Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy.

Background and Objectives: Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis. Methods: Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis. Results: Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ10 levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle. Discussion: This report describes a new neurologic phenotype of COQ7-related primary CoQ10 deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ10 deficiency previously reported in the literature.

Supplemented phase diagrams for vitrification CPA cocktails: DP6, VS55 and M22.

DP6, VS55 and M22 are the most commonly used cryoprotective agent (CPA) cocktails for vitrification experiments in tissues and organs. However, complete phase diagrams for the three CPAs are often unavailable or incomplete (only available for full strength CPAs) thereby hampering optimization of vitrification and rewarming procedures. In this paper, we used differential scanning calorimetry (DSC) to measure the transition temperatures including heterogeneous nucleation temperatures (Thet), glass transition temperatures (Tg), rewarming phase crystallization (devitrification and/or recrystallization) temperatures (Td) and melting temperatures (Tm) while cooling or warming the CPA sample at 5 °C/min and plotted the obtained transition temperatures for different concentrations of CPAs into the phase diagrams. We also used cryomicroscopy cooling or warming the sample at the same rate to record the ice crystallization during the whole process, and we presented the cryomicroscopic images at the transition temperatures, which agreed with the DSC presented phenomena.

A guideline to frame stressor effects in freshwater ecosystems.

Environmental policies fall short in protecting freshwater ecosystems, which are heavily threatened by human pressures and their associated stressors. One reason is that stressor effects depend on the context in which they occur and it is difficult to extrapolate patterns to predict the effect of stressors without these being contextualized in a general frame. This study aims at improving existing decision-making frameworks such as the DPSIR approach (Driver-Pressure-State-Impact-Response) or ERA (Environmental Risk Assessment) in the context of stressors. Here, we delve into stressor-impact relationships in freshwater ecosystems and develop a guideline which includes key characteristics such as stressor type, stressor duration, location, the natural levels of environmental variables to which each ecosystem is used to, among others. This guideline is intended to be useful in a wide range of ecosystem conditions and stressors. Incorporating these guidelines may favor the comparability of scientific results and may lead to a substantial advancement in the efficacy of diagnosis and predictive approaches of impacts.

Simultaneous Eulerian-Lagrangian velocity measurements of particulate pipe flow in transitional regime.

We present a unique pipe flow rig capable of simultaneous particle tracking and flow velocity measurements in a dilute, neutrally buoyant particulate pipe flow in regimes of transition to turbulence. The flow consists of solid glass spheres for the disperse phase and a density-matching fluid for the carrier phase. The measurements are conducted using a bespoke, combined two-dimensional particle image velocimetry and particle tracking velocimetry technique. The technique takes advantage of a phase discrimination approach that involves separating the disperse and carrier phases based on their respective image characteristics. Our results show that the rig and the technique it implements can effectively be employed to study transitional particulate pipe flows at dilute concentrations.

Renal medullary carcinoma and its association with sickle cell trait: a case report and literature review.

Renal medullary carcinoma (rmc) is a rare and aggressive renal malignancy that usually presents at an advanced stage, has a poor prognosis, and is associated with sickle cell trait. We present a case of rmc including radiologic and pathology findings, treatment, and outcome. A review of the literature is also presented, with an emphasis on the association of rmc with sickle cell trait, which was an unknown diagnosis in our patient preoperatively.

Bilateral Vocal Cord Paralysis and Cervicolumbar Radiculopathy as the Presenting Paraneoplastic Manifestations of Small Cell Lung Cancer: A Case Report and Literature Review.

Introduction. Bilateral vocal cord paralysis (BVCP) is a potential medical emergency. The Otolaryngologist plays a crucial role in the diagnosis and management of BVCP and must consider a broad differential diagnosis. We present a rare case of BVCP secondary to anti-Hu paraneoplastic syndrome. Case Presentation. A 58-year-old female presented to an Otolaryngology clinic with a history of progressive hoarseness and dysphagia. Flexible nasolaryngoscopy demonstrated BVCP. Cross-sectional imaging of the brain and vagus nerves was negative. An antiparaneoplastic antibody panel was positive for anti-Hu antibodies. This led to an endobronchial biopsy of a paratracheal lymph node, which confirmed the diagnosis of small cell lung cancer. Conclusion. Paraneoplastic neuropathy is a rare cause of BVCP and should be considered when more common pathologies are ruled out. This is the second reported case of BVCP as a presenting symptom of paraneoplastic syndrome secondary to small cell lung cancer.

Subcutaneous Immunoglobulin Therapy in the Chronic Management of Myasthenia Gravis: A Retrospective Cohort Study.

BACKGROUND: Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a practical and effective option in chronic management of MG. We analyzed clinical outcomes and patient satisfaction in nine cases of chronic disabling MG who were either transitioned to, or started de novo on SCIg. METHODS AND FINDINGS: This was a retrospective cohort study for the period of 2015-2016, with a mean follow-up period of 6.8 months after initiation of SCIg. All patients with MG treated with SCIg at the Ottawa Hospital, a large Canadian tertiary hospital with subspecialty expertise in neuromuscular disorders were included, regardless of MG severity, clinical subtype and antibody status. The primary outcome was MG disease activity after SCIg initiation. This outcome was measured by 1) the Myasthenia Gravis Foundation of America (MGFA) clinical classification, and 2) subjective scales of disease activity including the Myasthenia Gravis activities of daily living profile (MG-ADL), Myasthenia Gravis Quality-of-life (MG-QOL 15), Visual Analog (VA) satisfaction scale. We also assessed any requirement for emergency department visits or hospitalizations. Safety outcomes included any SCIg related complication. All patients were stable or improved for MGFA class after SCIg initiation. Statistically significant improvements were documented in the MG-ADL, MG-QOL and VAS scales. There were no exacerbations after switching therapy and no severe SCIg related complications. CONCLUSIONS: SCIg may be a beneficial therapy in the chronic management of MG, with favorable clinical outcome and patient satisfaction results.

Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

IMPORTANCE: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG. OBJECTIVE: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies. INTERVENTIONS: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution. MAIN OUTCOMES AND MEASURES: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications. RESULTS: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths. CONCLUSIONS AND RELEVANCE: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.

An optimization approach for analysing nonlinear stability with transition to turbulence in fluids as an exemplar.

This article introduces and reviews recent work using a simple optimization technique for analysing the nonlinear stability of a state in a dynamical system. The technique can be used to identify the most efficient way to disturb a system such that it transits from one stable state to another. The key idea is introduced within the framework of a finite-dimensional set of ordinary differential equations (ODEs) and then illustrated for a very simple system of two ODEs which possesses bistability. Then the transition to turbulence problem in fluid mechanics is used to show how the technique can be formulated for a spatially-extended system described by a set of partial differential equations (the well-known Navier-Stokes equations). Within that context, the optimization technique bridges the gap between (linear) optimal perturbation theory and the (nonlinear) dynamical systems approach to fluid flows. The fact that the technique has now been recently shown to work in this very high dimensional setting augurs well for its utility in other physical systems.

Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program.

IMPORTANCE: Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease. OBSERVATIONS: Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure. CONCLUSIONS AND RELEVANCE: Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.

A nine-year review of medicolegal claims in neurosurgery.

INTRODUCTION: Neurosurgery remains among the highest malpractice risk specialties. This study aimed to identify areas in neurosurgery associated with litigation, attendant causes and costs. METHODS: Retrospective analysis was conducted of 42 closed litigation cases treated by neurosurgeons at one hospital between March 2004 and March 2013. Data included clinical event, timing and reason for claim, operative course and legal outcome. RESULTS: Twenty-nine claims were defended out of court and twelve were settled out of court. One case required court attendance and was defended. Of the 42 claims, 28, 13 and 1 related to spinal (0.3% of caseload), cranial (0.1% of caseload) and peripheral nerve (0.07% of caseload) surgery respectively. The most common causes of claims were faulty surgical technique (43%), delayed diagnosis/misdiagnosis (17%), lack of information (14%) and delayed treatment (12%), with a likelihood of success of 39%, 29%, 17% and 20% respectively. The highest median payouts were for claims against faulty surgical technique (£230,000) and delayed diagnosis/misdiagnosis (£212,650). The mean delay between clinical event and claim was 664 days. CONCLUSIONS: Spinal surgery carries the highest litigation risk versus cranial and peripheral nerve surgery. Claims are most commonly against faulty surgical technique and delayed diagnosis/misdiagnosis, which have the highest success rates and payouts. In spinal surgery, the most common cause of claims is faulty surgical technique. In cranial surgery, the most common cause is lack of information. Claims may occur years after the clinical event, necessitating thorough contemporaneous documentation for adequate future defence. We emphasise thorough patient consultation and meticulous surgical technique to minimise litigation in neurosurgical practice.

Nonadditive effects of leaf litter species diversity on breakdown dynamics in a detritus-based stream.

Since species loss is predicted to be nonrandom, it is important to understand the manner in which those species that we anticipate losing interact with other species to affect ecosystem function. We tested whether litter species diversity, measured as richness and composition, affects breakdown dynamics in a detritus-based stream. Using full-factorial analyses of single- and mixed-species leaf packs (15 possible combinations of four dominant litter species; red maple [Acer rubrum], tulip poplar [Liriodendron tulipifera], chestnut oak [Quercus prinus], and rhododendron [Rhododendron maximum]), we tested for single-species presence/absence (additive) or species interaction (nonadditive) effects on leaf pack breakdown rates, changes in litter chemistry, and microbial and macroinvertebrate biomass. Overall, we found significant nonadditive effects of litter species diversity on leaf pack breakdown rates, which were explained both by richness and composition. Leaf packs containing higher litter species richness had faster breakdown rates, and antagonistic effects of litter species composition were observed when any two or three of the four litter species were mixed. Less-consistent results were obtained with respect to changes in litter chemistry and microbial and macroinvertebrate biomass. Our results suggest that loss of litter species diversity will decrease species interactions involved in regulating ecosystem function. To that end, loss of species such as eastern hemlock (Tsuga canadensis) accompanied by predicted changes in riparian tree species composition in the southeastern United States could have nonadditive effects on litter breakdown at the landscape scale.

Optimising non-viral gene delivery in a tumour spheroid model.

BACKGROUND: Our current understanding of how the unique tumour microenvironment influences the efficacy of gene delivery is limited. The current investigation systematically examines the efficiency of several non-viral gene transfer agents to transfect multicellular tumour spheroids (MCTS), an in vitro model that displays a faithful three-dimensional (3D) representation of solid tumour tissue. METHODS: Using a luciferase reporter assay, gene transfer to MCTS was optimised for 22 kDa linear and 25 kDa branched polyethyleneimine (PEI), the cationic lipids Lipofectamine(trade mark) and DCChol : DOPE, and the physical approach of tissue electroporation. Confocal microscopy was used to take optical tissue slices to identify the tissue localisation of green fluorescent protein (GFP) reporter gene expression and the distribution of fluorescently labelled complexes. A MCTS model of quiescent tumour regions was used to establish the influence of cellular proliferation status on gene transfer efficiency. RESULTS: Of the polyplexes tested, 22 kDa linear PEI provided optimal gene delivery, with gene expression peaking at 46 h. Despite being the optimal vector tested, PEI-mediated transfection was limited to cells at the MCTS periphery. Using fluorescent PEI, it was found that complexes could only penetrate the outer 3-5 proliferating cell layers of the MCTS, sparing the deeper quiescent cells. Gene delivery in an MCTS model comprised entirely of quiescent cells demonstrated that in addition to being inaccessible to the vector, quiescent tumour regions are inherently less susceptible to PEI-mediated transfection than proliferating regions. This 'resistance' to transfection observed in quiescent cells was overcome through the use of electroporation. Despite the improved efficacy of electroporation in quiescent tissue, the gene expression was still confined to the outer regions of MCTS. The results suggest that limited access to central regions of an MCTS remain a significant barrier to gene delivery. CONCLUSIONS: This data provides new insights into tumour-specific factors affecting non-viral gene transfer and highlights the difficulties in delivering genes to avascular tumour regions. The MCTS model is a useful system for the initial screening of future gene therapy strategies for solid tumours.

Ecological forecasts: an emerging imperative.

Planning and decision-making can be improved by access to reliable forecasts of ecosystem state, ecosystem services, and natural capital. Availability of new data sets, together with progress in computation and statistics, will increase our ability to forecast ecosystem change. An agenda that would lead toward a capacity to produce, evaluate, and communicate forecasts of critical ecosystem services requires a process that engages scientists and decision-makers. Interdisciplinary linkages are necessary because of the climate and societal controls on ecosystems, the feedbacks involving social change, and the decision-making relevance of forecasts.

A stream visual assessment protocol (SVAP) for riparian landowners.

A user-friendly Stream Visual Assessment Protocol (SVAP) was recently developed in a joint effort by the Natural Resources Conservation Service (NRCS) of the U.S. Department of Agriculture and the University of Georgia. SVAP was designed to be an introductory screening-level assessment method for people unfamiliar with stream assessments. It was designed for use by NRCS field staff who work with agricultural landowners. NRCS is in a key position to influence conservation practices since the organization works with private stakeholders, maintaining more than 2000 field offices throughout the U.S. with a central office in each state. The SVAP measures a maximum of 15 elements and is based on visual inspection of the physical and biological characteristics of instream and riparian environments. Each element is assigned a numerical score relative to reference conditions and an overall score for the stream reach is calculated. A qualitative description of the stream reach is made based on overall numerical score. While SVAP is not intended to replace more robust stream assessment protocols, it provides quick and reliable information for use in NRCS farm assistance programs. It is also an educational tool through which landowners can learn about conservation of aquatic resources. An abridged copy of SVAP is attached as an appendix to this article and the complete document can be found on the web at http://www.ncg.nrcs.usda.gov/tech_notes.html.

Prevention of bronchiolitis.

This review evaluates the current situation and long-term prospects for containment of human respiratory syncytial virus (HRSV) infection and bronchiolitis in infancy. The biology and immunopathology of HRSV infection are complex. Initial attempts to control HRSV infection using a conventional formalin-inactivated vaccine had the unexpected outcome that the disease was potentiated in some vaccinees experiencing natural HRSV infection at a later date. Much effort has been devoted to defining the nature of protective immunity, and several candidate sub-unit and live attenuated vaccines have been developed by empirical and semi-empirical routes, and most recently by reverse genetics. None has yet received approval for clinical use, and attention has switched from active to passive immunization. Both concentrated human immune globulin (RespiGam) and a humanized monoclonal antibody (Palivizumab) have been approved for clinical use. On grounds of cost-effectiveness these treatments are recommended only for treatment of high-risk infants. An effective antiviral is not yet available.