The Erector Spinae Plane Block as Novel Therapy for Renal Colic: A Case Series.

We present a 10-patient case series supporting the use of the erector spinae plane block (ESPB) as a novel approach for the treatment of acute pain from renal colic. An in-plane needle approach was used with either transverse or longitudinal orientation of the ultrasound probe on the affected side, in either seated or prone patient position. These cases showed significant improvement in patient reported pain; suggesting that the ESPB can be used safely and effectively for either primary or adjunctive treatment of acute pain due to renal colic in the emergency department.

SKOPE-Study of Ketorolac vs Opioid for Pain after Endoscopy: A Double-Blinded Randomized Control Trial in Patients Undergoing Ureteroscopy.

PURPOSE: Pain is the leading cause of unplanned emergency department visits and readmissions after ureteroscopy, making postoperative analgesic stewardship a priority given the current opioid epidemic. We conducted a double-blinded, randomized controlled trial, with noninferiority design, comparing nonsteroidal anti-inflammatory drugs to opiates for postoperative pain control in patients undergoing ureteroscopy for urolithiasis. MATERIALS AND METHODS: Patients were randomized and blinded to either oxycodone (5 mg) or ketorolac (10 mg), taken as needed, with 3 nonblinded oxycodone rescue pills for breakthrough pain. Primary study outcome was visual analogue scale pain score on postoperative days 1-5. Secondary outcomes included medication utilization, side effects, and Ureteral Stent Symptom Questionnaire scores. RESULTS: A total of 81 patients were included (43 oxycodone, 38 ketorolac). The 2 groups had comparable patient, stone, and perioperative characteristics. No differences were found in postoperative pain scores, study medication or rescue pill usage, or side effects. Higher maximum pain scores on days 1-5 (p <0.05) and higher questionnaire score (28.1 vs 21.7, p=0.045) correlated with analgesic usage, irrespective of treatment group. Patients receiving ketorolac reported significantly fewer days confined to bed (mean±SD 1.3±1.3 vs 2.3±2.6, p=0.02). There was no difference in unscheduled postoperative physician encounters. CONCLUSIONS: This is the first double-blinded randomized controlled trial comparing nonsteroidal anti-inflammatory drugs and opiates post-ureteroscopy, and demonstrates noninferiority of nonsteroidal anti-inflammatory drugs in pain control with similar efficacy, safety profile, physician contact and notably, earlier convalescence compared to the opioid group. This provides strong evidence against routine opioid use post-ureteroscopy, justifying continued investigation into reducing postoperative opiate prescriptions.

Peripheral nerve injury and myelination: Potential therapeutic strategies.

Traumatic peripheral nerve injury represents a major clinical and public health problem that often leads to significant functional impairment and permanent disability. Despite modern diagnostic procedures and advanced microsurgical techniques, functional recovery after peripheral nerve repair is often unsatisfactory. Therefore, there is an unmet need for new therapeutic or adjunctive strategies to promote the functional recovery in nerve injury patients. In contrast to the central nervous system, Schwann cells in the peripheral nervous system play a pivotal role in several aspects of nerve repair such as degeneration, remyelination, and axonal growth. Several non-surgical approaches, including pharmacological, electrical, cell-based, and laser therapies, have been employed to promote myelination and enhance functional recovery after peripheral nerve injury. This review will succinctly discuss the potential therapeutic strategies in the context of myelination following peripheral neurotrauma.

Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury.

Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC +/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC +/- animals had significantly reduced remyelination during recovery. In addition, the microglial phagocytic response and elevation of Trem2, both necessary for clearing damaged myelin, were markedly reduced in GALC +/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused by mutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a single mutant GALC allele, suggesting such carriers may have increased vulnerability to myelin damage following injury or disease due to inefficient myelin debris clearance. We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome-wide association studies may contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms.

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity.

Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD.

4-Aminopyridine attenuates muscle atrophy after sciatic nerve crush injury in mice.

INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although muscle atrophy occurs very rapidly after nerve injury, the effect of 4-AP on muscle atrophy and intrinsic muscle contractile function is largely unknown. METHODS: Mice were assigned to sciatic nerve crush injury and no-injury groups and were followed for 3, 7, and 14 days with/without 4-AP or saline treatment. Morphological, functional, and transcriptional properties of skeletal muscle were assessed. RESULTS: In addition to improving in vivo function, 4-AP significantly reduced muscle atrophy with increased muscle fiber diameter and contractile force. Reduced muscle atrophy was associated with attenuated expression of atrophy-related genes and increased expression of proliferating stem cells. DISCUSSION: These findings provide new insights into the potential therapeutic benefits of 4-AP against nerve injury-induced muscle atrophy and dysfunction. Muscle Nerve 60: 192-201, 2019.

Rediscovery of Otto Frank's contribution to science.

In the late 19th century, German physiologist Otto Frank (1865-1944) embarked on a near life-long research program of laying down the mathematical, methodological, and theoretical foundations in order to understand and define the performance of the heart and circulatory system in all their complexity. The existence of the "Frank-Starling law" testifies to this. Two of his seminal publications have been translated into English previously, introducing Frank's research on the dynamics of the heart and the arterial pulse to a wider audience. It is likely that there are a host of other comparable achievements and publications of Frank that are still unknown to the international scientific (cardiological and physiological) community. However, their influence can still be felt and seen in modern cardiology and cardio-physiology, such as in the development of modern interactive simulating and teaching programs. We have translated and commented on ten of these papers, which can be read in parallel with the German originals. These publications show a wealth of theoretical assumptions and projections regarding the importance of the sarcomere, the development of models of contraction, thermo-dynamical considerations for muscular activity, differences between cardiac and skeletal muscles, problems related to methodology and measurement, and the first pressure-volume diagram (published 120 years ago). These topics were envisioned by Frank long before they became a focus of subsequent modern research. Nowadays, frequent measurements of pressure-volume relationships are made in research using the pressure-volume conductance catheter technique. In commenting Frank's scientific topics, we try to show how interconnected his thinking was, and thus how it enabled him to cover such a wide range of subjects.

A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden.

Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model. These mice recapitulate many of the characteristics of A-T seen in humans, with the notable exception of neurodegeneration. In order to study how an N-terminal mutation affects the disease phenotype, we generated an inducible Atm mutant mouse model (Atm(tm1Mmpl/tm1Mmpl), referred to as A-T [M]) predicted to express only the first 62 amino acids of Atm. Cells derived from A-T [M] mutant mice exhibited reduced cellular proliferation and an altered DNA damage response, but surprisingly, showed no evidence of an oxidative imbalance. Examination of the A-T [M] animals revealed an altered immunophenotype consistent with A-T. In contrast to mice harboring C-terminal Atm mutations that disproportionately develop thymic lymphomas, A-T [M] mice developed lymphoma at a similar rate as human A-T patients. Morphological analyses of A-T [M] cerebella revealed no substantial cellular defects, similar to other models of A-T, although mice display behavioral defects consistent with cerebellar dysfunction. Overall, these results suggest that loss of Atm is not necessarily associated with an oxidized phenotype as has been previously proposed and that loss of ATM protein is not sufficient to induce cerebellar degeneration in mice.

Erythropoietin accelerates functional recovery after moderate sciatic nerve crush injury.

INTRODUCTION: Erythropoietin (EPO) has been identified as a neuroregenerative agent. We hypothesize that it may accelerate recovery after crush injury and may vary with crush severity. METHODS: Mice were randomized to mild, moderate, or severe crush of the sciatic nerve and were treated with EPO or vehicle control after injury. The sciatic function index (SFI) was monitored over the first week. Microstructural changes were analyzed by immunofluorescence for neurofilament (NF) and myelin (P0 ), and electron microscopy was used to assess ultrastructural changes. RESULTS: In moderate crush injuries, EPO significantly improved SFI at 7 days post-injury, an effect not observed with other severity levels. Increases in the ratio of P0 to NF were observed after EPO treatment in moderate crush injuries. Electron microscopy demonstrated endothelial cell hypertrophy in the EPO group. CONCLUSIONS: EPO accelerates recovery in moderately crushed nerves, which may be through effects on myelination and vascularization. Injury severity may influence the efficacy of EPO. Muscle Nerve 56: 143-151, 2017.

Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.

Systemic Inflammatory Response Syndrome after Percutaneous Nephrolithotomy: A Randomized Single-Blind Clinical Trial Evaluating the Impact of Irrigation Pressure.

PURPOSE: We evaluated the impact of intraoperative irrigation pressures on the risk of systemic inflammatory response after percutaneous nephrolithotomy. MATERIALS AND METHODS: Between January 2014 and March 2015, 90 patients with renal stones planned for percutaneous nephrolithotomy were randomized between low (80 mm Hg) and high (200 mm Hg) irrigation pressure. Patient demographics, perioperative outcomes and systemic inflammatory response incidence rates were compared using the chi-square and Wilcoxon signed rank tests. RESULTS: Mean patient age, gender, body mass index and other perioperative outcomes were similar in both arms. High pressure irrigation was associated with a higher risk of systemic inflammatory response syndrome (46%) compared to low pressure irrigation (11%, p=0.0002). On multivariate analysis only high irrigation pressure, paraplegia or neurogenic bladder and nonquinolone perioperative medication were predictive of postoperative systemic inflammatory response syndrome. CONCLUSIONS: High pressure fluid irrigation fluid increases the risk of postoperative systemic inflammatory response syndrome after percutaneous nephrolithotomy.

Erythropoietin Enhanced Recovery After Traumatic Nerve Injury: Myelination and Localized Effects.

PURPOSE: We previously found that administration of erythropoietin (EPO) shortens the course of recovery after experimental crush injury to the mouse sciatic nerve. The course of recovery was more rapid than would be expected if EPO's effects were caused by axonal regeneration, which raised the question of whether recovery was instead the result of promoting remyelination and/or preserving myelin on injured neurons. This study tested the hypothesis that EPO has a direct and local effect on myelination in vivo and in vitro. METHODS: Animals were treated with EPO after standard calibrated sciatic nerve crush injury; immunohistochemical analysis was performed to assay for myelinated axons. Combined in vitro neuron-Schwann cell co-cultures were performed to assess EPO-mediated effects directly on myelination and putative protective effects against oxidative stress. In vivo local administration of EPO in a fibrin glue carrier was used to demonstrate early local effects of EPO treatment well in advance of possible neuroregenerative effects. RESULTS: Systemic Administration of EPO maintained more in vivo myelinated axons at the site of nerve crush injury. In vitro, EPO treatment promoted myelin formation and protected myelin from the effects of nitric oxide exposure in co-cultures of Schwann cells and dorsal root ganglion neurons. In a novel, surgically applicable local treatment using Food and Drug Administration-approved fibrin glue as a vehicle, EPO was as effective as systemic EPO administration at time points earlier than those explainable using standard models of neuroregeneration. CONCLUSIONS: In nerve crush injury, EPO may be exerting a primary influence on myelin status to promote functional recovery. CLINICAL RELEVANCE: Mixed injury to myelin and axons may allow the opportunity for the repurposing of EPO for use as a myeloprotective agent in which injuries spare a requisite number of axons to allow early functional recovery.

Cool-1-mediated inhibition of c-Cbl modulates multiple critical properties of glioblastomas, including the ability to generate tumors in vivo.

We discovered that glioblastoma (GBM) cells use Cool-1/ß-pix to inhibit normal activation of the c-Cbl ubiquitin ligase via the redox/Fyn/c-Cbl pathway and that c-Cbl inhibition is critical for GBM cell function. Restoring normal c-Cbl activity by Cool-1 knockdown in vitro reduced GBM cell division, almost eliminated generation of adhesion-independent spheroids, reduced the representation of cells expressing antigens thought to identify tumor initiating cells (TICs), reduced levels of several proteins of critical importance in TIC function (such as Notch-1 and Sox2), and increased sensitivity to BCNU (carmustine) and temozolomide (TMZ). In vivo, Cool-1 knockdown greatly suppressed the ability of GBM cells to generate tumors, an outcome that was c-Cbl dependent. In contrast, Cool-1 knockdown did not reduce division or increase BCNU or TMZ sensitivity in primary glial progenitor cells and Cool-1/c-Cbl complexes were not found in normal brain tissue. Our studies provide the first evidence that Cool-1 may be critical in the biology of human tumors, that suppression of c-Cbl by Cool-1 may be critical for generation of at least a subset of GBMs and offer a novel target that appears to be selectively necessary for TIC function and modulates chemoresistance in GBM cells. Targeting such proteins that inhibit c-Cbl offers potentially attractive opportunities for therapeutic development.

MEK1/2 inhibition suppresses tamoxifen toxicity on CNS glial progenitor cells.

It is increasingly apparent that treatment with a variety of anticancer agents often is associated with adverse neurological consequences. Clinical studies indicate that exposure even to tamoxifen (TMX), a putatively benign antihormonal agent widely used in breast cancer treatment, causes cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure. We found that TMX is toxic for a variety of CNS cell populations in vitro and also increased cell death in the corpus callosum and reduced cell division in the mouse subventricular zone, the hippocampal dentate gyrus, and the corpus callosum. We further discovered that MEK1/2 inhibition selectively rescued primary glial progenitors from TMX toxicity in vitro while enhancing TMX effects on MCF7 luminal human breast cancer cells. In vivo, MEK1/2 inhibition prevented TMX-induced cell death in systemically treated mice. Our results demonstrate unexpected cytotoxicity of this putatively benign antihormonal agent and offer a potential strategy for rescuing CNS cells from adverse effects of TMX.

Oligodendrocyte/type-2 astrocyte progenitor cells and glial-restricted precursor cells generate different tumor phenotypes in response to the identical oncogenes.

Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs), and in astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU. In vivo, cells differed in their ability to form tumors, in malignancy and even in the type of host-derived cells infiltrating the tumor mass. Moreover, identical genetic modification of these different cells yielded benign infiltrative astrocytomas, malignant astrocytomas, or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas, indicating a contribution of cell-of-origin to the characteristic properties expressed by these different tumors. Our studies also revealed unexpected relationships between the cell-of-origin, differentiation, and the order of oncogene acquisition at different developmental stages in enabling neoplastic growth. These studies thus provide multiple novel demonstrations of the importance of the cell-of-origin in respect to the properties of transformed cells derived from them. In addition, the approaches used enable analysis of the role of cell-of-origin in tumor biology in ways that are not accessible by other more widely used approaches.

Structural equation models and the quantification of behavior.

Quantifying behavior often involves using variables that contain measurement errors and formulating multiequations to capture the relationship among a set of variables. Structural equation models (SEMs) refer to modeling techniques popular in the social and behavioral sciences that are equipped to handle multiequation models, multiple measures of concepts, and measurement error. This work provides an overview of latent variable SEMs. We present the equations for SEMs and the steps in modeling, and we provide three illustrations of SEMs. We suggest that the general nature of the model is capable of handling a variety of problems in the quantification of behavior, where the researcher has sufficient knowledge to formulate hypotheses.