RESUMEN
BACKGROUND AND PURPOSE: Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. MATERIALS AND METHODS: A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. RESULTS: Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. CONCLUSIONS: DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms.
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Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Neuroimagen/métodos , Trastornos Parkinsonianos/diagnóstico por imagen , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder. Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses. Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients. Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker. Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (i.e. different disease stages and/or clinical subtypes), experimental designs (i.e. cross-sectional vs. longitudinal), and image analysis methodologies (i.e. automatic vs. manual segmentation). This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues.
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Progresión de la Enfermedad , Sustancia Gris/patología , Enfermedad de Parkinson/patología , Sustancia Gris/diagnóstico por imagen , Humanos , Enfermedad de Parkinson/diagnóstico por imagenRESUMEN
We assess the feasibility of using airborne imagery for Buffel grass detection in Australian arid lands and evaluate four commonly used image classification techniques (visual estimate, manual digitisation, unsupervised classification and normalised difference vegetation index (NDVI) thresholding) for their suitability to this purpose. Colour digital aerial photography captured at approximately 5 cm of ground sample distance (GSD) and four-band (visiblenear-infrared) multispectral imagery (25 cm GSD) were acquired (14 February 2012) across overlapping subsets of our study site. In the field, Buffel grass projected cover estimates were collected for quadrates (10 m diameter), which were subsequently used to evaluate the four image classification techniques. Buffel grass was found to be widespread throughout our study site; it was particularly prevalent in riparian land systems and alluvial plains. On hill slopes, Buffel grass was often present in depressions, valleys and crevices of rock outcrops, but the spread appeared to be dependent on soil type and vegetation communities. Visual cover estimates performed best (r 2 0.39), and pixel-based classifiers (unsupervised classification and NDVI thresholding) performed worst (r 2 0.21). Manual digitising consistently underrepresented Buffel grass cover compared with field- and image-based visual cover estimates; we did not find the labours of digitising rewarding. Our recommendation for regional documentation of new infestation of Buffel grass is to acquire ultra-high-resolution aerial photography and have a trained observer score cover against visual standards and use the scored sites to interpolate density across the region.
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Conservación de los Recursos Naturales , Monitoreo del Ambiente/métodos , Procesamiento de Imagen Asistido por Computador , Fotograbar , Poaceae/crecimiento & desarrollo , Tecnología de Sensores Remotos , AustraliaRESUMEN
Parkinson's disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in bradykinesia and rigidity, but does not explain resting tremor in PD. To understand the roles of cerebello-thalamo-cortical (CTC) and STC circuits in the pathophysiology of the heterogeneous clinical presentation of PD, we collected functional magnetic resonance imaging (fMRI) data from 17 right-handed PD patients [nine tremor predominant (PDT) and eight akinetic-rigidity predominant (PDAR)] and 14 right-handed controls while they performed internally-guided (IG) sequential finger tapping tasks. The percentage of voxels activated in regions constituting the STC and CTC [divided as cerebellar hemisphere-thalamo-cortical (CHTC) and vermis-thalamo-cortical (CVTC)] circuits was calculated. Multivariate analysis of variance compared the activation patterns of these circuits between study groups. Compared to controls, both PDAR and PDT subjects displayed an overall increase in the percentage of voxels activated in both STC and CTC circuits. These increases reached statistical significance in contralateral STC and CTC circuits for PDT subjects, and in contralateral CTC pathways for PDAR subjects. Comparison of PDAR and PDT subjects revealed significant differences in ipsilateral STC (P=0.005) and CTC (P=0.043 for CHTC and P=0.003 for CVTC) circuits. These data support the differential involvement of STC and CTC circuits in PD subtypes, and help explain the heterogeneous presentation of PD symptoms. These findings underscore the importance of integrating CTC circuits in understanding PD and other disorders of the basal ganglia.
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Cerebelo/metabolismo , Cuerpo Estriado/metabolismo , Rigidez Muscular/metabolismo , Enfermedad de Parkinson/metabolismo , Tálamo/metabolismo , Temblor/metabolismo , Adulto , Anciano , Cerebelo/fisiopatología , Cuerpo Estriado/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rigidez Muscular/etiología , Rigidez Muscular/fisiopatología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Tálamo/fisiopatología , Temblor/etiología , Temblor/fisiopatologíaRESUMEN
Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson's disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI 2 years apart from 5 PD (57+/-8 yr) and five Controls (57+/-9 yr) performing either externally- (EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the mean of the dominant and non-dominant hands of Controls. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD.
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Cerebelo/fisiopatología , Corteza Cerebral/fisiopatología , Enfermedad de Parkinson/fisiopatología , Tálamo/fisiopatología , Mapeo Encefálico , Progresión de la Enfermedad , Dedos/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Persona de Mediana Edad , Movimiento/fisiología , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Desempeño Psicomotor/fisiologíaRESUMEN
BACKGROUND: A recent case report suggested the presence of asymmetrical lateral ventricular enlargement associated with motor asymmetry in Parkinson's disease (PD). The current study explored these associations further. METHODS: Magnetic resonance imaging (3T) scans were obtained on 17 PD and 15 healthy control subjects at baseline and 12-43 months later. Baseline and longitudinal lateral ventricular volumetric changes were compared between contralateral and ipsilateral ventricles in PD subjects relative to symptom onset side and in controls relative to their dominant hand. Correlations between changes in ventricular volume and United Parkinson's disease rating scale motor scores (UPDRS-III) whilst on medication were determined. RESULTS: The lateral ventricle contralateral to symptom onset side displayed a faster rate of enlargement compared to the ipsilateral (P = 0.004) in PD subjects, with no such asymmetry detected (P = 0.312) in controls. There was a positive correlation between ventricular enlargement and worsening motor function assessed by UPDRS-III scores (r = 0.96, P < 0.001). DISCUSSION: There is asymmetrical lateral ventricular enlargement that is associated with PD motor asymmetry and progression. Further studies are warranted to investigate the underlying mechanism(s), as well as the potential of using volumetric measurements as a marker for PD progression.
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Lateralidad Funcional , Ventrículos Laterales/patología , Enfermedad de Parkinson/patología , Antiparkinsonianos/uso terapéutico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Actividad Motora/fisiología , Tamaño de los Órganos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
The motor deficits in Parkinson's disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [(123)I](-)-2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of functional magnetic resonance imaging (fMRI) data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twin's activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (cerebellar-cortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG-cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar-cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG-cortical and cerebellar-cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG-cortical pathway, but "over-corrected" the activation in the ipsilateral BG-cortical and bilateral cerebellar-cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG-cortical and cerebellar-cortical pathways are task-specifically influenced by PD. The levodopa-induced "over-activation" of BG-cortical and cerebellar-cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration.
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Encéfalo/fisiología , Vías Nerviosas/fisiología , Enfermedad de Parkinson/fisiopatología , Desempeño Psicomotor/fisiología , Antiparkinsonianos/uso terapéutico , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiología , Ganglios Basales/fisiopatología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Estudios de Casos y Controles , Cerebelo/efectos de los fármacos , Cerebelo/fisiología , Cerebelo/fisiopatología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Corteza Cerebral/fisiopatología , Humanos , Intención , Levodopa/uso terapéutico , Imagen por Resonancia Magnética , Análisis por Apareamiento , Vías Nerviosas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Desempeño Psicomotor/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/fisiología , Tálamo/fisiopatología , Tomografía Computarizada de Emisión de Fotón Único , Gemelos MonocigóticosRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder that results in major motor disturbances due primarily to loss of midbrain dopamine neurons. The mainstream treatment has been dopaminergic replacement therapy aimed at symptomatic relief, with the gold standard drug being the dopamine precursor levodopa. The general dogma has been that levodopa works primarily by indirectly activating the D(2) family of dopamine receptors. Recently, a number of direct dopamine agonists that target the D(2) and D(3) dopamine receptors have been used as dopaminergic replacement strategies. Although these direct D(2) and D(3) drugs cause only modest improvement in motor function compared to levodopa, they can delay the initiation of levodopa and can act synergistically with levodopa. In addition, they can delay the onset of levodopa-related motor complications. Recent imaging data also suggest that they may have neuroprotective effects. Whereas D(2)/D(3) agonists have received much attention as several drugs are available for clinical trials and usage, there has been a large body of data showing that the D(1) receptor actually may play a larger role in restoration of normal motor function. This review examines the current use of dopamine D(2)/D(3) agonists in treatment of PD and their potential for providing neuroprotection. Furthermore, we also examine the potential that D(1) agonists might have in neuroprotective actions in the disease progression.
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Agonistas de Dopamina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/prevención & control , Receptores de Dopamina D1/agonistas , Animales , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacología , Humanos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/fisiopatología , Receptores de Dopamina D1/fisiologíaRESUMEN
Benign and malignant papillary lesions of the breast (PBL) can be difficult to distinguish in fine-needle aspirates (FNA). This study evaluates the use of smooth muscle actin (SMA) and a new smooth muscle-specific protein, calponin, for identifying myoepithelial cells (MEC) by immunohistochemical methods in paraffin-embedded cell blocks of FNA of PBL. Formalin-fixed, paraffin-embedded cell blocks of 40 cases of PBL were stained using SMA and calponin, steam heat-induced epitope retrieval, and an avidin biotin-complex technique. Staining was evaluated in MEC, epithelial, and stromal cells. The diagnosis of benign vs. malignant papillary lesion was made by using cytomorphological criteria and the presence/absence of MEC in the cell block. These results were compared to the original cytologic and subsequent histologic diagnoses. Of 40 cases of FNA diagnosed as PBL, there were 27 intraductal papillomas (IP), 6 papillary lesions with atypical features (PLAF), and 7 papillary carcinomas (PC). In all of the IP, MEC stained both with SMA and calponin. None of the PC cases was positive for MEC with calponin, and 2 out of 7 cases were weakly positive by SMA. In 6 cases of PLAF, 2 were negative for MEC, both by SMA and calponin, and a malignant papillary lesion was confirmed by histology. The remaining 4 cases were positive for MEC with both markers and were confirmed to be benign by histology. SMA stained stromal cells strongly in all of the cases where stroma was present (18 of a total of 40 cases of PBL), while calponin stained stroma focally in only 7 cases. More than half of all cases had nuclear staining of epithelial cells with SMA; calponin did not show any nuclear staining.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Proteínas de Unión al Calcio/análisis , Carcinoma Papilar/química , Proteínas de Neoplasias/análisis , Papiloma Intraductal/química , Papiloma/química , Actinas/análisis , Biopsia con Aguja , Neoplasias de la Mama/diagnóstico , Carcinoma Papilar/diagnóstico , Células Epiteliales/química , Femenino , Humanos , Técnicas para Inmunoenzimas , Proteínas de Microfilamentos/análisis , Papiloma/patología , Papiloma Intraductal/diagnóstico , Adhesión en Parafina , CalponinasAsunto(s)
Secuestro Broncopulmonar/diagnóstico por imagen , Disnea/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano , Aorta Torácica/anomalías , Secuestro Broncopulmonar/etiología , Cateterismo Cardíaco , Circulación Colateral/fisiología , Diagnóstico Diferencial , Humanos , MasculinoRESUMEN
OBJECTIVE: To evaluate the diagnostic efficacy of computed tomography (CT)-guided needle biopsies of head and neck lesions. DESIGN: All CT-guided needle biopsies of head and neck lesions performed between September 1994 and February 1999 were included. Cytopathologic and histologic records, along with patient clinical records, were reviewed. SETTING: A tertiary care medical center. PATIENTS: Patients referred for evaluation of lesions inaccessible to routine methods of needle biopsy. RESULTS: Thirty-seven patients underwent 42 CT-guided biopsies. There were included 12 lesions in or adjacent to the skull base and 9 lesions around the pharyngoesophageal or laryngotracheal complex; the other lesions were located in the deep lobe of the parotid gland (n = 7), deep neck area (n = 12), and thyroid gland (n = 2). Diagnostic cytologic biopsy specimens were obtained in 38 (91%) of 42 needle biopsy procedures. The results were supported histologically and/or clinically in 36 cases (95%). Eighteen patients underwent open surgical procedures. Histologic confirmation was found in 86% of cases. Nineteen patients (51%) avoided an open surgical procedure: 11 with benign disease and 8 with recurrent malignancy. There were no false-positive or false-negative results, and no complications were identified. CONCLUSIONS: Computed tomography-guided needle biopsy is a safe and reliable minimally invasive technique for the diagnosis of poorly accessible or deep-seated lesions of the head and neck. Diagnostic needle biopsies allow improved preoperative planning and patient counseling in surgical patients and avoidance of open surgical procedures in patients with benign disease or recurrent malignant neoplasms.
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Biopsia con Aguja/instrumentación , Neoplasias de Cabeza y Cuello/patología , Tomografía Computarizada por Rayos X/instrumentación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
OPC-14597 {aripiprazole; 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl) butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales.
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Antipsicóticos/farmacología , Piperazinas/farmacología , Quinolonas/farmacología , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Animales , Aripiprazol , Células CHO , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cricetinae , Glioma , Ratas , Receptores Dopaminérgicos/clasificación , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/genética , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/clasificación , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/genética , Células Tumorales CultivadasRESUMEN
In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewhat lower than the two parent compounds, 3 and 4. Compounds with N-propyl and N-allyl substituents (5b, 5c, 6c, and 6d) had higher affinity for the D2 dopamine receptor than did their corresponding secondary amines (5a and 6a). Slightly different effects on affinity of an n-propyl and an n-allyl group in the new analogues of 3 and 4 suggest that different binding orientations may be invoked at the receptor.
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Agonistas de Dopamina/síntesis química , Isoquinolinas/química , Naftoles/química , Quinolinas/química , Receptores de Dopamina D2/efectos de los fármacos , Animales , Unión Competitiva , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacología , Técnicas In Vitro , Masculino , Neostriado/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
This study examined the ability of 63 subjects to discriminate a length difference, using a precision grip with the thumb and the index finger. To assess the relative contribution of different peripheral inputs associated with the discriminative ability of precision grip, three tasks were performed under each of three conditions-normal conditions; when vibratory stimuli were delivered to the forearm muscles; and when a local anesthetic was administered to the index finger. Under the first and second conditions, the length difference detected most frequently was 2.0 mm; in the third task, it was 3.0 mm. When a 100-Hz vibratory stimulus was applied to the forearm muscles, no difference in the threshold for length discrimination was observed for three of seven subjects. After injection of lidocaine into the metacarpophalangeal joint of the index finger, the threshold for length discrimination was significantly different for five of seven subjects. The detected length difference ranged from 1.0 to 4.0 mm. The authors question whether a single peripheral input is likely to make a major contribution to the complex perception that is used for discrimination tasks.
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Anestésicos Locales/efectos adversos , Dedos/fisiología , Fuerza de la Mano/fisiología , Nervios Periféricos/fisiología , Percepción del Tamaño/fisiología , Vibración/efectos adversos , Adolescente , Adulto , Humanos , Movimiento/fisiología , Traumatismos de los Nervios Periféricos , Desempeño Psicomotor , Reproducibilidad de los Resultados , Umbral Sensorial , TactoRESUMEN
The role of drug efficacy in agonist-induced desensitization was studied in C-6 glioma cells transfected with the monkey dopamine D1A (mD1A) receptor. Dopamine pretreatment for 2 hr produced greater than 80% loss of responsiveness in the stimulation of cAMP accumulation that was blocked by the D1 antagonist SCH23390. A series of full and partial D1 agonists from structurally dissimilar classes were then examined. Three full agonists (dihydrexidine, SKF82958, A77636) desensitized the receptor to the same extent as dopamine, whereas two other full agonists (dinapsoline and A68930) and all the partial agonists tested (SKF38393, pergolide and d-lysergic acid diethylamide tartrate) produced only partial desensitization (i.e., 50% that of dopamine). Whereas partial agonists (i.e., SKF38393, pergolide and d-lysergic acid diethylamide tartrate) caused no alteration in ligand-accessible mD1A receptors, four of the full agonists (dopamine, dihydrexidine, dinapsoline, A68930) caused a 30 to 40% reduction in receptor number. One full agonist, A77636, caused nearly an 80% decrease in receptor number, despite the fact that the degree of functional desensitization was similar to the other full agonists. The desensitization of the D1 receptor was homologous, not affecting beta-2 adrenergic receptors endogenous to C-6 cells. Neither incubation with cAMP analogs, nor inhibition of protein kinase A, affected dopamine-induced desensitization, suggesting a cAMP-independent mechanism in this cell line. Together, these data suggest that functional desensitization of the mD1A receptor expressed in C-6 glioma cells is a cAMP-independent mechanism, cannot be predicted reliably from agonist efficacy for stimulating adenylate cyclase and can occur in the absence of changes in receptor number.
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Receptores de Dopamina D1/fisiología , Animales , Benzazepinas/metabolismo , AMP Cíclico/biosíntesis , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Macaca mulatta , Trastornos Relacionados con Sustancias/etiologíaRESUMEN
A series of substituted racemic naphthofurans were synthesized as "hybrid" molecules of the two major prototypical hallucinogenic drug classes, the phenethylamines and the tryptamines/ergolines. Although it was hypothesized that these new agents might possess high affinity for the serotonin 5-HT2A/2C receptor subtypes, unexpected affinity for muscarinic receptors was observed. The compounds initially synthesized for this study were (+/-)-anti- and syn-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan (4a,b), respectively, and their 8-bromo derivatives 4c,d, respectively. The brominated primary amines 4c,d were assayed initially for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0. 08 mg/kg). Also, 4c,d were evaluated for their ability to compete against agonist and antagonist radioligands at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. After the syn diastereomers were found to have the highest activity in these preliminary assays, the N-alkylated analogues syn-N,N-dimethyl-4-amino-6-methoxy-2a,3,4, 5-tetrahydro-2H-naphtho[1,8-bc]furan (4e) and syn-N, N-dipropyl-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1, 8-bc]furan (4f) were prepared and assayed for their affinities at [3H]ketanserin-labeled 5-HT2A and [3H]-8-OH-DPAT-labeled 5-HT1A sites. All of the molecules tested had relatively low affinity for serotonin receptors, yet a preliminary screen indicated that compound 4d had affinity for muscarinic receptors. Thus, 4b,d,e were evaluated for their affinity at muscarinic M1-M5 receptors and also assessed for their functional characteristics at the M1 and M2 isoforms. Compound 4d had affinities of 12-33 nM at all of the muscarinic sites, with 4b,e having much lower affinity. All three compounds fully antagonized the effects of carbachol at the M1 receptor, while only 4d completely antagonized carbachol at the M2 receptor. The fact that the naphthofurans lack LSD-like activity suggests that they do not bind to the serotonin receptor in a way such that the tricyclic naphthofuran nucleus is bioisosteric with, and directly superimposable upon, the A, B, and C rings of LSD. This also implies, therefore, that the hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation for these two chemical classes, contrary to previous hypotheses.
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Ergolinas/química , Furanos , Alucinógenos , Antagonistas Muscarínicos , Fenetilaminas/química , Tetrahidronaftalenos , Animales , Unión Competitiva , Encéfalo/metabolismo , Línea Celular , Cricetinae , Aprendizaje Discriminativo/efectos de los fármacos , Furanos/síntesis química , Furanos/química , Furanos/metabolismo , Furanos/farmacología , Alucinógenos/síntesis química , Alucinógenos/química , Alucinógenos/metabolismo , Alucinógenos/farmacología , Humanos , Dietilamida del Ácido Lisérgico/farmacología , Masculino , Ratones , Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/química , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacologíaRESUMEN
The aim of the study was to assess the pharmacokinetic properties and clinical effectiveness of L-dopa/carbidopa solution treatment in patients with parkinsonian motor fluctuations. No significant difference in maximal L-dopa concentration, time to peak L-dopa concentration and area under curve was found in single dose studies which compared equivalent tablet and solution L-dopa/carbidopa doses in 9 patients. Seven out of 10 patients treated with hourly doses of liquid L-dopa/carbidopa were improved after switching from conventional tablet medication. Less 'off' time per day and less 'off' phase disability were the usual benefits. Six of these patients maintained this improvement and continued on long-term liquid medication. The benefits of this treatment do not relate to improved L-dopa delivery to the bloodstream. The ability of patients to fractionate the treatment into small, frequent doses which can be used more flexibly than tablets appears to confer the main advantages of liquid L-dopa/carbidopa in the management of parkinsonian motor fluctuations.
RESUMEN
The clinical behavior of giant cell tumor is related to the radiological appearance. To test the hypothesis that in vitro proliferation of the neoplastic stromal cell population of giant cell tumors is related to the radiological appearance, this study was undertaken. A prospective analysis of the cells migrating from 13 consecutive tumors was conducted. Growth curves and population doubling-times (PDT) for first and fifth passages were calculated and alkaline phosphatase levels were measured and compared to preoperative radiographic staging. A strong negative correlation was found between PDT and the radiographic stage. Tumors in stages I and II (low aggressiveness) were found to have an average cell population doubling-time of 11 (SD 2.2) days, while those in stage III (high aggressiveness) showed a doubling-time of 6 (SD 2.2) days. Low alkaline phosphatase activity was noted in all cultures, a finding consistent with the putative preosteoblastic potential of these stromal cells. This putative origin is also indicated by the differentiation response to retinoic acid. The findings suggest that the in vitro proliferation of the mononuclear stromal cell population of giant cell tumors is related to the radiographic stage and may predict the clinical behavior of these tumors.
Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Tumor Óseo de Células Gigantes/diagnóstico por imagen , Adolescente , Adulto , Fosfatasa Alcalina/metabolismo , Biomarcadores de Tumor , Biopsia , Neoplasias Óseas/enzimología , Neoplasias Óseas/patología , Recuento de Células , División Celular , Movimiento Celular , Preescolar , Fémur/diagnóstico por imagen , Fémur/enzimología , Fémur/patología , Tumor Óseo de Células Gigantes/enzimología , Tumor Óseo de Células Gigantes/patología , Humanos , Ilion/diagnóstico por imagen , Ilion/enzimología , Ilion/patología , Metacarpo/diagnóstico por imagen , Metacarpo/enzimología , Metacarpo/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Antígeno Nuclear de Célula en Proliferación/metabolismo , Estudios Prospectivos , Radiografía , Células del Estroma/enzimología , Células del Estroma/patología , Tibia/diagnóstico por imagen , Tibia/enzimología , Tibia/patología , Células Tumorales CultivadasRESUMEN
INTRODUCTION: The transport environment presents a unique setting in which the feasibility, advantages, and disadvantages of passengers accompanying a patient must be assessed carefully. The purpose of this study was to describe the current practice of including parents as passengers during pediatric interfacility transport. METHODS: One-hundred-eighty-eight critical care transport programs in the United States responded to a voluntary mail survey, providing information about current policies, practices, and crew perceptions of the advantages and disadvantages of carrying parents as passengers. RESULTS: Extra seating for passengers was available in 96% of ambulances, 86% of fixed-wing aircraft, and 54% of helicopters used for pediatric transport. Parents traveled as passengers in all types of vehicles; most frequently in ambulances and fixed-wing aircraft. Twenty percent of helicopter programs allowed parent passengers on more than half of their pediatric transports in this vehicle. Advantages of parent passengers included emotional benefit for the parent and child, availability of parents for history and consent, good public relations, and having the parent present if the child dies. Disadvantages included potential parent anxiety, crew distraction, and space limitations. DISCUSSION: This study reflects the widely diverse policies, practices, and opinions relevant to this topic and confirms a need for further study.