RESUMEN
Gene and protein expressions display circadian oscillations, which can be disrupted in diseases in most body organs. Whether these oscillations occur in the healthy hippocampus and whether they are altered in epilepsy are not known. We identified more than 1200 daily oscillating transcripts in the hippocampus of control mice and 1600 in experimental epilepsy, with only one-fourth oscillating in both conditions. Comparison of gene oscillations in control and epilepsy predicted time-dependent alterations in energy metabolism, which were verified experimentally. Although aerobic glycolysis remained constant from morning to afternoon in controls, it increased in epilepsy. In contrast, oxidative phosphorylation increased in control and decreased in epilepsy. Thus, the control hippocampus shows circadian molecular remapping, which is altered in epilepsy. We suggest that the hippocampus operates in a different functioning mode in epilepsy. These alterations need to be considered when studying epilepsy mechanisms, designing drug treatments, and timing their delivery.
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Epilepsia del Lóbulo Temporal , Epilepsia , Animales , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Ratones , Proteoma/metabolismo , TranscriptomaRESUMEN
The peripheral nervous system is subject to changes during the aging process, e.g., deep tendon reflexes decrease, as proprioception does. In contrast, polyneuropathies have to be distinguished from age-associated changes as independent diseases with etiologies similar to those in younger ages. Incidence of polyneuropathies is reported about 118/100,000, the overall prevalence in the general population is estimated to be about 1% and rises to up to 7% in the elderly. Etiology includes metabolic disorders, primary inflammatory polyneuropathies, systemic disorders and vasculitic neuropathies. Due to the age-specific increase of the prevalence of certain etiologies, neuropathies associated with diabetes, malignancy, and monoclonal gammopathies are even more common in older patients. However, the proportion of cryptogenic neuropathies, e.g. neuropathies without obvious cause, increases also with age. In older age, polyneuropathies additionally impair mobility and increase the risk of falling, thus the assessment of functional abilities is mandatory. It is essential to try to identify the underlying cause by a systematic approach including history, clinical investigation, neurophysiological and lab exams. Treatment of polyneuropathies is based on therapy of underlying conditions and requires management of neuropathic pain in the majority of cases. Physiotherapy and rehabilitation target pain relief and sustaining activities of daily living.
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Envejecimiento , Nefropatías Diabéticas , Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Polineuropatías/etiología , Actividades Cotidianas , Anciano , Humanos , Neuralgia , Manejo del DolorRESUMEN
In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.
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Terapia de Reemplazo Enzimático/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo II , alfa-Glucosidasas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Austria/epidemiología , Niño , Diagnóstico Tardío , Femenino , Estudios de Seguimiento , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Estudios Retrospectivos , Capacidad Vital/fisiologíaRESUMEN
OBJECTIVES: Most acquired neuropathies are treatable, whereas genetic neuropathies respond to treatment in Fabry's disease (FD), transthyretin-related familial amyloidosis (TTR-FA), and Pompe's disease (PD). This review summarizes and discusses recent findings and future perspectives concerning etiology, pathophysiology, clinical presentation, diagnosis, treatment, and outcome of neuropathy in FD, TTR-FA, and PD. METHODS: Literature review. RESULTS: Neuropathy in FD concerns particularly small, unmyelinated, or myelinated sensory fibers (small fiber neuropathy [SFN]) and autonomic fibers, manifesting as acroparesthesias, Fabry's crises, or autonomous disturbances. FD neuropathy benefits from agalsidase alpha (0.2 mg/kg every second week intravenously) or from beta (1.0 mg/kg every second week intravenously). Neuropathy in TTR-FA is axonal and affects large and small sensory, motor, and autonomous fibers. Neuropathy in TTR-FA profits from liver transplantation and the TTR kinetic stabilizer tafamidis (20 mg/d). Neuropathy in PD particularly occurs in late-onset PD and manifests as mononeuropathy, polyneuropathy, or SFN. PD neuropathy presumably responds to alglucosidase-alpha (20 mg/kg every second week intravenously). CONCLUSIONS: Neuropathy in FD, TTR-FA, and PD is predominantly a SFN and can be the dominant feature in FD and TTR-FA. SFN in FD, TTR-FA, and PD needs to be recognized and benefits from enzyme replacement treatment or TT-kinetic stabilizers.
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Neuropatías Amiloides Familiares/complicaciones , Enfermedad de Fabry/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedades del Sistema Nervioso , Femenino , Humanos , Masculino , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/terapiaRESUMEN
Cancer is becoming a treatable and even often curable disease. The neuromuscular system can be affected by direct tumor invasion or metastasis, neuroendocrine, metabolic, dysimmune/inflammatory, infections and toxic as well as paraneoplastic conditions. Due to the nature of cancer treatment, which frequently is based on a DNA damaging mechanism, treatment related toxic side effects are frequent and the correct identification of the causative mechanism is necessary to initiate the proper treatment. The peripheral nervous system is conventionally divided into nerve roots, the proximal nerves and plexus, the peripheral nerves (mono- and polyneuropathies), the site of neuromuscular transmission and muscle. This review is based on the anatomic distribution of the peripheral nervous system, divided into cranial nerves (CN), motor neuron (MND), nerve roots, plexus, peripheral nerve, the neuromuscular junction and muscle. The various etiologies of neuromuscular complications - neoplastic, surgical and mechanic, toxic, metabolic, endocrine, and paraneoplastic/immune - are discussed separately for each part of the peripheral nervous system.
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Neoplasias/complicaciones , Enfermedades Neuromusculares/complicaciones , Humanos , Neoplasias/diagnóstico , Neoplasias/fisiopatología , Neoplasias/terapia , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/fisiopatología , Enfermedades Neuromusculares/terapiaRESUMEN
ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Proteínas de Neoplasias/metabolismo , Tomografía de Emisión de Positrones/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Acridinas/farmacocinética , Adulto , Femenino , Humanos , Masculino , Proteínas de Neoplasias/genética , Proyectos Piloto , Polimorfismo de Nucleótido Simple , Quinolinas/farmacocinética , Tetrahidroisoquinolinas/farmacocinética , Distribución Tisular , Verapamilo/metabolismo , Verapamilo/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Some systemic diseases also affect the skeletal muscle to various degrees and with different manifestations. This review aimed at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases. METHOD: Literature review by search of MEDLINE, and Current Contents with appropriate search terms. RESULTS: Secondary muscle disease occurs in infectious disease, endocrine disorders, metabolic disorders, immunological disease, vascular diseases, hematological disorders, and malignancies. Muscle manifestations in these categories include pathogen-caused myositis, muscle infarction, rhabdomyolysis, myasthenia, immune-mediated myositis, necrotising myopathy, or vasculitis-associated myopathy. Muscle affection may concern only a single muscle, a group of muscles, or the entire musculature. Severity of muscle affection may be transient or permanent, may be a minor part of or may dominate the clinical picture, or may be mild or severe, requiring invasive measures including artificial ventilation if the respiratory muscles are additionally involved. Diagnostic work-up is similar to that of primary myopathies by application of non-invasive and invasive techniques. Treatment of muscle involvement in systemic diseases is based on elimination of the underlying cause and supportive measures. The prognosis is usually fair if the causative disorder is effectively treatable but can be fatal in single cases if the entire musculature including the respiratory muscles is involved, in case of infection, or in case of severe rhabdomyolysis. CONCLUSION: Secondary muscle manifestations of systemic diseases must be addressed and appropriately managed. Prognosis of secondary muscle disease in systemic diseases is usually fair if the underlying condition is accessible to treatment.
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Enfermedades Musculares/etiología , Humanos , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/patología , Enfermedades Musculares/terapia , PronósticoRESUMEN
This report represents a scientific and working clinical consensus statement on seizure management in dogs based on current literature and clinical expertise. The goal was to establish guidelines for a predetermined, concise, and logical sequential approach to chronic seizure management starting with seizure identification and diagnosis (not included in this report), reviewing decision-making, treatment strategies, focusing on issues related to chronic antiepileptic drug treatment response and monitoring, and guidelines to enhance patient response and quality of life. Ultimately, we hope to provide a foundation for ongoing and future clinical epilepsy research in veterinary medicine.
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Anticonvulsivantes/uso terapéutico , Enfermedades de los Perros/terapia , Epilepsia/veterinaria , Guías de Práctica Clínica como Asunto , Medicina Veterinaria/normas , Terapia por Acupuntura/veterinaria , Animales , Anticonvulsivantes/administración & dosificación , Perros , Epilepsia/terapia , Homeopatía , Calidad de Vida , Estimulación del Nervio Vago/veterinariaRESUMEN
BACKGROUND: Neurophysiological data are lacking in the research of nerve injury during regional anaesthesia. The aim of this pilot study was to establish a large animal model in order to test the hypothesis that needle trauma alone or in combination with intraneural injection would result in measurable nerve injury. METHODS: The experimental set-up was elaborated in four pre-test animals. In the remaining animals (n = 11), 22 sciatic nerves were randomly assigned to one of four groups: needle trauma (n = 5) generated by ultrasound-guided forced needle advancement; intraneural injection of 2.5 ml saline (n = 6); intraneural injection of 5 ml saline (n = 6); extraneural injection of 5 ml saline (n = 5) as control group. Compound muscle action potential (CMAP) amplitudes as well as latencies were taken as outcome parameter and monitored over 180 min. Sonographic assessments were performed simultaneously. RESULTS: Following needle trauma and intraneural injection, CMAP amplitudes declined significantly over 180 min (P < 0.001). The control group showed no electrophysiological alterations. At 60 min, decreases in amplitude were significant after needle trauma (P = 0.04) and intraneural injection of 2.5 ml (P = 0.045), and highly significant after injection of 5 ml (P = 0.006) when compared to controls. Sustained nerve swelling was observed after intraneural injection, but not after needle trauma and perineural injection. CONCLUSIONS: Isolated mechanical trauma caused by forced needle advancement alone or in combination with intraneural injection of saline was followed by a significant decline in CMAP amplitudes indicating conduction block due to disruption of myelin or axon loss (pseudo-conduction block).
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Inyecciones/efectos adversos , Nervio Ciático/lesiones , Potenciales de Acción , Animales , Modelos Animales , Agujas , Proyectos Piloto , Nervio Ciático/fisiología , PorcinosRESUMEN
Iatrogenic nerve lesions (INLs) are an integral part of peripheral neurology and require dedicated neurologists to manage them. INLs of peripheral nerves are most frequently caused by surgery, immobilization, injections, radiation, or drugs. Early recognition and diagnosis is important not to delay appropriate therapeutic measures and to improve the outcome. Treatment can be causative or symptomatic, conservative, or surgical. Rehabilitative measures play a key role in the conservative treatment, but the point at which an INL requires surgical intervention should not be missed or delayed. This is why INLs require close multiprofessional monitoring and continuous re-evaluation of the therapeutic effect. With increasing number of surgical interventions and increasing number of drugs applied, it is quite likely that the prevalence of INLs will further increase. To provide an optimal management, more studies about the frequency of the various INLs and studies evaluating therapies need to be conducted. Management of INLs can be particularly improved if those confronted with INLs get state-of-the-art education and advanced training about INLs. Management and outcome of INLs can be further improved if the multiprofessional interplay is optimized and adapted to the needs of the patient, the healthcare system, and those responsible for sustaining medical infrastructure.
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Procedimientos Neuroquirúrgicos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Humanos , Enfermedad Iatrogénica , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/terapiaRESUMEN
As a result of the growing availability of genetically engineered mouse lines, the pilocarpine post-status epilepticus (SE) model of temporal lobe epilepsy is increasingly used in mice. A discrepancy in pilocarpine sensitivity in FVB/N wild-type versus P-glycoprotein (PGP)-deficient mice precipitated the investigation of the interaction between pilocarpine and two major multidrug transporters at the blood-brain barrier. Doses of pilocarpine necessary for SE induction were determined in male and female wild-type and PGP-deficient mice. Brain and plasma concentrations were measured following low (30-50 mgâ kg(-1) i.p.) and/or high (200 mgâ kg(-1) i.p.) doses of pilocarpine in wild-type mice, and mice lacking PGP, breast cancer resistance protein (BCRP), or both transporters, as well as in rats with or without pretreatment with lithium chloride or tariquidar. Concentration equilibrium transport assays (CETA) were performed using cells overexpressing murine PGP or BCRP. Lower pilocarpine doses were necessary for SE induction in PGP-deficient mice. Brain-plasma ratios were higher in mice lacking PGP or PGP and BCRP, which was also observed after pretreatment with tariquidar in mice and in rats. Lithium chloride did not change brain penetration of pilocarpine. CETA confirmed transport of pilocarpine by PGP and BCRP. Pilocarpine is a substrate of PGP and BCRP at the rodent blood-brain barrier, which restricts its convulsive action. Future studies to reveal whether strain differences in pilocarpine sensitivity derive from differences in multidrug transporter expression levels are warranted.
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Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Pilocarpina/metabolismo , Pilocarpina/farmacología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Animales , Transporte Biológico , Barrera Hematoencefálica/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Pilocarpina/farmacocinética , Ratas , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client-owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital-treated dogs, significantly increased levels of alkaline phosphatase, gamma-glutamyl-transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no-observed-adverse-event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs.
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Anticonvulsivantes/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Epilepsia/veterinaria , Imidazoles/uso terapéutico , Fenobarbital/uso terapéutico , Animales , Anticonvulsivantes/efectos adversos , Perros , Relación Dosis-Respuesta a Droga , Epilepsia/tratamiento farmacológico , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Fenobarbital/efectos adversosRESUMEN
The Interlaken Leadership Awards (ILAs), established in 2010, are monetary grants pledged annually by CSL Behring to fund research into the use of immunoglobulin (Ig) therapy, especially into its use in neurological disorders. Five recipients of the 2011/2012 Awards were invited to present their research at the 7th International Immunoglobulin Conference. Dr Honnorat reports on paraneoplastic neurological syndromes (PNS). His multi-centre Phase II trial, currently under way, will assess the efficacy of IVIg therapy in treating PNS in the first 3 months of treatment. Dr Geis shows improved disease scores after IVIg treatment in a mouse model of neuromyelitis optica (NMO). It is hoped that these promising results will translate well into human NMO. Dr Schmidt studied IVIg therapy in an mdx mouse model for Duchenne muscular dystrophy (DMD). He reports that motor function improved and myopathic changes in skeletal muscles and creatine kinase release were decreased. Dr Gamez presents the design and rationale for a Phase II clinical trial investigating the preoperative use of IVIg therapy in myasthenia gravis patients to prevent post-operative myasthenic crisis. Dr Goebel reports results from studies elucidating the immune-mediated pathogenesis of complex regional pain syndrome (CRPS), the successful IVIg therapy in a proportion of CRPS patients, and the development of a model for predicting which patients are more likely to respond to Ig therapy.
Asunto(s)
Inmunoglobulinas/inmunología , Inmunoglobulinas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Síndromes de Dolor Regional Complejo/inmunología , Síndromes de Dolor Regional Complejo/terapia , Humanos , Inmunización Pasiva/métodos , Liderazgo , Distrofia Muscular de Duchenne/inmunología , Distrofia Muscular de Duchenne/terapia , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/terapiaRESUMEN
The research presented in this section explores novel applications of immunoglobulin (Ig) therapy in neurological disorders. The results from the upcoming and ongoing trials of Drs Honnorat and Gamez are expected to provide meaningful insights into the treatment of two serious and disabling diseases. The results already being reported from the work of Drs Schmidt and Geis in animal models seem promising, but further proof-of-concept research is warranted to translate their significance to human diseases. Dr Goebel's work in developing animal models of complex regional pain syndrome (CRPS) may provide new insights into predicting which CRPS patients could respond to Ig therapy or other immunotherapies. The work being made possible by a number of the Interlaken Leadership Awards may provide fundamental insights in understanding neurological disorders and improving quality of life for the patients who suffer from them.
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Inmunoglobulinas/farmacología , Inmunoglobulinas/uso terapéutico , Animales , Distinciones y Premios , Síndromes de Dolor Regional Complejo/inmunología , Síndromes de Dolor Regional Complejo/terapia , Modelos Animales de Enfermedad , Humanos , Inmunización Pasiva/métodos , Inmunoglobulinas/inmunología , LiderazgoRESUMEN
We studied whether pharmacological blockade of the IL-1ß-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1ß signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist, and VX-765 a specific non-peptide inhibitor of IL-1ß cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1ß expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1ß signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes.
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Epilepsia del Lóbulo Temporal/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-1beta/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Dipéptidos/uso terapéutico , Modelos Animales de Enfermedad , Estimulación Eléctrica/efectos adversos , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/prevención & control , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Proteína Antagonista del Receptor de Interleucina 1/sangre , Proteína Antagonista del Receptor de Interleucina 1/líquido cefalorraquídeo , Litio/toxicidad , Masculino , Pilocarpina/toxicidad , Ratas , Ratas Sprague-Dawley , para-Aminobenzoatos/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Little is known about the natural history of non-traumatic compressive mononeuropathies. To improve patient management, prognostic factors and outcome in patients with non-traumatic peroneal and radial mononeuropathies were studied. METHODS: Retrospective clinical, electrophysiological and sonographic data of patients with non-traumatic peroneal and radial mononeuropathies were evaluated. Clinical, electrophysiological and sonographic evaluations had to take place 2-12 weeks after symptom onset and follow-up had to be for >6 months. RESULTS: Twenty-five patients with peroneal mononeuropathy and 58 with radial mononeuropathy were included. Mean follow-up was 8.9 ± 2.4 months. Approximately 90% of patients recovered to a muscle strength of British Medical Research Council grade 4 or 5. Multiple logistic regression analysis revealed conduction block on nerve conduction studies, younger age and less severe initial weakness as indicators for a good prognosis. Peripheral nerve ultrasound was not prognostic in the 40 patients where it was available. CONCLUSIONS: The present study shows a good prognosis for spontaneous recovery after non-traumatic acute-onset compressive peroneal and radial mononeuropathies. Patients with denervation on needle electromyography, older age and severe initial weakness have a poorer prognosis and should be closely monitored to facilitate timely surgery whenever weakness persists. Peripheral nerve ultrasound seems to be of limited prognostic value in these mononeuropathies.
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Neuropatías Peroneas/diagnóstico , Neuropatías Peroneas/epidemiología , Neuropatía Radial/diagnóstico , Neuropatía Radial/epidemiología , Radiculopatía/diagnóstico , Radiculopatía/epidemiología , Enfermedad Aguda , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mononeuropatías/diagnóstico , Mononeuropatías/epidemiología , Pronóstico , Estudios RetrospectivosRESUMEN
Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.