Intraspinal microstimulation produces over-ground walking in anesthetized cats.

OBJECTIVE: Spinal cord injury causes a drastic loss of motor, sensory and autonomic function. The goal of this project was to investigate the use of intraspinal microstimulation (ISMS) for producing long distances of walking over ground. ISMS is an electrical stimulation method developed for restoring motor function by activating spinal networks below the level of an injury. It produces movements of the legs by stimulating the ventral horn of the lumbar enlargement using fine penetrating electrodes (≤50 µm diameter). APPROACH: In each of five adult cats (4.2-5.5 kg), ISMS was applied through 16 electrodes implanted with tips targeting lamina IX in the ventral horn bilaterally. A desktop system implemented a physiologically-based control strategy that delivered different stimulation patterns through groups of electrodes to evoke walking movements with appropriate limb kinematics and forces corresponding to swing and stance. Each cat walked over an instrumented 2.9 m walkway and limb kinematics and forces were recorded. MAIN RESULTS: Both propulsive and supportive forces were required for over-ground walking. Cumulative walking distances ranging from 609 to 835 m (longest tested) were achieved in three animals. In these three cats, the mean peak supportive force was 3.5 ± 0.6 N corresponding to full-weight-support of the hind legs, while the angular range of the hip, knee, and ankle joints were 23.1 ± 2.0°, 29.1 ± 0.2°, and 60.3 ± 5.2°, respectively. To further demonstrate the viability of ISMS for future clinical use, a prototype implantable module was successfully implemented in a subset of trials and produced comparable walking performance. SIGNIFICANCE: By activating inherent locomotor networks within the lumbosacral spinal cord, ISMS was capable of producing bilaterally coordinated and functional over-ground walking with current amplitudes <100 µA. These exciting results suggest that ISMS may be an effective intervention for restoring functional walking after spinal cord injury.

Real-time control of walking using recordings from dorsal root ganglia.

OBJECTIVE: The goal of this study was to decode sensory information from the dorsal root ganglia (DRG) in real time, and to use this information to adapt the control of unilateral stepping with a state-based control algorithm consisting of both feed-forward and feedback components. APPROACH: In five anesthetized cats, hind limb stepping on a walkway or treadmill was produced by patterned electrical stimulation of the spinal cord through implanted microwire arrays, while neuronal activity was recorded from the DRG. Different parameters, including distance and tilt of the vector between hip and limb endpoint, integrated gyroscope and ground reaction force were modelled from recorded neural firing rates. These models were then used for closed-loop feedback. MAIN RESULTS: Overall, firing-rate-based predictions of kinematic sensors (limb endpoint, integrated gyroscope) were the most accurate with variance accounted for >60% on average. Force prediction had the lowest prediction accuracy (48 ± 13%) but produced the greatest percentage of successful rule activations (96.3%) for stepping under closed-loop feedback control. The prediction of all sensor modalities degraded over time, with the exception of tilt. SIGNIFICANCE: Sensory feedback from moving limbs would be a desirable component of any neuroprosthetic device designed to restore walking in people after a spinal cord injury. This study provides a proof-of-principle that real-time feedback from the DRG is possible and could form part of a fully implantable neuroprosthetic device with further development.

Feed forward and feedback control for over-ground locomotion in anaesthetized cats.

The biological central pattern generator (CPG) integrates open and closed loop control to produce over-ground walking. The goal of this study was to develop a physiologically based algorithm capable of mimicking the biological system to control multiple joints in the lower extremities for producing over-ground walking. The algorithm used state-based models of the step cycle each of which produced different stimulation patterns. Two configurations were implemented to restore over-ground walking in five adult anaesthetized cats using intramuscular stimulation (IMS) of the main hip, knee and ankle flexor and extensor muscles in the hind limbs. An open loop controller relied only on intrinsic timing while a hybrid-CPG controller added sensory feedback from force plates (representing limb loading), and accelerometers and gyroscopes (representing limb position). Stimulation applied to hind limb muscles caused extension or flexion in the hips, knees and ankles. A total of 113 walking trials were obtained across all experiments. Of these, 74 were successful in which the cats traversed 75% of the 3.5 m over-ground walkway. In these trials, the average peak step length decreased from 24.9 ± 8.4 to 21.8 ± 7.5 (normalized units) and the median number of steps per trial increased from 7 (Q1 = 6, Q3 = 9) to 9 (8, 11) with the hybrid-CPG controller. Moreover, within these trials, the hybrid-CPG controller produced more successful steps (step length ≤ 20 cm; ground reaction force ≥ 12.5% body weight) than the open loop controller: 372 of 544 steps (68%) versus 65 of 134 steps (49%), respectively. This supports our previous preliminary findings, and affirms that physiologically based hybrid-CPG approaches produce more successful stepping than open loop controllers. The algorithm provides the foundation for a neural prosthetic controller and a framework to implement more detailed control of locomotion in the future.

Four cases of omental herniation in cattle.

Four cases in cattle of omental herniation through an acquired omental rent are described. Clinical signs were indistinguishable from other causes of mechanical ileus and exploratory laparotomy was necessary to establish a diagnosis. In all cases a variably sized portion of jejunal loops was obstructed in an omental rent in the deep layer of the greater omentum. In two cases simple reduction was possible, and in one case incision of the hernial ring was necessary before reduction could be performed. Resection was necessary only in a calf, in which the incarceration was complicated by severe abomasal distension and local peritonitis. In all four cases the omental rent was closed by a serosa-serosa suture. Three cases made an uneventful recovery and returned to normal production, but one of these animals died three months postoperatively from an unknown cause. The calf was euthanased two days postoperatively because of persistent ileus.

Limb-state feedback from ensembles of simultaneously recorded dorsal root ganglion neurons.

Functional electrical stimulation (FES) holds great potential for restoring motor functions after brain and spinal cord injury. Currently, most FES systems are under simple finite state control, using external sensors which tend to be bulky, uncomfortable and prone to failure. Sensory nerve signals offer an interesting alternative, with the possibility of continuous feedback control. To test feasibility, we recorded from ensembles of sensory neurons with microelectrode arrays implanted in the dorsal root ganglion (DRG) of walking cats. Limb position and velocity variables were estimated accurately (average R2 values >0.5) over a range of walking speeds (0.1-0.5 m s(-1)) using a linear combination of firing rates from 10 or more neurons. We tested the feasibility of sensory control of intraspinal FES by recording from DRG neurons during hindlimb movements evoked by intraspinal microstimulation of the lumbar spinal cord in an anesthetized cat. Although electrical stimulation generated artifacts, this problem was overcome by detecting and eliminating events that occurred synchronously across the array of microelectrodes. The sensory responses to limb movement could then be measured and decoded to generate an accurate estimate of the limb state. Multichannel afferent recordings may thus provide FES systems with the feedback needed for adaptive control and perturbation compensation, though long-term stability remains a challenge.

Tracheal carcinosarcoma (true malignant mixed tumour) in a Belgian Blue heifer.

This report describes a case of a carcinosarcoma or true malignant mixed tumour (salivary gland type) of the trachea in a Belgian Blue heifer. At post-mortem examination a nodular, well-circumscribed, firmly attached mass was found in the tracheal wall, severely compressing the tracheal lumen. Histologically the tumour was biphasic, with varying proportions of epithelial elements dispersed throughout a matrix showing varying degrees of myxo-chondroid and cartilaginous differentiation. The histological features of the tumour were consistent with a combination of an adenoid cystic carcinoma and a chondrosarcoma. Immunolabelling demonstrated smooth muscle actin in the cytoplasm of both the epithelial and mesenchymal components, thus fulfilling the diagnostic criteria for a mixed tumour. To our knowledge this is the first report of a mixed tumour of the trachea in a domestic animal.

Shoulder girdle elevation during neurodynamic testing: an assessable sign?

One of the signs advocated for monitoring during neurodynamic testing in the assessment of patients with upper quadrant disorders, is the response of the shoulder girdle. It is stated that a protective rising of the shoulder girdle is present when patients with neurogenic disorders are assessed and that the elevation is absent in asymptomatic subjects. As sensory responses are elicited in the majority of asymptomatic subjects and as the range of motion (ROM) is often limited during neurodynamic testing, it is questionable whether the elevation of the shoulder girdle would be absent in asymptomatic subjects. The aim of this study was to measure the shoulder girdle elevation force during five variants of the neural tissue provocation test for the median nerve. Thirty-five asymptomatic male subjects were assessed. A load cell was used to measure the amount of shoulder girdle elevation force and two electrogoniometers were used to measure the ROM at the elbow and wrist. When the ROM at the end of the test was restricted, a gradual increase in shoulder girdle elevation force could be observed throughout the test. Compared to the initial force at the start of the test, all variants resulted in a significant increase in force. It is concluded that a gradual increase in shoulder girdle elevation force should not be regarded as an abnormal sign in the interpretation of neurodynamic tests.

Addition of test components during neurodynamic testing: effect on range of motion and sensory responses.

STUDY DESIGN: Single session, repeated-measures design. OBJECTIVES: To analyze the impact of different components of the neural tissue provocation test for the median nerve (NTPT1) on the range of motion (ROM) of the elbow and wrist and the sensory responses elicited by the test. BACKGROUND: The assessment of minor peripheral nerve injuries by neurodynamic tests is becoming more integrated in physical therapy practice. The influence of different test components on the nervous system has been analyzed in numerous in vitro studies, but in vivo studies are still lacking. METHODS AND MEASURES: Five test variations were performed on 35 asymptomatic men (23.5 +/- 2.3 years). Elbow extension was performed (1) without additional components (NTPT1NEUTRAL), (2) with wrist extension (NTPT1WE), (3) with cervical contralateral lateral flexion (NTPT1CLLF), and (4) with both wrist extension and cervical contralateral lateral flexion (NTPT1WE+CLLF). In the fifth variant, the wrist was extended from a preloaded position (WENTPT1). The range of elbow and wrist extension when a submaximal discomfort was elicited was measured with 2 electrogoniometers. RESULTS: The addition of each test component resulted in a significantly reduced ROM (NTPT1NEUTRAL: 179.5 +/- 8.8 degrees, NTPT1WE: 169.0 +/- 13.9 degrees, NTPT1CLLF: 154.7 +/- 13.2 degrees, NTPT1WE+CLLF: 143.9 +/- 16.1 degrees; WENTPT1: 67.1 +/- 11.0 degrees). Sensory responses were predominantly evoked at the region of the added component. CONCLUSIONS: The different test components, whose mechanical influence on the nervous system has been demonstrated in anatomical studies, also have an effect on joint ROM and sensory responses during neurodynamic testing, when individually or simultaneously added. If the nerve bedding is elongated throughout its whole length, the available ROM is markedly reduced and sensory responses can be elicited throughout the entire arm.

Comparison of self-administration and face-to-face interview for surveys of low back pain in adolescents.

UNLABELLED: The aim of this study was to compare self-administration with face-to-face interview in the investigation of low back pain in adolescents. Fifty-seven adolescents with low back pain (mean age 17.3 y; range 16-18) first completed a questionnaire and were then invited to an interview. Analysis included item completion, percentages of agreement and weighted kappa. Item completion rates were high and comparable between self-administration and interview. Information between both methods was analogous for severity and localization of problems, sleep behaviour, medical consultation and sports/leisure activities. Onset, progression, duration of low back pain and some items on the influence of movement/positions presented less comparable data. CONCLUSION: Even when two different methods of data acquisition are used, results suggest that the method used does not change the interpretation of results in the case of most items.

Reproducibility of a survey questionnaire for the investigation of low back problems in adolescents.

A test-retest design was used to investigate the reproducibility of the results obtained using a survey questionnaire for low back problems in adolescents. A 1-wk interval between test and retest was chosen. Participants were recruited from four schools. Selection of schools was based on geographic location, size of the school and educational level. Sixty-seven adolescents (mean age = 16.62 y; SD = 0.57; range = 16-18) suffering from low back problems agreed to participate. A questionnaire on perceived characteristics of back problems and functional limitations was designed. Item completion rate and the reproducibility of results were investigated by means of percentage agreement and (weighted) kappa. High levels of reproducibility were found for items that evaluated perceived characteristics of back problems and functional limitations (Kw = 0.70-0.93). Results suggest that the questionnaire used in the present study provided reproducible information. Detailed information on low back problems in adolescents could be obtained using this questionnaire.

Measuring small linear displacements with a three-dimensional video motion analysis system: determining its accuracy and precision.

OBJECTIVES: To determine accuracy, precision, and smallest detectable difference for a three-dimensional (3D) video motion analysis system specifically configured for measuring small and slow displacements within a small measurement volume (0.7 x 0.5 x 0.3 m). DESIGN: Repeated measurements with random sequence of conditions. SETTING: Rehabilitation research laboratory. INTERVENTION: A reference sliding device was used to control cyclic displacements of two reflective markers over 5 calibrated ranges (1, 3, 10, 30, and 60 mm). Nine cycles were performed for each of 9 conditions (3 directions x 3 zones). Four cameras recorded all trials on tapes, which were digitized with a Kinemetrix system. MAIN OUTCOME MEASURES: Change in distance of the moving markers relative to a third static marker was averaged over 50 frames per trial. Mean error, mean absolute error, and intertrial and intratrial standard deviations (SDs) were calculated for each zone and direction. RESULTS: For 810 trials, mean error and absolute error were, respectively, .034 mm and .094 mm. The mean intertrial and intratrial SDs and 99% confidence interval were .047 mm (CI = +/- .121 mm) and .030 mm (CI = +/- .077 mm). The corresponding smallest detectable differences were .171 mm and .109 mm. CONCLUSION: Motion analysis configured for registration within small volumes allows measurement of minuscule displacements with great accuracy and may therefore be suitable for many applications in rehabilitation research other than gait analysis.

A qualitative assessment of shoulder girdle elevation during the upper limb tension test 1.

The 'feel through range' and the 'end-feel' of the elbow extension, and the elevation of the shoulder girdle during the upper limb tension test for the median nerve are considered important in clinical decision making. As no objective measurements have been published regarding these parameters, a special device was designed in order to obtain objective information on the force by which the shoulder girdle is elevated during the test. The purpose of this technical note is to describe the technical aspects of the device and its practical application. In a pilot study, five asymptomatic subjects have been assessed. The relationship between the elevation of the shoulder girdle and the range of elbow extension has been analysed. The data of five subjects and representative curves of one subject are presented. All five subjects demonstrate a considerable increase in force elevating the shoulder girdle. The results show that the device can be used to measure the force by which the shoulder girdle is elevated throughout the test. Although the number of subjects and the number of repetitions is limited, the data suggest that the method is accurate and that the phenomenon of shoulder girdle elevation during the upper limb tension test in asymptomatic subjects is consistent.

Reliability of manual skinfold tests in a healthy male population.

OBJECTIVE: To assess the intra- and interexaminer agreement of a manual skinfold thickness test and a manual skinfold compliance test. The relation between the weekly routine of the examiners and the intraexaminer reliability was also assessed for both tests. DESIGN: This is a reliability study of a common palpatory procedure to assess skinfold thickness and skinfold compliance. Twelve healthy subjects were palpated twice in two sessions by 12 examiners. SETTING: The study was conducted at the Polytechnic of Utrecht (the Netherlands), Faculty of Health Care, Department of Physiotherapy. SUBJECTS: Healthy male subjects recruited from students of the Polytechnic of Utrecht (the Netherlands), Department of Physiotherapy. RESULTS: The intraexaminer agreement Intraclass Correlation Coefficient [ICC(3.1)] was .25 for skinfold thickness and .28 for skinfold compliance. The interexaminer agreement [ICC(2,1)] ranged from .01 to .24. The Pearson correlation coefficient between the examiners age and routine vs. intraexaminer agreement ranged from -.41 to .23 (nonsignificant). CONCLUSIONS: The intra- and interexaminer agreement of the manual skinfold test produced poor-to-fair reliability. The correlation between the examiners' weekly routine and the intraexaminer reliability ranged from low negative to little (if any). This study shows a lack of reliability of palpatory tests for skinfold thickness and skinfold compliance. This outcome agrees with results of previous studies found in the literature.

2'-Azido-2',3'-dideoxythymidine: synthesis and crystal structure of a 2'-substituted dideoxynucleoside.

1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (2'-N3ddThd) was synthesized from 1-(5-O-trityl-2,3-anhydro-beta-D-lyxofuranosyl)thymine by two different procedures. Method A prepared the title compound by opening of the oxirane ring with LiEt3BH followed by mesylation of the 2'-hydroxyl function, introduction of the 2'-azido substituent and deblocking of the 5'-function. In method B nucleophilic opening of 3'-deoxy-5'-O-(tert-butyldimethylsilyl)-5-methyl-2,2'-anhydrouridine+ ++ was carried out with sodium azide in hexamethylphosphoramide in the presence of benzoic acid. Single X-ray crystallographic studies indicated a solid state conformation (3T2), which was opposite to that of the A form of AZT (2T3) but closely resembled that of 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine (2'-FddThd) (3T2) and of 3'-azido-2',3'-dideoxy-2,6-diaminopurine riboside (3'-N3ddDAP) (3T2). Whereas the latter displayed significant inhibitory activity against human immunodeficiency virus (HIV) replication, 2'-FddThd and 2'-N3ddThd were essentially inactive.

Structure of a nucleoside analogue, 3'-deoxy-3'-fluorothymidine.

1-(2,3-Dideoxy-3-fluoro-beta-D-erythro-pentofuranosyl)thymine, C10H13FN2O4, Mr = 244.22, monoclinic, P21, a = 6.408 (14), b = 18.716 (26), c = 9.329 (7) A, beta = 98.4 (1) degrees, V = 1107 (3) A3, Z = 4, Dm = 1.46, Dx = 1.465 Mg m-3, graphite-monochromated Mo K alpha radiation, lambda = 0.71073 A, mu = 0.1169 mm-1, F(000) = 512, T = 298 K, final R = 0.035 for 1425 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of -138.4 (5) degrees in the anti range; the sugar pucker is 2E with P = 164 (1) degrees and psi m = 36 (1) degrees and the C4'--C5' conformation is +sc with gamma = 50.2 (7) degrees. For molecule B: the N-glycosidic torsion angle chi has a value of -159.6 (5) degrees in the anti range; the sugar pucker is 2T3 with P = 169 (1) degrees and psi m = 32 (1) degrees and the C4'--C5' conformation is + sc with gamma = 52.8 (7) degrees. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. Base-pair formation occurs between the two molecules A and B.

Synthesis and anti-HIV evaluation of 2',3'-dideoxyribo-5-chloropyrimidine analogues: reduced toxicity of 5-chlorinated 2',3'-dideoxynucleosides.

In view of the selective anti-HIV activity of 2',3'-dideoxy-3'-fluoro-5-chlorouridine (11), a series of eight 2',3'-dideoxy-5-chloropyrimidines were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) replication in MT-4 cells. A marked improvement in selectivity was noted for the 5-chlorouracil derivatives of 2,3-dideoxyribofuranose, 3-azido-2,3-dideoxyribofuranose, and 3-fluoro-2,3-dideoxyribofuranose, mainly due to decreased toxicity of the compounds for the host cells. While chlorination of 2',3'-dideoxycytidine removed the anti-HIV activity, introduction of a chlorine at the C-5 position of 3'-fluoro-, 3'-azido- or 2',3'-didehydro-2',3'-dideoxycytidine led to reduced cytotoxicity with only slightly reduced anti-HIV activity. X-ray analysis showed compound 11 to have two molecules in the asymmetric unit with chi = -168.8 (3) degrees and -131.3 (3) degrees and P = 179 (1) degree and 163 (1) degree, respectively; thus revealing no close resemblance to 3'-azido-3'-deoxythymidine (AZT).