RESUMEN
The purpose of this study was to develop a defined approach (DA) for eye hazard identification according to the three UN GHS categories for surfactants (DASF). The DASF is based on a combination of Reconstructed human Cornea-like Epithelium test methods (OECD TG 492; EpiOcular™ EIT and SkinEthic™ HCE EIT) and the modified Short Time Exposure (STE) test method (0.5% concentration of the test substance after a 5-min exposure). DASF performance was assessed by comparing the prediction results with the historical in vivo data classification and against the criteria established by the OECD expert group on eye/skin. The DASF yielded a balanced accuracy of 80.5% and 90.9% of Cat. 1 (N = 22), 75.0% of Cat. 2 (N = 8), and 75.5% of No Cat. (N = 17) surfactants were correctly predicted. The percentage of mispredictions was below the established maximum values except for in vivo No Cat. surfactants that were over-predicted as Cat. 1 (5.6%, N = 17), with a maximum value set at 5%. The percentage of correct predictions did meet the minimum performance values of 75% Cat. 1, 50% Cat. 2, and 70% No Cat. established by the OECD experts. The DASF has shown to be successful for eye hazard identification of surfactants.
Asunto(s)
Ojo , Surfactantes Pulmonares , Humanos , Animales , Tensoactivos/toxicidad , Irritantes/toxicidad , Pruebas de Toxicidad/métodos , Córnea , Naciones Unidas , Alternativas a las Pruebas en Animales , Reproducibilidad de los ResultadosRESUMEN
A prospective study of the Bovine Corneal Opacity and Permeability (BCOP) Laser Light-Based Opacitometer (LLBO) test method was conducted to evaluate its usefulness to identify chemicals as inducing serious eye damage (Cat. 1) or chemicals not requiring classification for eye irritation (No Cat.) applying United Nations Globally Harmonized System of Classification and Labelling of Chemicals (UN GHS). The aim was to demonstrate the reproducibility of the BCOP LLBO protocol for liquids and solids and define its predictive capacity. Briefly, 145 chemicals were simultaneously tested with BCOP LLBO and OP-KIT (OECD TG 437), one to two times in one laboratory. When used to identify Cat. 1, the BCOP LLBO has a false negative rate (FNR) of 24.1% (N = 56) compared to 34.8% (N = 56) for the BCOP OP-KIT, with a comparable false positive rate (FPR, N = 89) of 18.5% and 20.8%, respectively. When used to identify chemicals not requiring classification (No Cat.) the BCOP LLBO and BCOP OP-KIT had a FNR (N = 104) of 6.2% and 7.2% and a FPR (N = 41) of 45.1% and 42.7%, respectively. The OP-KIT and LLBO devices are interchangeable at no cost to data quality and reliability. The OP-KIT and LLBO devices are interchangeable at no cost to data quality and reliability. The performance of the LLBO is at least as good as the OP-KIT, both methods can be used to identify UN GHS Cat. 1 and UN GHS No Cat. chemicals.
Asunto(s)
Opacidad de la Córnea/inducido químicamente , Irritantes/toxicidad , Pruebas de Toxicidad/métodos , Alternativas a las Pruebas en Animales , Animales , Bovinos , Ojo/efectos de los fármacos , Ojo/metabolismo , Rayos Láser , Luz , Permeabilidad/efectos de los fármacosRESUMEN
The focus of Cosmetics Europe's ocular toxicity programme is on development of testing strategies and defined approaches for identification of ocular effects of chemicals in the context of OECD's Guidance Document on an Integrated Approach on Testing and Assessment (IATA) for Serious Eye Damage and Eye Irritation. Cosmetics Europe created a comprehensive database of chemicals for which in vitro data are available with corresponding historical in vivo Draize eye data and physicochemical properties. This database allowed further exploration of the initially proposed strategies from the CON4EI project and to identify opportunities for refinement. One key outcome of this project is that combining in vitro test methods (RhCE and BCOP LLBO) with physicochemical properties in a two-step Bottom-Up approach applicable to neat liquids, resulted in an improvement of the specificity, without reducing the sensitivity, when compared to the combination of in vitro methods alone. The Bottom-Up approach proposed here for neat liquids correctly predicted 58.3% (EpiOcular™ EIT followed by BCOP LLBO) to 62.6% (SkinEthic™ HCE EIT followed by BCOP LLBO) of No Cat., 59.1% to 68.7% of Cat. 2, and 76.5% of Cat. 1. Incorporating specific physicochemical properties with this Bottom-Up approach increased the correct identification of No Cat. neat liquids to between 72.7% and 79.7%.
Asunto(s)
Alternativas a las Pruebas en Animales , Cosméticos/toxicidad , Irritantes/toxicidad , Pruebas de Toxicidad/métodos , Animales , Bovinos , Opacidad de la Córnea/inducido químicamente , Epitelio Corneal/efectos de los fármacos , HumanosRESUMEN
The focus of Cosmetics Europe's programme on serious eye damage/eye irritation is on development of testing strategies and defined approaches for identification of ocular effects of chemicals in the context of OECD's Guidance Document on an Integrated Approach on Testing and Assessment (IATA) for Serious Eye Damage and Eye Irritation. Cosmetics Europe created a comprehensive database of chemicals for which in vitro data are available with corresponding historical in vivo Draize eye data. This database allowed further exploration of the initially proposed strategies from the CON4EI project and to identify opportunities for refinement. The current analysis focused on the development of a defined approach, applicable to liquid non-surfactant chemicals, neat and in dilution, that can distinguish between the three UN GHS categories (Cat. 1, Cat. 2, and No Cat.). Combining the modified-protocol Short Time Exposure (STE) test method (OECD TG 491 with extension to highly volatile substances) with the Bovine Corneal Opacity and Permeability Laser Light-Based Opacitometer (BCOP LLBO) test method in a Bottom-Up approach identified 81.2% Cat. 1, 56.3% Cat. 2, and 85.3% No. Cat correctly, with an NPV of 96.7% and a PPV of 68.6%. Therefore, the performance of the defined approach was better than the standalone test methods.
Asunto(s)
Cosméticos/toxicidad , Ojo/efectos de los fármacos , Irritantes/toxicidad , Pruebas de Toxicidad/métodos , Animales , Bovinos , Opacidad de la Córnea/inducido químicamenteRESUMEN
We have developed a new in vitro skin irritation test based on an open source reconstructed epidermis (OS-REp) with openly accessible protocols for tissue production and test performance. Due to structural, mechanistic and procedural similarity, a blinded catch-up validation study for skin irritation according to OECD Performance Standards (PS) was conducted in three laboratories to promote regulatory acceptance, with OS-REp models produced at a single production site only. While overall sensitivity and predictive capacity met the PS requirements, overall specificity was only 57%. A thorough analysis of the test results led to the assumption that some of the false-positive classifications could have been evoked by volatile skin-irritating chemicals tested in the same culture plate as the non-irritants falsely predicted as irritants. With GC/MS and biological approaches the cross-contamination effect was confirmed and the experimental set-up adapted accordingly. Retesting of the affected chemicals with the improved experimental set-up and otherwise identical protocol resulted in correct classifications as non-irritants. Taking these re-test results into account, 93% overall sensitivity, 70% specificity and 82% accuracy was achieved, which is in accordance with the OECD PS. A sufficient reliability of the method was indicated by a within-laboratory-reproducibility of 85-95% and a between-laboratory-reproducibility of 90%.
Asunto(s)
Epidermis/efectos de los fármacos , Irritantes/toxicidad , Pruebas de Irritación de la Piel , Alternativas a las Pruebas en Animales , Epidermis/anatomía & histología , Humanos , Técnicas In Vitro , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
To replace the Draize skin irritation assay (OECD guideline 404) several test methods based on reconstructed human epidermis (RHE) have been developed and were adopted in the OECD test guideline 439. However, all validated test methods in the guideline are linked to RHE provided by only three companies. Thus, the availability of these test models is dependent on the commercial interest of the producer. To overcome this limitation and thus to increase the accessibility of in vitro skin irritation testing, an open source reconstructed epidermis (OS-REp) was introduced. To demonstrate the capacity of the OS-REp in regulatory risk assessment, a catch-up validation study was performed. The participating laboratories used in-house generated OS-REp to assess the set of 20 reference substances according to the performance standards amending the OECD test guideline 439. Testing was performed under blinded conditions. The within-laboratory reproducibility of 87% and the inter-laboratory reproducibility of 85% prove a high reliability of irritancy testing using the OS-REp protocol. In addition, the prediction capacity was with an accuracy of 80% comparable to previous published RHE based test protocols. Taken together the results indicate that the OS-REp test method can be used as a standalone alternative skin irritation test replacing the OECD test guideline 404.
Asunto(s)
Epidermis/efectos de los fármacos , Irritantes/toxicidad , Pruebas de Irritación de la Piel , Alternativas a las Pruebas en Animales , Epidermis/anatomía & histología , Humanos , Técnicas In Vitro , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Cosmetics Europe recently established HPLC/UPLC-spectrophotometry as a suitable alternative endpoint detection system for measurement of formazan in the MTT-reduction assay of reconstructed human tissue test methods irrespective of the test system involved. This addressed a known limitation for such test methods that use optical density for measurement of formazan and may be incompatible for evaluation of strong MTT reducer and/or coloured chemicals. To build on the original project, Cosmetics Europe has undertaken a second study that focuses on evaluation of chemicals with functionalities relevant to cosmetic products. Such chemicals were primarily identified from the Scientific Committee on Consumer Safety (SCCS) 2010 memorandum (addendum) on the in vitro test EpiSkin™ for skin irritation testing. Fifty test items were evaluated in which both standard photometry and HPLC/UPLC-spectrophotometry were used for endpoint detection. The results obtained in this study: 1) provide further support for Within Laboratory Reproducibility of HPLC-UPLC-spectrophotometry for measurement of formazan; 2) demonstrate, through use a case study with Basazol C Blue pr. 8056, that HPLC/UPLC-spectrophotometry enables determination of an in vitro classification even when this is not possible using standard photometry and 3) addresses the question raised by SCCS in their 2010 memorandum (addendum) to consider an endpoint detection system not involving optical density quantification in in vitro reconstructed human epidermis skin irritation test methods.
Asunto(s)
Cosméticos/toxicidad , Epidermis/efectos de los fármacos , Pruebas de Irritación de la Piel , Bioensayo , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Humanos , Técnicas In Vitro , Oxidación-Reducción , Espectrofotometría , Sales de Tetrazolio/metabolismo , Tiazoles/metabolismoRESUMEN
A number of in vitro test methods using Reconstructed human Tissues (RhT) are regulatory accepted for evaluation of skin corrosion/irritation. In such methods, test chemical corrosion/irritation potential is determined by measuring tissue viability using the photometric MTT-reduction assay. A known limitation of this assay is possible interference of strongly coloured test chemicals with measurement of formazan by absorbance (OD). To address this, Cosmetics Europe evaluated use of HPLC/UPLC-spectrophotometry as an alternative formazan measurement system. Using the approach recommended by the FDA guidance for validation of bio-analytical methods, three independent laboratories established and qualified their HPLC/UPLC-spectrophotometry systems to reproducibly measure formazan from tissue extracts. Up to 26 chemicals were then tested in RhT test systems for eye/skin irritation and skin corrosion. Results support that: (1) HPLC/UPLC-spectrophotometry formazan measurement is highly reproducible; (2) formazan measurement by HPLC/UPLC-spectrophotometry and OD gave almost identical tissue viabilities for test chemicals not exhibiting colour interference nor direct MTT reduction; (3) independent of the test system used, HPLC/UPLC-spectrophotometry can measure formazan for strongly coloured test chemicals when this is not possible by absorbance only. It is therefore recommended that HPLC/UPLC-spectrophotometry to measure formazan be included in the procedures of in vitro RhT-based test methods, irrespective of the test system used and the toxicity endpoint evaluated to extend the applicability of these test methods to strongly coloured chemicals.
Asunto(s)
Colorantes/toxicidad , Formazáns/toxicidad , Pruebas de Irritación de la Piel/métodos , Alternativas a las Pruebas en Animales , Cromatografía Líquida de Alta Presión , Cosméticos/toxicidad , Oftalmopatías/inducido químicamente , Humanos , Irritantes/toxicidad , Reproducibilidad de los Resultados , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/patología , Espectrofotometría Ultravioleta , Sales de Tetrazolio/química , Tiazoles/químicaRESUMEN
We have developed a 3-dimensional human hemi-cornea which comprises an immortalized epithelial cell line and keratocytes embedded in a collagen stroma. In the present study, we have used MTT reduction of the whole tissue to clarify whether the production of this complex 3-D-model is transferable into other laboratories and whether these tissues can be constructed reproducibly. Our results demonstrate the reproducible production of the hemi-cornea model according to standard operation procedures using 15 independent batches of reconstructed hemi-cornea models in two independent laboratories each. Furthermore, the hemi-cornea tissues have been treated with 20 chemicals of different eye-irritating potential under blind conditions to assess the performance and limitations of our test system comparing three different prediction models. The most suitable prediction model revealed an overall in vitro-in vivo concordance of 80% and 70% in the participating laboratories, respectively, and an inter-laboratory concordance of 80%. Sensitivity of the test was 77% and specificity was between 57% and 86% to discriminate classified from non-classified chemicals. We conclude that additional physiologically relevant endpoints in both epithelium and stroma have to be developed for the reliable prediction of all GHS classes of eye irritation in one stand alone test system.
Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Córnea/efectos de los fármacos , Irritantes/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Técnicas In Vitro , Modelos Biológicos , Control de Calidad , Reproducibilidad de los ResultadosRESUMEN
In recent years many efforts have been made to replace dermal toxicity testing of chemicals in the animal by in vitro assays. As a member of a German research consortium, we have previously contributed to the validation of an in vitro test protocol for percutaneous absorption studies on the basis of reconstructed human epidermis and both human and pig skin ex vivo. Aiming to assess the barrier properties of a newly developed reconstructed skin model, this protocol has now been transferred to the Phenion Full-Thickness Skin Model (FT model). The permeation of testosterone and caffeine was quantified in parallel to that of pig skin using Franz-type diffusion cells. In addition, the permeation of benzoic acid and nicotine was studied. As expected, the FT model is more permeable than pig skin, yet its barrier properties are well in accordance with those of reconstructed human epidermis when compared to previous data. In fact, the FT model most efficiently retards testosterone as the compound of highest lipophilicity, which can be explained by an additional uptake by a reservoir formed by the dermis equivalent. Thus, the structure closely parallels human skin. In consequence, the Phenion FT model appears to be suitable for percutaneous absorption studies in hazard analysis and should be subjected to a catch-up validation study.
Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Modelos Biológicos , Absorción Cutánea , Animales , Ácido Benzoico/farmacocinética , Cafeína/farmacocinética , Humanos , Nicotina/farmacología , Permeabilidad , Especificidad de la Especie , Porcinos , Testosterona/farmacocinéticaRESUMEN
We report a patient with Parkinson's disease whose whole body drenching sweats were completely alleviated by stimulation of the subthalamic nucleus and/or adjacent structures. Sweating reappeared 4h after the pulse generator (stimulation) was turned off and ceased when stimulation was resumed. Imaging studies with reconstruction indicated that stimulation of, or spread of stimulation from, the caudal medial aspect of the right subthalamic nucleus and/or the caudal aspect of the ventral thalamus/zona incerta may be responsible for alleviating the drenching sweats.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiopatología , Sudoración/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/cirugía , Trastornos del Movimiento/terapia , Enfermedad de Parkinson/cirugía , Núcleo Subtalámico/patología , Tálamo/patología , Tálamo/fisiopatología , Factores de Tiempo , Resultado del TratamientoRESUMEN
The resilience of the human skin is mediated by elastic fibres mainly consisting of fibrillins and elastin. In order to establish a model system to study the impact of cosmetic and pharmaceutical compounds on the elastic system in vitro, we analyzed the expression of elastin in a newly developed full-thickness skin model. After a 5-week cultivation period the skin model developed a fully differentiated epidermis including a stratum corneum. The dermis contains fibroblasts embedded in extracellular matrix proteins. The models were viable until at least 51 days at the air-liquid interface (ALI) culture. Using immunohistochemistry we detected elastin first on day 7 of ALI. With proceeding culture time, elastin-positive fibres of different lengths and distribution patterns accumulated in the dermal compartment. Elastin mRNA expression started on day 7 of ALI, increased until day 10 and then dropped to a level comparable to that of day 7. Our results demonstrate that in our full-thickness skin model an in vivo-like elastic system, which clearly mimics at least two subsets of dermal elastic fibres, is generated. This physiological property favours the model as a promising animal-free approach to study those processes leading to an environment- and age-dependent decrease in skin elasticity.
Asunto(s)
Elastina/biosíntesis , Piel/metabolismo , Animales , Bovinos , Células Cultivadas , Colágeno , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Humanos , Inmunohistoquímica , Queratinocitos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/citologíaRESUMEN
Single-cell recording of the subthalamic nucleus (STN) was undertaken in 14 patients with Parkinson's disease submitted to surgery. Three hundred and fifty neurones were recorded and assessed for their response to passive and active movements. Thirty-two per cent were activated by passive and active movement of the limbs, oromandibular region and abdominal wall. All neurones with sensorimotor responses were in the dorsolateral region of the STN. Arm-related neurones were lateral (> or =14 mm plane) to leg-related neurones, which were found more medially (< or =12 mm). Representation of the oromandibular musculature was in the middle of the sensorimotor region (approximately 13 mm plane) and ventral to the arm and leg. Two hundred neurones were adequately isolated for 'off-line' analysis. The mean frequency of discharge was 33 +/- 17 Hz (13-117 Hz). Three types of neuronal discharges were distinguished: irregular (60.5%), tonic (24%) and oscillatory (15.5 %). They were statistically differentiated on the basis of their mean firing frequency and the coefficient of variation of the interspike interval. Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded. The majority (84%) of these were sensitive to movement and were located in the dorsolateral region of the STN. Cross power analysis (n = 16) between the rhythmic neuronal activity and tremor in the limbs showed a peak frequency of 5 Hz (4-8 Hz). Neuronal activity of the substantia nigra pars reticulata was recorded 0.5-3 mm below the STN. Eighty neurones were recorded 'on-line' and 27 were isolated for 'off-line' analysis. A tonic pattern of discharge characterized by a mean firing rate of 71 +/- 28 Hz (35-122 Hz) with a mean coefficient of variation of the interspike interval of 0.85 +/- 0.29 ms was found. In only three neurones (11%) was there a response to sensorimotor stimulation. The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys.
Asunto(s)
Neuronas/fisiología , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/citología , Núcleo Subtalámico/fisiopatología , Potenciales de Acción/fisiología , Mapeo Encefálico , Electromiografía , Electrofisiología , Humanos , Movimiento/fisiología , Periodicidad , Temblor/fisiopatologíaRESUMEN
Microelectrode recording was performed in the basal ganglia of 3 patients with generalized dystonia and 1 patient with hemiballismus secondary to a brainstem hemorrhage. Neuronal activity was recorded from the internal and external segments of the globus pallidus and assessed for mean discharge rate and pattern of spontaneous activity. The responses of neurons in the internal segment of the globus pallidus to passive and active movements were also evaluated. Mean discharge rates of neurons in both segments of the pallidum in patients with dystonia and the patient with hemiballismus were considerably lower than those reported for patients with idiopathic Parkinson's disease. In addition, the pattern of spontaneous neuronal activity was highly irregular, occurring in intermittent grouped discharges separated by periods of pauses. Although receptive fields in the dystonia patients were widened and less specific than those reported in normal monkeys, neuronal responses to movement were uncommon in the hemiballismus patient. Before surgery, patients with dystonia experienced abnormal posturing and involuntary movements. Coactivation of agonist-antagonist muscle groups was observed both at rest and during the performance of simple movements. After pallidotomy there was a significant reduction in the involuntary movement associated with these disorders and a more normal pattern of electromyographic activity during rest and movement. Given the improvement in dystonic and hemiballistic movements in these patients after ablation of the sensorimotor portion of the internal segment of the globus pallidus, we suggest that pallidotomy can be an effective treatment for patients with dystonia and also for patients with medically intractable hemiballismus. Based on the finding of decreased neuronal discharge rates in pallidal neurons, we propose that physiologically dystonia most closely resembles a hyperkinetic movement disorder. A model for dystonia is proposed that incorporates the observed changes in the rate and pattern of neuronal activity in the pallidum with data from neuroimaging with positron emission tomography and 2-deoxyglucose studies.
Asunto(s)
Ganglios Basales/fisiopatología , Distonía/fisiopatología , Trastornos del Movimiento/fisiopatología , Neuronas/fisiología , Adulto , Anciano , Mapeo Encefálico , Electromiografía , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The role of the subthalamic nucleus (STN) in the origin of parkinsonian tremor is discussed. Previous studies in monkeys made parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration suggested a direct participation of the STN in the pathophysiology of tremor. We recorded tremor-related activity in the STN in 12 patients with Parkinson's disease (PD) and found that microstimulation of the sensorimotor region of the nucleus, where these neurons are present, stopped the tremor with a very short latency. Long-term treatment by means of bilateral deep-brain stimulation (DBS) in the same 12 patients led to a significant reduction of tremor as well as other cardinal features of PD. This effect was blindly assessed at 3 months after implantation. In another group of seven patients, a unilateral lesion of the STN was performed. Both postural and resting tremor were significantly improved on the limbs contralateral to the lesion side. In three patients, tremor disappeared completely after 12 months of follow up. The electrophysiologic data and therapeutic effect of inactivating the STN strongly indicated that this structure is directly involved in the origin of parkinsonian tremor, as suggested by the MPTP model.
Asunto(s)
Enfermedad de Parkinson/complicaciones , Núcleos Talámicos/cirugía , Temblor/etiología , Temblor/terapia , Adulto , Anciano , Estimulación Eléctrica/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Periodo Posoperatorio , Cuidados PreoperatoriosRESUMEN
OBJECT: The authors describe the microelectrode recording and stimulation techniques used for localizing the caudal sensorimotor portion of the globus pallidus internus (GPi) and nearby structures (internal capsule and optic tract) in patients undergoing GPi pallidotomy. METHODS: Localization is achieved by developing a topographic map of the abovementioned structures based on the physiological characteristics of neurons in the basal ganglia and the microexcitable properties of the internal capsule and optic tract. The location of the caudal GPi can be determined by "form fitting" the physiological map on relevant planes of a stereotactic atlas. A sensorimotor map can be developed by assessing neuronal responses to passive manipulation or active movement of the limbs and orofacial structures. The internal capsule and optic tract, respectively, can be identified by the presence of stimulation-evoked movement or the patient's report of flashes or speckles of light that occur coincident with stimulation. The optic tract may also be located by identifying the neural response to flashes of light. The anatomical/physiological map is used to guide lesion placement within the sensorimotor portion of the pallidum while sparing nearby structures, for example, the external globus pallidus, nucleus basalis, optic tract, and internal capsule. The lesion location and size predicted by using physiological recording together with thin-slice high-resolution magnetic resonance imaging reconstructions of the lesion were confirmed in one patient on histological studies. CONCLUSIONS: These data provide important information concerning target identification for ablative or deep brain stimulation procedures in idiopathic Parkinson's disease and other movement disorders.
Asunto(s)
Globo Pálido/cirugía , Microelectrodos , Enfermedad de Parkinson/cirugía , Antiparkinsonianos/uso terapéutico , Ganglios Basales/fisiopatología , Ganglios Basales/cirugía , Encefalopatías/fisiopatología , Encefalopatías/cirugía , Mapeo Encefálico , Tolerancia a Medicamentos , Estimulación Eléctrica/instrumentación , Electroencefalografía/instrumentación , Músculos Faciales/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Ilustración Médica , Neuronas Motoras/fisiología , Movimiento , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/cirugía , Músculo Esquelético/fisiopatología , Vías Nerviosas/fisiopatología , Vías Nerviosas/cirugía , Neuronas Aferentes/fisiología , Nervio Óptico/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Estimulación Luminosa , Radiología Intervencionista/instrumentaciónRESUMEN
The objective of this study was to describe the incidence and types of visual field defects after posterior globus pallidus internus (GPi) pallidotomy for Parkinson's disease. The creation of the pallidotomy lesion carries a risk of damaging neighboring structures such as the optic tract. The reported frequency of visual field defects in patients after pallidotomy varies from 0 to 40%. Goldmann visual field testing was performed on 40 patients who underwent microelectrode-guided posterior GPi pallidotomy. The optic tract was identified during the procedure by listening during microelectrode recording for the evoked responses to light flashes and by assessing stimulation-induced subjective responses. After the first 18 patients, lesioning thresholds were increased from 0.5 to > or =1.0 mA so that the lesion was placed more distant from the optic tract. The location of individual lesions was determined on postsurgical MRI. Three patients (7.5%) had visual field defects likely related to the pallidotomy. These were contralateral homonymous superior quadrantanopias, associated in two patients with small paracentral scotomas. The incidence of visual field defects with the early technique was 11% (2/18) and decreased to 4.5% (1/22) after thresholds for lesioning were increased. Except for the location of the lesion relative to the optic tract (more ventral, adjacent to or extending into the optic tract), no other variable correlated with a post-pallidotomy visual field defect. Microelectrode-guided GPi pallidotomy is a relatively safe procedure as regards visual function even when the optic tract is used as a guide for lesion placement.
Asunto(s)
Globo Pálido/cirugía , Enfermedad de Parkinson/cirugía , Complicaciones Posoperatorias/epidemiología , Baja Visión/etiología , Campos Visuales , Adulto , Anciano , Femenino , Humanos , Incidencia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Baja Visión/epidemiología , Vías Visuales/fisiopatología , Vías Visuales/cirugíaRESUMEN
The role of the subthalamic nucleus (STN) in the origen of parkinsonian tremor is discussed. Previous studies in monkeys made parkinsonian by MPTP (1-methyl-4-phenil-1,2,3,6-tetrahydropyridine) administration suggested a direct participation of the STN in the pathophysiology of tremor. We recorded tremor-related activity in the STN in 12 patients with Parkinso's disease (PD) and found that microstimulation of the sensorimotor region of the nucleus, where these neurons are present, stopped the tremor sith a very short latency. Long-term treatment by means of bilateral deep-brain stimulation (DBS) in the same 12 patients led to a significant reduction of tremor as well as other cardinal features of PD. This effect was blindly assessed at 3 months after implantation. In another group of seven patients, a unilaeral lesion of the STN was performed. Both postural and resting tremor were significantly improved on the limbs contralateral to the lesion side. In three patients, tremor disappearedcompletely after 12 months of follow up. The electrophysiologic data and therapeutic effect of inactivating the STN strongly indicated that this structure is directly involved in the origin of paarkinsonian tremor, as suggested by the MPTP model(AU)
Asunto(s)
Humanos , Temblor , Enfermedad de Parkinson/cirugía , Tálamo/cirugíaRESUMEN
Pharmacokinetics were studied in relation to hepatic side-effects in 20 patients (19 adults aged 18-53 years and one child of 11 years) undergoing BMT after conditioning with 1 mg/kg busulfan (every 6 hours for 16 doses). Busulfan was quantitated in plasma samples at 10 time points within the 6 h dosing interval using HPLC before and after dose numbers 1, 2, 5, 13 and 14. For 13 patients data on all five doses are available; for the remaining seven patients three to four doses were studied. Mean maximum concentrations were 1512 ng/ml; mean trough levels for second and subsequent doses were 615 ng/ml. Maxima (Cmax) tended to be lower and times of maxima (Tmax) were later when busulfan was taken with a meal. Correlation of the area under the concentration versus time curve (AUC0-6h) between different doses was low within patients. In several patients problems with compartmental fitting of concentration data were observed mainly caused by the short dosing interval, which made estimates of T1/2 and model derived AUCs unstable. Three patients experienced hepatic veno-occlusive disease; kinetic parameters were not helpful in describing a particulate risk constellation for this subgroup. In our experience, the role of drug monitoring in this setting needs to be defined more clearly.