Pedal : identification of models for duodenal administration of levodopa

Backgound and aims: The main purpose of the PEDAL study is to identify and estimate sample individual pharmacokinetic- pharmacodynamic (PK/PD) models for duodenal infusion of levodopa/carbidopa (Duodopa®) that can be used for in numero simulation of treatment strategies. Other objectives are to study the absorption of Duodopa® and to form a basis for power calculation for a future larger study. PK/PD based on oral levodopa is problematic because of irregular gastric emptying. Preliminary work with data from [Gundert-Remy U et al. Eur J Clin Pharmacol 1983;25:69-72] suggested that levodopa infusion pharmacokinetics can be described by a two-compartment model. Background research led to a hypothesis for an effect model incorporating concentration-unrelated fluctuations, more complex than standard E-max models. Methods: PEDAL involved a few patients already on Duodopa®. A bolus dose (normal morning dose plus 50%) was given after a washout during night. Data collection continued until the clinical effect was back at baseline. The procedure was repeated on two non-consecutive days per patient. The following data were collected in 5 to 15 minutes intervals: i) Accelerometer data. ii) Three e-diary questions about ability to walk, feelings of “off” and “dyskinesia”. iii) Clinical assessment of motor function by a physician. iv) Plasma concentrations of levodopa, carbidopa and the metabolite 3-O-methyldopa. The main effect variable will be the clinical assessment. Results: At date of abstract submission, lab analyses were currently being performed. Modelling results, simulation experiments and conclusions will be presented in our poster.

A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion

Objective Levodopa in presence of decarboxylase inhibitors is following two-compartment kinetics and its effect is typically modelled using sigmoid Emax models. Pharmacokinetic modelling of the absorption phase of oral distributions is problematic because of irregular gastric emptying. The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of levodopa/carbidopa (Duodopa®) that can be used for in numero simulation of treatment strategies. Methods The modelling involved pooling data from two studies and fixing some parameters to values found in literature (Chan et al. J Pharmacokinet Pharmacodyn. 2005 Aug;32(3-4):307-31). The first study involved 12 patients on 3 occasions and is described in Nyholm et al. Clinical Neuropharmacology 2003:26:156-63. The second study, PEDAL, involved 3 patients on 2 occasions. A bolus dose (normal morning dose plus 50%) was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function from video recordings on a treatment response scale between -3 and 3, where -3 represents severe parkinsonism and 3 represents severe dyskinesia.) were repeatedly collected until the clinical effect was back at baseline. At this point, the usual infusion rate was started and sampling continued for another two hours. Different structural absorption models and effect models were evaluated using the value of the objective function in the NONMEM package. Population mean parameter values, standard error of estimates (SE) and if possible, interindividual/interoccasion variability (IIV/IOV) were estimated. Results Our results indicate that Duodopa absorption can be modelled with an absorption compartment with an added bioavailability fraction and a lag time. The most successful effect model was of sigmoid Emax type with a steep Hill coefficient and an effect compartment delay. Estimated parameter values are presented in the table. Conclusions The absorption and effect models were reasonably successful in fitting observed data and can be used in simulation experiments.

12-month results from a novel test battery used in a duodenal levodopa infusion trial

A novel test battery consisting of self-assessments and motor tests (tapping and spiral drawing) for patients with Parkinson’s disease (PD) was developed for a hand computer with touch screen in a telemedicine setting. Tests are performed four times per day in the home environment during weeklong test periods. Results are processed into scores for different dimensions of the symptom state and an ‘overall score’ reflecting the global condition of a patient during a test period. The test battery was validated in a separate study recently submitted to Mov Disord. This test battery is currently being used in an open longitudinal trial (DAPHNE, EudraCT No. 2005- 002654-21) by sixty-five patients with advanced PD at nine clinics around Sweden. On inclusion, the patients were either receiving treatment with duodenal levodopa/carbidopa infusion (Duodopa®) (n=36), or they were candidates for receiving this treatment (n=29). We now present interim results for the first twelve months. Test periods were performed in three-month intervals. During most of the periods, UPDRS ratings were performed in afternoons at the start of the week. In twenty of the patients, scores were available during individually optimized oral polypharamacy, before receiving infusion and at least one test period after having started infusion treatment. Usability and compliance with performing tests, this far are good, both with patients and clinical staff. Correlations between test periods 2 and 3 during infusion treatment (three months apart) are stronger for overall test score than for total UPDRS, indicating good reliability. The correlation between overall test score and UPDRS for all test periods is adequate (r=-0.6). In an exact Wilcoxon signed rank test, where the endpoint is the change from the first to the twelve month test period (n=25), there was no change in test results in any of the test battery dimensions for the patients already receiving infusion when included. However, in the patients entering the study before receiving infusion, there was a significant change (improvement) from the baseline to the twelve month test period in dimensions; ‘off’, ‘dyskinesia’ and ‘satisfied’ and in the ‘overall score’ (n=15). The mean improvement in overall score after infusion was 29% (p=0.015). We conclude that the test battery is able to measure a functional improvement with infusion that is sustained over at least twelve months.

Computerized identification of motor complications in Parkinson's disease

Objective: To investigate whether spirography-based objective measures are able to effectively characterize the severity of unwanted symptom states (Off and dyskinesia) and discriminate them from motor state of healthy elderly subjects. Background: Sixty-five patients with advanced Parkinson’s disease (PD) and 10 healthy elderly (HE) subjects performed repeated assessments of spirography, using a touch screen telemetry device in their home environments. On inclusion, the patients were either treated with levodopa-carbidopa intestinal gel or were candidates for switching to this treatment. On each test occasion, the subjects were asked trace a pre-drawn Archimedes spiral shown on the screen, using an ergonomic pen stylus. The test was repeated three times and was performed using dominant hand. A clinician used a web interface which animated the spiral drawings, allowing him to observe different kinematic features, like accelerations and spatial changes, during the drawing process and to rate different motor impairments. Initially, the motor impairments of drawing speed, irregularity and hesitation were rated on a 0 (normal) to 4 (extremely severe) scales followed by marking the momentary motor state of the patient into 2 categories that is Off and Dyskinesia. A sample of spirals drawn by HE subjects was randomly selected and used in subsequent analysis. Methods: The raw spiral data, consisting of stylus position and timestamp, were processed using time series analysis techniques like discrete wavelet transform, approximate entropy and dynamic time warping in order to extract 13 quantitative measures for representing meaningful motor impairment information. A principal component analysis (PCA) was used to reduce the dimensions of the quantitative measures into 4 principal components (PC). In order to classify the motor states into 3 categories that is Off, HE and dyskinesia, a logistic regression model was used as a classifier to map the 4 PCs to the corresponding clinically assigned motor state categories. A stratified 10-fold cross-validation (also known as rotation estimation) was applied to assess the generalization ability of the logistic regression classifier to future independent data sets. To investigate mean differences of the 4 PCs across the three categories, a one-way ANOVA test followed by Tukey multiple comparisons was used. Results: The agreements between computed and clinician ratings were very good with a weighted area under the receiver operating characteristic curve (AUC) coefficient of 0.91. The mean PC scores were different across the three motor state categories, only at different levels. The first 2 PCs were good at discriminating between the motor states whereas the PC3 was good at discriminating between HE subjects and PD patients. The mean scores of PC4 showed a trend across the three states but without significant differences. The Spearman’s rank correlations between the first 2 PCs and clinically assessed motor impairments were as follows: drawing speed (PC1, 0.34; PC2, 0.83), irregularity (PC1, 0.17; PC2, 0.17), and hesitation (PC1, 0.27; PC2, 0.77). Conclusions: These findings suggest that spirography-based objective measures are valid measures of spatial- and time-dependent deficits and can be used to distinguish drug-related motor dysfunctions between Off and dyskinesia in PD. These measures can be potentially useful during clinical evaluation of individualized drug-related complications such as over- and under-medications thus maximizing the amount of time the patients spend in the On state.

Visualization of spirography-based objective measures in Parkinson's disease

Objective: To investigate whether advanced visualizations of spirography-based objective measures are useful in differentiating drug-related motor dysfunctions between Off and dyskinesia in Parkinson’s disease (PD). Background: During the course of a 3 year longitudinal clinical study, in total 65 patients (43 males and 22 females with mean age of 65) with advanced PD and 10 healthy elderly (HE) subjects (5 males and 5 females with mean age of 61) were assessed. Both patients and HE subjects performed repeated and time-stamped assessments of their objective health indicators using a test battery implemented on a telemetry touch screen handheld computer, in their home environment settings. Among other tasks, the subjects were asked to trace a pre-drawn Archimedes spiral using the dominant hand and repeat the test three times per test occasion. Methods: A web-based framework was developed to enable a visual exploration of relevant spirography-based kinematic features by clinicians so they can in turn evaluate the motor states of the patients i.e. Off and dyskinesia. The system uses different visualization techniques such as time series plots, animation, and interaction and organizes them into different views to aid clinicians in measuring spatial and time-dependent irregularities that could be associated with the motor states. Along with the animation view, the system displays two time series plots for representing drawing speed (blue line) and displacement from ideal trajectory (orange line). The views are coordinated and linked i.e. user interactions in one of the views will be reflected in other views. For instance, when the user points in one of the pixels in the spiral view, the circle size of the underlying pixel increases and a vertical line appears in the time series views to depict the corresponding position. In addition, in order to enable clinicians to observe erratic movements more clearly and thus improve the detection of irregularities, the system displays a color-map which gives an idea of the longevity of the spirography task. Figure 2 shows single randomly selected spirals drawn by a: A) patient who experienced dyskinesias, B) HE subject, and C) patient in Off state. Results: According to a domain expert (DN), the spirals drawn in the Off and dyskinesia motor states are characterized by different spatial and time features. For instance, the spiral shown in Fig. 2A was drawn by a patient who showed symptoms of dyskinesia; the drawing speed was relatively high (cf. blue-colored time series plot and the short timestamp scale in the x axis) and the spatial displacement was high (cf. orange-colored time series plot) associated with smooth deviations as a result of uncontrollable movements. The patient also exhibited low amount of hesitation which could be reflected both in the animation of the spiral as well as time series plots. In contrast, the patient who was in the Off state exhibited different kinematic features, as shown in Fig. 2C. In the case of spirals drawn by a HE subject, there was a great precision during the drawing process as well as unchanging levels of time-dependent features over the test trial, as seen in Fig. 2B. Conclusions: Visualizing spirography-based objective measures enables identification of trends and patterns of drug-related motor dysfunctions at the patient’s individual level. Dynamic access of visualized motor tests may be useful during the evaluation of drug-related complications such as under- and over-medications, providing decision support to clinicians during evaluation of treatment effects as well as improve the quality of life of patients and their caregivers. In future, we plan to evaluate the proposed approach by assessing within- and between-clinician variability in ratings in order to determine its actual usefulness and then use these ratings as target outcomes in supervised machine learning, similarly as it was previously done in the study performed by Memedi et al. (2013).

A web-based system for visualizing upper limb motor performance of Parkinson’s disease patients

Objective To design, develop and set up a web-based system for enabling graphical visualization of upper limb motor performance (ULMP) of Parkinson’s disease (PD) patients to clinicians. Background Sixty-five patients diagnosed with advanced PD have used a test battery, implemented in a touch-screen handheld computer, in their home environment settings over the course of a 3-year clinical study. The test items consisted of objective measures of ULMP through a set of upper limb motor tests (finger to tapping and spiral drawings). For the tapping tests, patients were asked to perform alternate tapping of two buttons as fast and accurate as possible, first using the right hand and then the left hand. The test duration was 20 seconds. For the spiral drawing test, patients traced a pre-drawn Archimedes spiral using the dominant hand, and the test was repeated 3 times per test occasion. In total, the study database consisted of symptom assessments during 10079 test occasions. Methods Visualization of ULMP The web-based system is used by two neurologists for assessing the performance of PD patients during motor tests collected over the course of the said study. The system employs animations, scatter plots and time series graphs to visualize the ULMP of patients to the neurologists. The performance during spiral tests is depicted by animating the three spiral drawings, allowing the neurologists to observe real-time accelerations or hesitations and sharp changes during the actual drawing process. The tapping performance is visualized by displaying different types of graphs. Information presented included distribution of taps over the two buttons, horizontal tap distance vs. time, vertical tap distance vs. time, and tapping reaction time over the test length. Assessments Different scales are utilized by the neurologists to assess the observed impairments. For the spiral drawing performance, the neurologists rated firstly the ‘impairment’ using a 0 (no impairment) – 10 (extremely severe) scale, secondly three kinematic properties: ‘drawing speed’, ‘irregularity’ and ‘hesitation’ using a 0 (normal) – 4 (extremely severe) scale, and thirdly the probable ‘cause’ for the said impairment using 3 choices including Tremor, Bradykinesia/Rigidity and Dyskinesia. For the tapping performance, a 0 (normal) – 4 (extremely severe) scale is used for first rating four tapping properties: ‘tapping speed’, ‘accuracy’, ‘fatigue’, ‘arrhythmia’, and then the ‘global tapping severity’ (GTS). To achieve a common basis for assessment, initially one neurologist (DN) performed preliminary ratings by browsing through the database to collect and rate at least 20 samples of each GTS level and at least 33 samples of each ‘cause’ category. These preliminary ratings were then observed by the two neurologists (DN and PG) to be used as templates for rating of tests afterwards. In another track, the system randomly selected one test occasion per patient and visualized its items, that is tapping and spiral drawings, to the two neurologists. Statistical methods Inter-rater agreements were assessed using weighted Kappa coefficient. The internal consistency of properties of tapping and spiral drawing tests were assessed using Cronbach’s α test. One-way ANOVA test followed by Tukey multiple comparisons test was used to test if mean scores of properties of tapping and spiral drawing tests were different among GTS and ‘cause’ categories, respectively. Results When rating tapping graphs, inter-rater agreements (Kappa) were as follows: GTS (0.61), ‘tapping speed’ (0.89), ‘accuracy’ (0.66), ‘fatigue’ (0.57) and ‘arrhythmia’ (0.33). The poor inter-rater agreement when assessing “arrhythmia” may be as a result of observation of different things in the graphs, among the two raters. When rating animated spirals, both raters had very good agreement when assessing severity of spiral drawings, that is, ‘impairment’ (0.85) and irregularity (0.72). However, there were poor agreements between the two raters when assessing ‘cause’ (0.38) and time-information properties like ‘drawing speed’ (0.25) and ‘hesitation’ (0.21). Tapping properties, that is ‘tapping speed’, ‘accuracy’, ‘fatigue’ and ‘arrhythmia’ had satisfactory internal consistency with a Cronbach’s α coefficient of 0.77. In general, the trends of mean scores of tapping properties worsened with increasing levels of GTS. The mean scores of the four properties were significantly different to each other, only at different levels. In contrast from tapping properties, kinematic properties of spirals, that is ‘drawing speed’, ‘irregularity’ and ‘hesitation’ had a questionable consistency among them with a coefficient of 0.66. Bradykinetic spirals were associated with more impaired speed (mean = 83.7 % worse, P < 0.001) and hesitation (mean = 77.8% worse, P < 0.001), compared to dyskinetic spirals. Both these ‘cause’ categories had similar mean scores of ‘impairment’ and ‘irregularity’. Conclusions In contrast from current approaches used in clinical setting for the assessment of PD symptoms, this system enables clinicians to animate easily and realistically the ULMP of patients who at the same time are at their homes. Dynamic access of visualized motor tests may also be useful when observing and evaluating therapy-related complications such as under- and over-medications. In future, we foresee to utilize these manual ratings for developing and validating computer methods for automating the process of assessing ULMP of PD patients.

Self-reported symptoms and motor tests via telemetry in a 36-month levodopa-carbidopa intestinal gel infusion trial

Objective To investigate if a home environment test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression. Background Seventy-seven patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study at 10 clinics in Sweden and Norway; 40 of them were treated with levodopa-carbidopa intestinal gel (LCIG) and 37 patients were candidates for switching from oral PD treatment to LCIG. They utilized a mobile device test battery, consisting of self-assessments of symptoms and objective measures of motor function through a set of fine motor tests (tapping and spiral drawings), in their homes. Both the LCIG-naïve and LCIG-non-naïve patients used the test battery four times per day during week-long test periods. Methods Assessments The LCIG-naïve patients used the test battery at baseline (before LCIG), month 0 (first visit; at least 3 months after intraduodenal LCIG), and thereafter quarterly for the first year and biannually for the second and third years. The LCIG-non-naïve patients used the test battery from the first visit, i.e. month 0. Out of the 77 patients, only 65 utilized the test battery; 35 were LCIG-non-naïve and 30 LCIG-naïve. In 20 of the LCIG-naïve patients, assessments with the test battery were available during oral treatment and at least one test period after having started infusion treatment. Three LCIG-naïve patients did not use the test battery at baseline but had at least one test period of assessments thereafter. Hence, n=23 in the LCIG-naïve group. In total, symptom assessments in the full sample (including both patient groups) were collected during 379 test periods and 10079 test occasions. For 369 of these test periods, clinical assessments including UPDRS and PDQ-39 were performed in afternoons at the start of the test periods. The repeated measurements of the test battery were processed and summarized into scores representing patients’ symptom severities over a test period, using statistical methods. Six conceptual dimensions were defined; four subjectively-reported: ‘walking’, ‘satisfied’, ‘dyskinesia’, and ‘off’ and two objectively-measured: ‘tapping’ and ‘spiral’. In addition, an ‘overall test score’ (OTS) was defined to represent the global health condition of the patient during a test period. Statistical methods Change in the test battery scores over time, that is at baseline and follow-up test periods, was assessed with linear mixed-effects models with patient ID as a random effect and test period as a fixed effect of interest. The within-patient variability of OTS was assessed using intra-class correlation coefficient (ICC), for the two patient groups. Correlations between clinical rating scores and test battery scores were assessed using Spearman’s rank correlations (rho). Results In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. However, there were no significant changes in mean OTS scores of LCIG-non-naïve patients, except for worse mean OTS at month 36 (p<0.01, n=16). The mean scores of all subjectively-reported dimensions improved significantly throughout the course of the study, except ‘walking’ at month 36 (p=0.41, n=4). However, there were no significant differences in mean scores of objectively-measured dimensions between baseline and other test periods, except improved ‘tapping’ at month 6 and month 36, and ‘spiral’ at month 3 (p<0.05). The LCIG-naïve patients had a higher within-subject variability in their OTS scores (ICC=0.67) compared to LCIG-non-naïve patients (ICC=0.71). The OTS correlated adequately with total UPDRS (rho=0.59) and total PDQ-39 (rho=0.59). Conclusions In this 3-year follow-up study of advanced PD patients treated with LCIG we found that it is possible to monitor PD progression over time using a home environment test battery. The significant improvements in the mean OTS scores indicate that the test battery is able to measure functional improvement with LCIG sustained over at least 24 months.

Automatic spiral analysis for objective assessment of motor symptoms in Parkinson's disease

Objective: To develop a method for objective quantification of PD motor symptoms related to Off episodes and peak dose dyskinesias, using spiral data gathered by using a touch screen telemetry device. The aim was to objectively characterize predominant motor phenotypes (bradykinesia and dyskinesia), to help in automating the process of visual interpretation of movement anomalies in spirals as rated by movement disorder specialists. Background: A retrospective analysis was conducted on recordings from 65 patients with advanced idiopathic PD from nine different clinics in Sweden, recruited from January 2006 until August 2010. In addition to the patient group, 10 healthy elderly subjects were recruited. Upper limb movement data were collected using a touch screen telemetry device from home environments of the subjects. Measurements with the device were performed four times per day during week-long test periods. On each test occasion, the subjects were asked to trace pre-drawn Archimedean spirals, using the dominant hand. The pre-drawn spiral was shown on the screen of the device. The spiral test was repeated three times per test occasion and they were instructed to complete it within 10 seconds. The device had a sampling rate of 10Hz and measured both position and time-stamps (in milliseconds) of the pen tip. Methods: Four independent raters (FB, DH, AJ and DN) used a web interface that animated the spiral drawings and allowed them to observe different kinematic features during the drawing process and to rate task performance. Initially, a number of kinematic features were assessed including ‘impairment’, ‘speed’, ‘irregularity’ and ‘hesitation’ followed by marking the predominant motor phenotype on a 3-category scale: tremor, bradykinesia and/or choreatic dyskinesia. There were only 2 test occasions for which all the four raters either classified them as tremor or could not identify the motor phenotype. Therefore, the two main motor phenotype categories were bradykinesia and dyskinesia. ‘Impairment’ was rated on a scale from 0 (no impairment) to 10 (extremely severe) whereas ‘speed’, ‘irregularity’ and ‘hesitation’ were rated on a scale from 0 (normal) to 4 (extremely severe). The proposed data-driven method consisted of the following steps. Initially, 28 spatiotemporal features were extracted from the time series signals before being presented to a Multilayer Perceptron (MLP) classifier. The features were based on different kinematic quantities of spirals including radius, angle, speed and velocity with the aim of measuring the severity of involuntary symptoms and discriminate between PD-specific (bradykinesia) and/or treatment-induced symptoms (dyskinesia). A Principal Component Analysis was applied on the features to reduce their dimensions where 4 relevant principal components (PCs) were retained and used as inputs to the MLP classifier. Finally, the MLP classifier mapped these components to the corresponding visually assessed motor phenotype scores for automating the process of scoring the bradykinesia and dyskinesia in PD patients whilst they draw spirals using the touch screen device. For motor phenotype (bradykinesia vs. dyskinesia) classification, the stratified 10-fold cross validation technique was employed. Results: There were good agreements between the four raters when rating the individual kinematic features with intra-class correlation coefficient (ICC) of 0.88 for ‘impairment’, 0.74 for ‘speed’, 0.70 for ‘irregularity’, and moderate agreements when rating ‘hesitation’ with an ICC of 0.49. When assessing the two main motor phenotype categories (bradykinesia or dyskinesia) in animated spirals the agreements between the four raters ranged from fair to moderate. There were good correlations between mean ratings of the four raters on individual kinematic features and computed scores. The MLP classifier classified the motor phenotype that is bradykinesia or dyskinesia with an accuracy of 85% in relation to visual classifications of the four movement disorder specialists. The test-retest reliability of the four PCs across the three spiral test trials was good with Cronbach’s Alpha coefficients of 0.80, 0.82, 0.54 and 0.49, respectively. These results indicate that the computed scores are stable and consistent over time. Significant differences were found between the two groups (patients and healthy elderly subjects) in all the PCs, except for the PC3. Conclusions: The proposed method automatically assessed the severity of unwanted symptoms and could reasonably well discriminate between PD-specific and/or treatment-induced motor symptoms, in relation to visual assessments of movement disorder specialists. The objective assessments could provide a time-effect summary score that could be useful for improving decision-making during symptom evaluation of individualized treatment when the goal is to maximize functional On time for patients while minimizing their Off episodes and troublesome dyskinesias.

Automatic spiral analysis for objective assessment of motor symptoms in Parkinson's disease

A challenge for the clinical management of advanced Parkinson’s disease (PD) patients is the emergence of fluctuations in motor performance, which represents a significant source of disability during activities of daily living of the patients. There is a lack of objective measurement of treatment effects for in-clinic and at-home use that can provide an overview of the treatment response. The objective of this paper was to develop a method for objective quantification of advanced PD motor symptoms related to off episodes and peak dose dyskinesia, using spiral data gathered by a touch screen telemetry device. More specifically, the aim was to objectively characterize motor symptoms (bradykinesia and dyskinesia), to help in automating the process of visual interpretation of movement anomalies in spirals as rated by movement disorder specialists. Digitized upper limb movement data of 65 advanced PD patients and 10 healthy (HE) subjects were recorded as they performed spiral drawing tasks on a touch screen device in their home environment settings. Several spatiotemporal features were extracted from the time series and used as inputs to machine learning methods. The methods were validated against ratings on animated spirals scored by four movement disorder specialists who visually assessed a set of kinematic features and the motor symptom. The ability of the method to discriminate between PD patients and HE subjects and the test-retest reliability of the computed scores were also evaluated. Computed scores correlated well with mean visual ratings of individual kinematic features. The best performing classifier (Multilayer Perceptron) classified the motor symptom (bradykinesia or dyskinesia) with an accuracy of 84% and area under the receiver operating characteristics curve of 0.86 in relation to visual classifications of the raters. In addition, the method provided high discriminating power when distinguishing between PD patients and HE subjects as well as had good test-retest reliability. This study demonstrated the potential of using digital spiral analysis for objective quantification of PD-specific and/or treatment-induced motor symptoms.

Qualidade da água de nascentes com diferentes usos do solo na bacia hidrográfica do córrego rico, São Paulo, Brasil

Com o objetivo de verificar a influência de remanescentes de vegetação ciliar e da ação antrópica na qualidade da água, estudaram-se quatro nascentes, sendo duas com a presença de vegetação natural remanescente e duas com predominância de atividades agrícolas. Essas nascentes fazem parte da bacia hidrográfica do Córrego Rico, estando localizadas nos municípios de Taquaritinga e de Guariba - SP, em duas classes de solo: Argissolo e Latossolo, respectivamente. Definiram-se pontos de coleta da água nas nascentes e ao longo dos cursos d'água (entre 0 a 50 m da nascente), em dois períodos (chuvoso e seco). Foram analisadas as seguintes variáveis: cor, pH, temperatura, turbidez, alcalinidade, dureza total, dureza em magnésio, dureza em cálcio, fósforo, nitrogênio e demanda bioquímica de oxigênio. de maneira geral, ocorreu agrupamento por nascentes e também por períodos, confirmando que os períodos de amostragem, assim como as características e diferentes usos do solo influenciam na qualidade da água das microbacias. As variáveis cor, turbidez, alcalinidade e nitrogênio total foram as que apresentaram maior importância relativa nas variáveis canônicas.

Faixas de proteção ambiental do Rio Pitimbu/RN: uma análise como subsídio ao planejamento e ordenamento do território

The Environmental Protection area sof Pitimbu river are important tools for planning and territorial land management. The Pitimbu river protection is aided in laws, so much of Federal stamp, as the Brazilian s Forest Code (Law No. 4771/1965), and in State s and City s Resolutions. So, this research begins in the State s Law No. 8426/2003interpretations, for being the most restrictive in the river's margin occupation and management. The objective is to analyze the applicability of the Environmental Protection areas of Pitimbu river, localized at the State of Rio Grande do Norte, considering environmental legislation and how to use this space by the man. Having specific goals for the discussion of the legislation s scope to this river; the identification of the types of soil s covering and evaluation the effectiveness of Law Nº.8426/2003, as protection instrument and land management. The river is characterized by its ecological importance and for feeding the Jiqui pond, an important reservoir that supplies 30% of drinking water to the east, west and south population sof the capital of the State. Pitimbu river is passing by a process of environmental degradation, originating from actions as deforestations of its ciliary forests by intensive agricultural practices; introduction of urban and industrial effluents leading to its contamination; increase of the pluvial drainage; erosion, sedimentation and discharge of urban waste , along with pressure for urban settlements along its banks. Under the methodological point of view is part of theoretical planning and land management research, and from a vision of social and environmental spaces. It was produced a survey map of the soil s covering, with 16 classes. Divided into coverage and disturbed natural covering. Using the 300 meters spatial limits of the Environmental Protection Strip, according to the State Law. The survey highlighted a higher percentage of classes disturbed, indicating man s interference in the balance of that system, as well as the lack of environmental actions. Leading to the degradation of riparian areas, and lack of conservation of water resources. Finally, it was considered that the strips of environmental protection are not effective as the preservation and territorial ordination

Avaliação ultra-estrutural dos efeitos tóxicos da mitomicina C no epitélio ciliar de olhos de coelhos normais com e sem tratamento hipotensor ocular prévio

OBJETIVO: Avaliar o epitélio ciliar interno (ECI) do corpo ciliar após aplicação de mitomicina C (MMC) sob retalho escleral, em animais tratados com dois tipos de inibidores da produção do humor aquoso. MÉTODOS: Foram estudados ambos os olhos de 16 coelhos divididos em 4 grupos experimentais. Foi realizado retalho escleral em todos os olhos dos animais, mas apenas os olhos direitos (OD) receberam MMC. No grupo 1 (G1) não houve tratamento prévio. Nos grupos G2 e G4 foi administrada acetazolamida e nos grupos G3 e G4 maleato de timolol. O ECI foi examinado à microscopia eletrônica de transmissão (MET). Os olhos esquerdos formaram os grupos controle. RESULTADOS: em todos os grupos exceto no G1 OE, foram observadas: retração das células e/ou alargamento entre invaginações, mitocôndrias com rarefação, vesículas claras e corpos densos. A membrana limitante interna estava espessada, descontínua ou descolada em todos grupos exceto G1 OE e G2 OE. Foi observada liberação de material citoplasmático apenas nos grupos tratados com inibidores da produção de humor aquoso. CONCLUSÕES: 1- MMC, acetazolamida e maleato de timolol causaram alterações morfológicas no epitélio ciliar mesmo usados isoladamente. 2- A associação MMC e acetazolamida causou mais alterações do que a acetazolamida isoladamente, mas não mais do que a MMC isoladamente. 3- Nas demais associações as alterações foram semelhantes.

Efeito da brimonidina na circulação retrobulbar em pacientes com glaucoma: estudo com Doppler colorido

Objetivo: Avaliar o efeito do tartarato de brimonidina a 0,2% tópico, instilado de 12/12 horas, na circulação retrobulbar em pacientes portadores de glaucoma. Métodos: Foram estudados os 2 olhos de 16 pacientes portadores de glaucoma primário de ângulo aberto e glaucoma crônico de ângulo estreito com iridotomia. Usando o Doppler colorido foram avaliados: velocidade sistólica máxima, velocidade diastólica final e índice de resistência das artéria central da retina, artéria ciliar posterior curta temporal e artéria oftálmica. As avaliações foram feitas antes e depois do uso da brimonidina. Resultados: O tartarato de brimonidina a 0,2% aumentou significativamente a velocidade sistólica máxima (28,24 para 34,23 cm/seg) e velocidade diastólica final (6,62 para 8,10 cm/seg) no olho direito e reduziu o índice de resistência (0,75 para 0,71) no olho esquerdo da artéria oftálmica. Conclusão: O tartarato de brimonidina 0,2% 2x/dia aumentou significativamente a velocidade sistólica máxima e velocidade diastólica final e reduziu índice de resistência da artéria oftálmica de pacientes glaucomatosos. Este efeito sugere que a brimonidina pode beneficiar pacientes glaucomatosos com insuficiência vascular na cabeça do nervo óptico.

Descolamento ciliocoroidal e hipotonia causados por supressores do humor aquoso: síndrome da supersensibilidade aos supressores do humor aquoso

Os autores descrevem um caso de hipotonia e descolamento ciliocoroidal que ocorreu com administração de drogas supressoras do humor aquoso (timolol e acetazolamida) em paciente que havia sido submetido à trabeculectomia (3 meses antes). Por ser o 6° ou o 7° caso descrito na literatura, chamam atenção para esta rara síndrome que inclui a supersensibilidade do corpo ciliar aos supressores do HA, como causa de hipotonia e descolamento ciliocoroidal tardios em pacientes submetidos à cirurgia filtrante. Apresentam também um resumo dos casos encontrados na literatura.

Alternative pathways for catecholamine action in oral motor control

Orofacial movement is a complex function performed by facial and jaw muscles. Jaw movement is enacted through the triggering of motoneurons located primarily in the trigeminal motor nucleus (Mo5). The Mo5 is located in the pontine reticular formation, which is encircled by premotor neurons. Previous studies using retrograde tracers have demonstrated that premotor neurons innervating the Mo5 are distributed in brainstem areas, and electrophysiological studies have suggested the existence of a subcortical relay in the corticofugal-Mo5 pathway. Various neurotransmitters have been implicated in oral movement. Dopamine is of special interest since its imbalance may produce changes in basal ganglia activity, which generates abnormal movements, including jaw motor dysfunction, as in oral dyskinesia and possibly in bruxism. However, the anatomical pathways connecting the dopaminergic systems with Mo5 motoneurons have not been studied systematically. After injecting retrograde tracer fluorogold into the Mo5, we observed retrograde-labeled neurons in brainstem areas and in a few forebrain nuclei, such as the central nucleus of the amygdala, and the parasubthalamic nucleus. By using dual-labeled immunohistochemistry, we found tyrosine hydroxylase (a catecholamine-processing enzyme) immunoreactive fibers in close apposition to retrograde-labeled neurons in brainstem nuclei, in the central nucleus of the amygdala and the parasubthalamic nucleus, suggesting the occurrence of synaptic contacts. Therefore, we suggested that catecholamines may regulate oralfacial movements through the premotor brainstem nuclei, which are related to masticatory control, and forebrain areas related to autonomic and stress responses. (C) 2005 Elsevier B.V.. All rights reserved.