Chronic Pain.

Functional neurosurgery encompasses surgical procedures geared towards treating movement disorders (such as Parkinson's disease and essential tremor), drug-resistant epilepsy, and various types of pain disorders. It is one of the most rapidly expanding fields within neurosurgery and utilizes both traditional open surgical methods such as open temporal lobectomy for epilepsy as well as neuromodulation-based treatments such as implanting brain or nerve stimulation devices. This review outlines the role functional neurosurgery plays in treatment of epilepsy, movement disorders, and pain, and how it is being implemented at the University of Missouri by the Department of Neurosurgery.

A Comparison of Precision and Safety using Three Recognized Ultrasound-Guided Approaches to Cervical Medial Branch Blocks: A Cadaver Study.

BACKGROUND: Ultrasound (US) guidance is widely used for needle positioning for cervical medial branch blocks (CMBB) and radiofrequency ablation, however, limited research is available comparing different approaches. OBJECTIVE: We aimed to assess the accuracy and safety of 3 different US-guided approaches for CMBB. STUDY DESIGN: A cadaveric study divided into ultrasound-guided needle placement and fluoroscopy evaluation stages. SETTING: Department of Pathology, Forensic, and Insurance Medicine, Semmelweis University. METHODS: Sonographically guided third occipital nerve (TON), C3, C4, C5 and C6 medial branch injections and radiology evaluations were performed.The 3 approaches compared were:1. ES (published by Eichenberger-Siegenthaler): US probe in the coronal plane to visualize the cervical articular pillars, needle approach out of the plane, from anterior to posterior.2. Fi (published by Finlayson): US probe in the transverse plane to visualize a cervical articular pillar and its lamina, needle approach in the plane, from posterior to anterior.3. FiM (Modified Finlayson approach): Needles are placed as in Fi, but then adjusted with a coronal view of the cervical articular pillars.Fluoroscopy images were taken and later evaluated, for "crude", "high precision" and "dangerous" placement. RESULTS: One hundred and fifty-five needle placements were assessed (10 were excluded, as no anterior-posterior fluoroscopy images were saved). Interobserver agreement on position of needle placement between the 5 observers was very high; the Fleiss' Kappa was 0.921. For crude placement, no significant differences were identified between various approaches; (77.6%, 79.5%, and 75.6% for the ES, Fi, and FiM respectively). However, for placement in predefined high-precision zones, ES resulted in significantly more success (ES: 42.9%, Fi: 22.7%, and FiM: 24.4%, P = 0.032). Fi and FiM resulted in no dangerous placements, while ES led to the potential compromise of the exiting nerve root and vertebral artery on three occasions. In 10% of the placements, the levels were identified wrongly, with no difference between the various approaches. LIMITATIONS: Feedback from a live patient, may prevent some existing nerve root injections, unlike in a cadaver. Though a higher number of needles were placed in this study than in most available publications, the number is still low at each individual medial branch level. CONCLUSION: Fi proved safer than ES. Fi was equally successful in targeting the articular pillar, however, ES proved the most successful in placing the needle in the center of the articular pillar. Adding another, (coronal) US view to check needle position in FiM did not improve safety or precision. Identifying CMB levels with the US is challenging with all approaches, therefore we still recommend using fluoroscopy for level identification. While there were pros and cons with either procedure, the efficacy findings of previous papers were not replicated on elderly cadavers with arthritic necks.

A comparison of frequency and magnitude of head impacts between Pee Wee And Bantam youth ice hockey.

The purpose of this research was to compare the frequency and magnitude of head impact events between Pee Wee and Bantam ice hockey players. Videos of Pee Wee and Bantam boys' ice hockey were analysed to determine the frequency and type of head impact events. The head impact events were then reconstructed in the laboratory using physical and finite element models to determine the magnitude of strain in the brain tissues. The results showed that Pee Wee boys experienced more head impacts from elbows and boards, while Bantam players had more head impacts to the glass. Pee Wee and Bantam players experienced similar frequency and magnitudes of very low, low, and medium and above (med+) levels of strain to the brain. This research suggests to ice hockey leagues and coaches that to reduce the incidence of these levels of brain trauma, consideration must be given to either reducing the level of contact along the boards or the removal of body checking. In addition, companies who innovate in ice hockey should develop protective devices and equipment strategies that aim to reduce the risk of head injury from shoulder and glass impacts for Bantam players.

Intra-Articular Laser Therapy May Be a Feasible Option in Treating Knee Osteoarthritis in Elderly Patients.

Knee osteoarthritis (OA) is a common problem in elderly patients. They are often troubled with altered knee function, such as pain and weakness. However, not all these patients are able to receive autologous platelet-rich plasma (PRP) injections as they may be taking antiplatelet or anticoagulant medications. Their physical condition may not allow them to receive total knee replacement surgery as well. Long-term oral intake of nonsteroidal anti-inflammatory drugs may be detrimental to the gastrointestinal tract. As a result, it is crucial to discover new treatment options that can alleviate painful knee symptoms in elderly knee OA patients. In this study, 19 elderly patients diagnosed with moderate degree of knee OA as well as suprapatellar bursitis were recruited. They received low-level laser therapy (LLLT) to their affected knees. Under ultrasound guidance, flexible fiber optic wire was inserted intra-articularly into the knee joint. Red laser followed by infrared irradiation was performed once every 2 weeks for a total of 3 times. The Lequesne index for knee OA and the volume of suprapatellar synovial fluid (SF) were measured. SF proteomic analyses were also performed up to a period of 6 months. The results revealed that after 3 LLLT, the Lequesne index significantly decreased, signifying improvement in the knee joint functional status. The volume of suprapatellar SF and SF proteins associated with inflammation also decreased significantly in the SF. These findings lasted up to a period of at least 3 months. Therefore, LLLT may be considered as a feasible option in treating elderly patients with knee OA who are not suitable for surgical interventions or intra-articular PRP injections.

A Conservative Approach to the Treatment of a Rare Case of Cervical Spine Double Expressor Diffuse Large B-cell Lymphoma: A Case Report.

Non-Hodgkin's lymphomas are a group of lymphoid neoplasms, with diffuse large B-cell lymphoma (DLBCL) being the most common subtype. Genetic alterations involving c-MYC, BCL-2, and BCL-6 have been implicated in the pathogenesis of subtypes of DLBCL with poor prognostic implications. This case report demonstrates a retropharyngeal mass with extension through the bilateral neuroforamina into the epidural space and posterior elements of the cervical spine (C2-C3), for which biopsy revealed diffuse large B-cell lymphoma. Here we present a unique case as it provides a solution for the dilemma on how to treat a patient with a known prior malignancy (gastrointestinal [GI] melanoma) with a retropharyngeal mass with epidural extension (dumbbell-shaped tumor) with an inconclusive initial CT-guided needle-core biopsy. A CT-guided biopsy only yielded that the mass was neoplasm; we had a choice between attempting gross total resection of the mass or open biopsy. Attempting gross total resection would have entailed an anterior approach (transoral with possible odontoidectomy or endoscopic endonasal with possible odontoidectomy) along with posterior instrumentation and fusion from occiput to C3, which is a rather morbid procedure that would subject the patient to a decreased quality of life as well as risks of vascular injury, dysphagia, and infection. We elected to perform an open biopsy of the epidural component of the mass through a decompressive laminectomy, which allowed for decompression of the spinal cord as well as a sampling of the mass. This provided treatment for possible increasing epidural compression from the mass, as well as diagnostic tissue. A multidisciplinary team discussed the case and developed a treatment plan for the patient with systemic and intrathecal chemotherapy in combination with radiotherapy.

Mucin O-glycans suppress quorum-sensing pathways and genetic transformation in Streptococcus mutans.

Mucus barriers accommodate trillions of microorganisms throughout the human body while preventing pathogenic colonization1. In the oral cavity, saliva containing the mucins MUC5B and MUC7 forms a pellicle that coats the soft tissue and teeth to prevent infection by oral pathogens, such as Streptococcus mutans2. Salivary mucin can interact directly with microorganisms through selective agglutinin activity and bacterial binding2-4, but the extent and basis of the protective functions of saliva are not well understood. Here, using an ex vivo saliva model, we identify that MUC5B is an inhibitor of microbial virulence. Specifically, we find that natively purified MUC5B downregulates the expression of quorum-sensing pathways activated by the competence stimulating peptide and the sigX-inducing peptide5. Furthermore, MUC5B prevents the acquisition of antimicrobial resistance through natural genetic transformation, a process that is activated through quorum sensing. Our data reveal that the effect of MUC5B is mediated by its associated O-linked glycans, which are potent suppressors of quorum sensing and genetic transformation, even when removed from the mucin backbone. Together, these results present mucin O-glycans as a host strategy for domesticating potentially pathogenic microorganisms without killing them.

Identification and characterization of co-purifying CHO host cell proteins in monoclonal antibody purification process.

Host cell proteins (HCPs) are process-related impurities derived from the host organism such as Chinese hamster ovary (CHO) cells used for the production of therapeutic mAbs in biopharmaceuticals and potentially pose a risk to patient safety and product efficacy. A number of HCPs have been reported as exceptionally difficult to remove and persist across downstream purification operations into final drug product because they exhibit association with mAbs. Therefore, understanding of HCP impurities and the mAb itself will provide insights into the rational design of efficient downstream process. The aim of this work is to understand mAb interaction with HCPs and identify co-purified HCP subpopulations using two different approaches: (1) Incubation of purified mAb with harvest cell culture fluid (HCCF) from mock-transfected CHO cells (null HCCF) or (2) Immobilization of mAb onto chromatography media followed by incubation with null HCCF. CHO HCP ELISA was used to semi-quantitatively measure the levels of total HCPs. Orthogonal techniques including 2-DE and LC-MS/MS were applied to detect variations in CHO HCP profiles and species. The HCP contents in protein A product pools were significantly higher compared to that in control sample without mAb spiked in and variable HCP levels shown in three different protein A product pools. The majority of HCPs identified by LC-MS/MS in the three protein A product pool showed overlap with the HCP identified in eluate pools from the column immobilized with three different mAbs. The interacting HCPs associated with mAbs were largely involved in catalytic activity. Both approaches demonstrated mAbs bind a common set of HCPs as well as HCPs unique to the mAb.

Research Needs Assessment for Children With Obstructive Sleep Apnea Undergoing Diagnostic or Surgical Procedures.

Recent concerns have been raised about the quality and safety of adenotonsillectomy, a common surgery performed to treat obstructive sleep apnea (OSA) in children. OSA is a risk factor for opioid-related perioperative respiratory complications including those associated with anoxic brain injury or death. Our objective was to identify controversial issues related to the care of children with OSA. A standardized Delphi consensus technique involving an interdisciplinary group of 24 pediatric OSA experts identified 3 key issues: "postoperative disposition, preoperative screening, and pain management." These topics are prime candidates for future systematic reviews and will guide Society of Anesthesia and Sleep Medicine-related research endeavors.

Charge Influences Substrate Recognition and Self-Assembly of Hydrophobic FG Sequences.

The nuclear pore complex controls the passage of molecules via hydrophobic phenylalanine-glycine (FG) domains on nucleoporins. Such FG domains consist of repeating units of FxFG, FG, or GLFG sequences, many of which are interspersed with highly charged amino acid sequences. Despite the high density of charge in certain FG domains, if and how charge influences FG-domain self-assembly and selective binding of nuclear transport receptors is largely unexplored. Using rationally designed short peptide sequences, we determined that the charge type and identity of amino acids surrounding FG sequences impact the structure and selectivity of FG-based gels. Moreover, we showed that spatial localization of the charged amino acids with respect to the FG sequence determines the degree to which charge influences hydrophobic interactions. Taken together, our study highlights that charge type and placement of amino acids regulate FG-sequence function and are important considerations when studying the mechanism of nuclear pore complex transport in vivo.

Pediatric concussion: biomechanical differences between outcomes of transient and persistent (> 4 weeks) postconcussion symptoms.

OBJECTIVE Currently, little is known about the biomechanics of head impact for concussion in youths (ages 5 to 18 years). Even less is known about the biomechanical characteristics and variables related to head impacts that may be useful in differentiating between transient and persistent postconcussion symptoms in a youth population. The purpose of this research was to examine the differences in biomechanics of youth head impact for transient postconcussion symptoms (TPCSs) and persistent postconcussion symptoms (PPCSs) by using data from a hospital population. METHODS In a laboratory setting and using physical, computational, and finite element models, the authors reconstructed falling events in a large cohort of patients who had sustained a brain injury that resulted in transient or persistent postconcussion symptoms. The falling events and resulting concussions for the TPCS and PPCS patient groups were analyzed in terms of force, energy, peak resultant linear and rotational accelerations, and maximum principal strain in the gray and white matter of the brain, as well as measurements of cumulative strain damage. RESULTS The results indicated that there were no significant differences between the groups for any of the variables analyzed. CONCLUSIONS With methods derived for use in an adult population, the magnitudes of peak linear acceleration for the youth data set were determined to be above the 50% risk of injury. The youth data set showed higher brain tissue strain responses for lower energy and impact velocities than measured in adults, suggesting that youths are at higher risk of concussive injury at lower event severities. A trend shown by some variables indicated that larger magnitudes of response were associated with PPCSs, but no single measurement variable consistently differentiated between the TPCS and PPCS groups. It is possible that using the biomechanics of head and brain responses to predict a subjective symptom load may not be appropriate. To enhance future biomechanical analyses, further investigations should include the use of quantifiable measures of brain injury linked to clinical outcomes and possible confounding factors such as history of brain injury and patient predisposition.

MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice.

BACKGROUND: By the time clinical symptoms of Alzheimer's disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice. METHODS: Starting at 3months of age, mice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2-18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9months of age. RESULTS: EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species. CONCLUSIONS: These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.

Increased tauopathy drives microglia-mediated clearance of beta-amyloid.

Alzheimer disease is characterized by the accumulation of ß-amyloid (Aß) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aß deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aß accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aß plaque load and insoluble Aß species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aß and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aß and that tau-induced changes in microglial activation state can promote the clearance of Aß.

Structure and expression of propanediol utilization microcompartments in Acetonema longum.

Numerous bacteria assemble proteinaceous microcompartments to isolate certain biochemical reactions within the cytoplasm. The assembly, structure, contents, and functions of these microcompartments are active areas of research. Here we show that the Gram-negative sporulating bacterium Acetonema longum synthesizes propanediol utilization (PDU) microcompartments when starved or grown on 1,2-propanediol (1,2-PD) or rhamnose. Electron cryotomography of intact cells revealed that PDU microcompartments are highly irregular in shape and size, similar to purified PDU microcompartments from Salmonella enterica serovar Typhimurium LT2 that were imaged previously. Homology searches identified a 20-gene operon in A. longum that contains most of the structural, enzymatic, and regulatory genes thought to be involved in PDU microcompartment assembly and function. Transcriptional data on PduU and PduC, which are major structural and enzymatic proteins, respectively, as well as imaging, indicate that PDU microcompartment synthesis is induced within 24 h of growth on 1,2-PD and after 48 h of growth on rhamnose.

Concise review: Can stem cells be used to treat or model Alzheimer's disease?

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the U.S. alone. AD patients suffer from progressive neurodegeneration that gradually impairs their memory, ability to learn, and carry out daily activities. Unfortunately, current therapies for AD are largely palliative and several promising drug candidates have failed in recent clinical trials. There is therefore an urgent need to improve our understanding of AD pathogenesis, create innovative and predictive models, and develop new and effective therapies. In this review, we will discuss the potential of stem cells to aid in these challenging endeavors. Because of the widespread nature of AD pathology, cell-replacement strategies have been viewed as an incredibly challenging and unlikely treatment approach. Yet recent work shows that transplantation of neural stem cells (NSCs) can improve cognition, reduce neuronal loss, and enhance synaptic plasticity in animal models of AD. Interestingly, the mechanisms that mediate these effects appear to involve neuroprotection and trophic support rather than neuronal replacement. Stem cells may also offer a powerful new approach to model and study AD. Patient-derived induced pluripotent stem cells, for example, may help to advance our understanding of disease mechanisms. Likewise, studies of human embryonic and NSCs are helping to decipher the normal functions of AD-related genes; revealing intriguing roles in neural development.