Intracranial dural based marginal zone MALT-type B-cell lymphoma: a case - Based update and literature review.

OBJECTIVES: Dural based Marginal Zone MALT-type B-Cell Lymphoma (MZBCL) is an intracranial tumor that can mimicking meningioma both from a clinical and a radiological point of view. A standard treatment protocol is still lacking. Aim of the present work is to provide an update of the present literature regarding this rare neoplasia. PATIENTS AND METHODS: We report the case of a patient with a dural-based lesion mimicking a meningioma of the tentorium. After surgical treatment, the diagnosis was of MZBCL. A literature review is performed to highlight the typical characteristics of this rare intracranial lesion and to define the best therapeutic approach. RESULTS: Literature review included 38 articles describing 126 cases of intracranial dural-based MZBCL. No clinical trial has been found. Clinical and histopathological features are properly collected to provide a guide for future cases. Different treatment options have been attempted. Combination of surgery with adjuvant radiation therapy is the most used option. CONCLUSIONS: MZBCL should be considered in differential diagnosis for dural-based intracranial lesion. Surgery followed by radiation therapy is the most reported treatment. As a consequence of the rarity of this disease, of its indolent progression and of the lack of adequate follow-up, it is not possible to define it is the best treatment option.

Triceps Brachii in Incomplete Tetraplegia: EMG and Dynamometer Evaluation of Residual Motor Resources and Capacity for Strengthening.

BACKGROUND: Candidates for activity-based therapy after spinal cord injury (SCI) are often selected on the basis of manual muscle test scores and the classification of the injury as complete or incomplete. However, these scores may not adequately predict which individuals have sufficient residual motor resources for the therapy to be beneficial. OBJECTIVE: We performed a preliminary study to see whether dynamometry and quantitative electromyography (EMG) can provide a more detailed assessment of residual motor resources. METHODS: We measured elbow extension strength using a hand-held dynamometer and recorded fine-wire EMG from the triceps brachii muscles of 4 individuals with C5, C6, or C7 level SCI and 2 able-bodied controls. We used EMG decomposition to measure motor unit action potential (MUAP) amplitudes and motor unit (MU) recruitment and firing-rate profiles during constant and ramp contractions. RESULTS: All 4 subjects with cervical SCI (cSCI) had increased MUAP amplitudes indicative of denervation. Two of the subjects with cSCI had very weak elbow extension strength (<4 kg), dramatically reduced recruitment, and excessive firing rates (>40 pps), suggesting profound loss of motoneurons. The other 2 subjects with cSCI had stronger elbow extension (>6 kg), more normal recruitment, and more normal firing rates, suggesting a substantial remaining motoneuron population. CONCLUSIONS: Dynamometry and quantitative EMG may provide information about the extent of gray matter loss in cSCI to help guide rehabilitation strategies.

Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Quantitative electrodiagnostic patterns of damage and recovery after spinal cord injury: a pilot study.

Study design: Prospective observational pilot study. Objectives: To compare quantitative electromyographic (EMG), imaging and strength data at two time points in individuals with cervical spinal cord injury (SCI). Setting: SCI center, Veterans Affairs Health Care System, Palo Alto, California, USA. Methods: Subjects without suspected peripheral nerve injury were recruited within 3 months of injury. Needle EMG examination was performed in myotomes above, at, and below the SCI level around 11- and 12-months post injury. EMG data were decomposed using custom software into constituent motor unit trains and each distinct motor unit was analyzed for firing rate and amplitude. Strength measurements were made with dynamometry and according to the International Standard of Neurologic Classification of SCI (ISNCSCI). Cervical magnetic resonance images (MRI) were evaluated by two neuroradiologists for gray and white matter damage around the SCI. Here, we compare the EMG, strength, and imaging findings of the one of the four participants who completed both 3- and 12-month EMG evaluations. Results: There was an increase in force generation in all muscles tested at 1 year. Localized findings of very fast firing motor units helped localize spinal cord damage and revealed gray matter damage in spinal segments where MRI was normal. Meanwhile, improvement in strength over time corresponded with different electrophysiologic patterns. Conclusions: Electromyographic decomposition at two time points provides valuable information about localization of spinal cord damage, integrity of motor neuron pools and may provide a unique understanding of neural recovery mechanisms.

Electrophysiological evidence of doubly innervated branched muscle fibers in the human brachioradialis muscle.

OBJECTIVE: Motor-unit action potentials (MUAPs) with unstable satellite (late-latency) components are found in EMG signals from the brachioradialis muscles of normal subjects. We analyzed the morphology and blocking behavior of these MUAPs to determine their anatomical origin. METHODS: EMG signals were recorded from the brachioradialis muscles of 5 normal subjects during moderate-level isometric contractions. MUAP waveforms, discharge patterns, and blocking were determined using computer-aided EMG decomposition. RESULTS: Twelve MUAPs with unstable satellite potentials were detected, always two together in the same signal. Each MUAP also had a second unstable component associated with its main spike. The blocking behavior of the unstable components depended on how close together the two MUAPs were when they discharged. CONCLUSIONS: The latencies and blocking behavior indicate that the unstable components came from branched muscle fibers innervated by two different motoneurons. The satellite potentials were due to action potentials that traveled to the branching point along one branch and back along the other. The blockings were due to action-potential collisions when both motoneurons discharged close together in time. SIGNIFICANCE: Animal studies suggest that branched muscle fibers may be a normal characteristic of series-fibered muscles. This study adds to our understanding of these muscles in humans.

EMGLAB: an interactive EMG decomposition program.

This paper describes an interactive computer program for decomposing EMG signals into their component motor-unit potential (MUP) trains and for averaging MUP waveforms. The program is able to handle single- or multi-channel signals recorded by needle or fine-wire electrodes during low and moderate levels of muscular contraction. It includes advanced algorithms for template matching, resolving superimpositions, and waveform averaging, as well as a convenient user interface for manually editing and verifying the results. The program also provides the ability to inspect the discharges of individual motor units more closely by subtracting out interfering activity from other MUP trains. Decomposition accuracy was assessed by cross-checking pairs of signals recorded by nearby electrodes during the same contraction. The results show that 100% accuracy can be achieved for MUPs with peak-to-peak amplitudes greater than 2.5 times the rms signal amplitude. Examples are presented to show how decomposition can be used to investigate motor-unit recruitment and discharge behavior, to study motor-unit architecture, and to detect action potential blocking in doubly innervated muscle fibers.

Traumatic brain injury in U.S. Veterans with traumatic spinal cord injury.

Patients with both a spinal cord injury (SCI) and traumatic brain injury (TBI) are often very difficult to manage and can strain the resources of clinical units specialized in treating either diagnosis. However, a wide range of estimates exists on the extent of this problem. The aim of this study was to describe the scope of the problem in a well-defined population attending a comprehensive SCI unit. Electronic medical records of all patients with SCI being followed by the SCI unit in a U.S. Veterans' hospital were searched to identify those with concurrent TBI. The data were analyzed for age, sex, cause of injury, level and completeness of SCI, cognitive impairment, relationship with Active Duty military, and date of injury. Of 409 Veterans with a traumatic SCI, 99 (24.2%) were identified as having had a concurrent TBI. The occurrence did not appear to be closely related to military conflict. Reports of TBI were much more common in the last 20 yr than in previous decades. Documentation of TBI in patients with SCI was inconsistent. Improved screening and documentation could identify all patients with this dual diagnosis and facilitate appropriate management.

Increased cytokine release from peripheral blood cells after acute stroke.

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-alpha release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-alpha release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-alpha release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorrhagic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-alpha production in peripheral blood cells, which are a major source of serum cytokines after stroke.

Decreased platelet glutamate uptake in patients with amyotrophic lateral sclerosis.

Decreased glutamate uptake and a loss of the astrocytic glutamate transporter EAAT2 (GLT-1) have been shown in spinal cord and motor cortex of patients with ALS. Because platelets express the three major glutamate transporter subtypes, including GLT-1, and possess a high-affinity glutamate uptake, the authors investigated glutamate uptake in platelets from patients with ALS and controls. A 43% reduction of high-affinity glutamate uptake rate (p < 0.0001) was observed in patients with ALS compared with normal controls and chronic neurologic disorder patients, suggesting a systemic impairment of glutamate uptake in ALS.

Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis.

Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).

Cisplatin-induced peripheral neurotoxicity in rats reduces the circulating levels of nerve growth factor.

The pathogenesis of the neurotoxicity of most antineoplastic drugs is unknown. Recent reports suggest that changes in the circulating levels of nerve growth factor (NGF) might be related to the dorsal root ganglia sensory neuron damage induced by cisplatin (CDDP), the first member of a family of widely used and very effective platinum-derived anticancer agents. Using a well-characterized model of CDDP neurotoxicity, we demonstrated that the NGF circulating level decreased during chronic CDDP administration in close accordance with the clinical course and returned to normal levels after recovery from the neurotoxic damage. Moreover, these changes were restricted to NGF and did not involve other trophic factors of the same neurotrophin family. Our findings are in agreement with previous in vitro and in vivo results and further suggest that NGF plays a specific role in the course of CDDP-induced primary sensory neuron damage.

Decreased density of lymphocyte benzodiazepine receptors in drug-resistant epileptic patients.

Peripheral benzodiazepine receptors (PBR) may have a role in epilepsy and in mediating antiepileptic drug effects. Since PBR in blood mononuclear cells may be acted on by anticonvulsant drugs, we investigated possible modifications of these receptors in newly diagnosed patients, before and after antiepileptic treatment and in drug-resistant epileptic patients. A significantly lower receptor density, with no difference in affinity, was observed in drug-resistant patients, compared to newly diagnosed patients and to normal age-related controls. We suggest the possible use of PBR as a peripheral marker of drug response.

Diazepam binding inhibitor (DBI) in the plasma of pediatric and adult epileptic patients.

The polypeptide diazepam binding inhibitor (DBI) displays epileptogenic activity by binding to benzodiazepine receptors. We analyzed DBI concentrations in the plasma of pediatric and adult epileptic patients, as a possible peripheral marker in epilepsy. DBI plasma concentrations are significantly higher (+ 62%, P < 0.001) in adult patients and slightly but significantly higher (+15%, P < 0.01) in pediatric patients, compared to age-related controls. Strikingly, plasma DBI is much higher (+81%, P < 0.001) in generalized epilepsy in adults and in drug-resistant pediatric and adult patients. Based on these findings, plasma DBI may be considered as a peripheral biological marker of epilepsy and, in association with lymphocyte benzodiazepine receptor density, of anticonvulsant drug responsiveness.

Retinoic acid differentiated SH-SY5Y human neuroblastoma cells: an in vitro model to assess drug neurotoxicity.

PURPOSE: To evaluate whether retinoic acid (RA) differentiated human neuroblastoma (HN) SH-SY5Y cells are a suitable and reliable model to test the neurotoxicity of chemotherapic drugs without the confusing effects of the neurotrophic factors commonly used to induce neuronal differentiation. METHODS: Cultures of the SH-SY5Y cell line were exposed to RA to induce neuronal differentiation which was assessed by measuring the neurite length. The effect of increasing concentrations of cisplatin (CDDP) on neurite outgrowth was determined. Cyclophosphamide (CTX) was used as negative control. RESULTS: CDDP induced a significant reduction in the mean neurite length in a dose dependent manner. The neurotoxic effect of CDDP was reversible. Cyclophosphamide did not induce changes in RA differentiated HN cells. CONCLUSIONS: RA differentiated HN cells are sensitive to the neurotoxic effect of CDDP and the course of the changes is similar to that observed in clinical practice and in in vivo experimental models. Therefore, this model is proposed as a screening method to test the neurotoxicity of chemotherapy drugs and the possible effect of neuroprotectant molecules and drugs.

Circulating nerve growth factor level changes during oxaliplatin treatment-induced neurotoxicity in the rat.

BACKGROUND: Oxaliplatin neurotoxicity represents a clinically-relevant problem and its etio-pathogenesis is still unknown. We explored the possible role of some neuronal growth factors ("neurotrophins") during the course of oxaliplatin sensory neuronopathy. MATERIALS AND METHODS: In our rat model two different doses of oxaliplatin were used (2 and 3 mg/kg i.v. twice weekly for 9 times). The neurotoxicity of the treatment was assessed with neurophysiological and pathological methods and serum neurotrophin levels were measured by ELISA. RESULTS: Both oxaliplatin-treated groups showed the neurophysiological and neuropathological changes which mimic the chronic effects of oxaliplatin administration in humans, e.g. reversible sensory impairment due to dorsal root ganglia neuron damage. These changes were associated with a significant and dose-dependent reduction only in the circulating level of nerve growth factor (NGF), which returned to normal values after neurophysiological and pathological recovery. CONCLUSION: This specific association between neurological impairment and NGF modulation indicates that NGF impairment has a role in the neurotoxicity of oxaliplatin.

Extracorporeal photochemotherapy reduces the severity of Lewis rat experimental allergic encephalomyelitis through a modulation of the function of peripheral blood mononuclear cells.

Extra corporeal photochemotherapy (ECP) is an immunomodulating procedure used in several nonneurological diseases which, similarly to multiple sclerosis, are likely to be due to T-cell-mediated autoimmunity and it is probable that ECP can modulate the normal activity of peripheral blood mononuclear cells (PBMC). Using the Lewis rat experimental allergic encephalomyelitis (EAE) model of human multiple sclerosis (MS) we examined the effect of extracorporeal UV-A irradiation on psoralen-activated PBMC. In our experiment the comparison between the two groups of animals (ECP or sham-treatment) evidenced that the ECP treatment reduced the severity of EAE on clinical grounds and this result was confirmed by the pathological examination. The changes in the titers of anti-myelin antigen antibodies typical of EAE were also modulated by the procedure. Ex vivo examination evidenced a significant reduction in tumor-necrosis factor-alpha (TNF-alpha) released by PBMC after lipopolysaccharides (LPS) stimulation in culture. We conclude that ECP modifies the normal activity of PBMC during the course of EAE and it is possible that one of the anti-inflammatory mechanisms of action of ECP is correlated to a down-regulation of T-helper 1 lymphocytes activity.

[The bioavailability of nicorandil after oral administration of a single dose of 10 or 20 mg preparations]. / Biodisponibilità del nicorandil dopo somministrazione orale in dose singola di preparati da 10 e da 20 mg.

To evaluate the bioavailability of 4 different formulations of nicorandil, 10 mg and 20 mg (Bracco) versus 10 mg ang 20 mg (Merck), we have carried out a study involving 24 young healthy volunteers. The drug was administered in single oral dose and the plasma concentration levels were evaluated by HPLC method. From the results obtained, we have seen that both the 2 products of 10 mg (A and B) and the 2 products of 20 mg (C and D) are equivalent and have high relative bioavailability: it reaches the values of 96.5% (A versus B) and 120% (C versus D). As regards the 2 formulation of 20 mg, the results of bioavailability are confirmed by data obtained from dissolution study in vitro, where the dissolution is almost complete in 30 minutes.

Assessing glutamatergic function and dysfunction in peripheral tissues.

Glutamate is the major mediator of excitatory signaling in the mammalian central nervous system (CNS) and it has recently been described to have a central role in the transduction of sensory input in the peripheral nervous system (PNS), too. However, functional glutamatergic systems are expressed by peripheral non-neural tissues as well, such as heart, kidney, lungs, ovary, testis, blood and skin. Interestingly, glutamatergic alterations have been repeatedly described in these tissues in various neuropsychiatric diseases. Here we will review evidence suggesting that glutamate measurements obtained from sampling ex vivo peripheral cells can permit the assessment of the dynamics of glutamate release, uptake, receptor-mediated signaling, synthesis and degradation, and mirror homologous dysfunctions operative within the CNS in each single patient. Among all the available cell types we will focus on leukocytes, platelets and fibroblasts that can be easily obtained from patients multiple times without concerns related to post-mortem changes. Finally, we will briefly review another possibility, offered by testing plasma (and CSF) glutamate levels, allowing the indirect investigation of glutamate-mediated crosstalk between central and peripheral compartments. Technical pitfalls of these biomarkers will be contextually emphasized.

History dependence of human muscle-fiber conduction velocity during voluntary isometric contractions.

The conduction velocity (CV) of a muscle fiber is affected by the fiber's discharge history going back ∼1 s. We investigated this dependence by measuring CV fluctuations during voluntary isometric contractions of the human brachioradialis muscle. We recorded electromyogram (EMG) signals simultaneously from multiple intramuscular electrodes, identified potentials belonging to the same motor unit using EMG decomposition, and estimated the CV of each discharge from the interpotential interval. In 12 of 14 subjects, CV increased by ∼10% during the first second after recruitment and then fluctuated by about ±2% in a way that mirrored the fluctuations in the instantaneous firing rate. The CV profile could be precisely described in terms of the discharge history by a simple mathematical model. In the other two subjects, and one subject retested after cooling the arm, the CV fluctuations were inversely correlated with instantaneous firing rate. In all subjects, CV was additionally affected by very short interdischarge intervals (<25 ms): it was increased in doublets at recruitment, but decreased in doublets during continuous firing and after short interdischarge intervals in doubly innervated fibers. CV also exhibited a slow trend of about -0.05%/s that did not depend on the immediate discharge history. We suggest that measurements of CV fluctuations during voluntary contractions, or during stimulation protocols that involve longer and more complex stimulation patterns than are currently being used, may provide a sensitive approach for estimating the dynamic characteristics of ion channels in the human muscle-fiber membrane.

Expression, distribution and glutamate uptake activity of high affinity-excitatory aminoacid transporters in in vitro cultures of embryonic rat dorsal root ganglia.

Glutamate is the major mediator of excitatory signalling in the mammalian central nervous system, but it has recently been shown to play a role in the transduction of sensory input at the periphery and in peripheral neuropathies. New advances in research have demonstrated that rat peripheral sensory terminals and dorsal root ganglia (DRG) express molecules involved in glutamate signalling, including high-affinity membrane-bound glutamate transporters (GLAST [glutamate aspartate transporter], GLT1 [glutamate transporter 1], EAAC1 [excitatory aminoacid transporter 1]) and that alterations in their expression and/or functionality can be implicated in several models of peripheral neuropathy, neuropathic pain and hyperalgesia. Here we describe, through immunoblotting, immunofluorescence assays and ß-counter analysis of [(3)H] l-glutamate uptake, the expression, distribution and activity of the glutamate transporters in in vitro cultures of embryonic dorsal root ganglia sensory neurons, sensory neurons+satellite cells and satellite cells. In this work we demonstrated that glutamate transporters are expressed in all cultures with a peculiar pattern of distribution. Even if GLAST is strongly detected in satellite cells, it is slightly expressed also in sensory neurons. GLT1 immunostaining is very weak in DRG neurons, but it was evident in the satellite cells. Finally, EAAC1 is localized in the soma and in the neuritis of sensory neurons, while it is not detectable in satellite cells. Moreover, all the cell cultures showed a strong sodium-energy-dependent glutamate uptake activity and it is more marked in neurons alone or in co-culture with satellite cells compared to satellite cells alone. Finally, we show that the complete or partial pharmacological inhibition of glutamate transporters virtually completely or partially abolish glutamate uptake in all cell culture. These results, that demonstrate that functionally active glutamate transporters can be studied in dorsal root ganglia cell cultures, provide further evidence for a role of glutamatergic transport in the peripheral nervous system and will be useful for testing whether any changes occur in in vitro models of peripheral nervous system damage.