Large deletion mutation of SPAST in a multi-generation family from Sardinia.

BACKGROUND AND PURPOSE: The hereditary spastic paraplegias (HSP) are characterized by progressive spasticity of the lower limbs, mostly inherited as an autosomal dominant trait. Analyses of large HSP pedigrees could help to better characterize the phenotype due to a single causative mutation. Patients in a seven-generation kindred carrying a large deletion in SPAST/SPG4 are described. METHODS: Individuals originating from Sardinia were clinically and genetically studied. RESULTS: Sixty-seven subjects carried a heterozygous deletion encompassing exons 2-17 of SPAST. Fifty patients (53.2 ± 15.4 years) presented a pure form of spastic paraparesis characterized by mild impairment and slow progression. Most patients showed spasticity, increased tendon reflexes in the lower limbs and Babinski sign, whilst weakness was rarely detected and urinary disturbances occasionally reported. Amongst the 17 asymptomatic carriers of the mutation, minimal neurological signs were detected in 11 cases. CONCLUSIONS: A focus on spasticity, increased tendon reflexes and Babinski sign, more than on weakness, could help clinicians to promote early diagnosis in asymptomatic carriers of SPAST deletions.

Myelinated retinal fibers in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

BACKGROUND: Myelinated retinal nerve fibers are considered a hallmark of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in French Canadian patients. The demonstration of a worldwide distribution of this disease, as well as the almost invariable presence of a normal retina on fundoscopy in cases outside Canada, suggests that more quantitative methodologies are needed to assess the retina in ARSACS. METHODS: To characterize better the retinal features of ARSACS, we studied five Italian patients by means of optical coherence tomography (OCT), a processing method that allows the creation of three-dimensional images with micrometer resolution. We compared OCT characteristics in ARSACS with those obtained from five subjects with persistent myelination of the retina, a rare congenital non-progressive anomaly. RESULTS: Four patients with ARSACS showed myelinated retinal nerve fibers on ophthalmoscopy, corresponding to an increased thickness of the retina on OCT, a characteristic not present in the subjects with persistent myelination of the retina. CONCLUSIONS: Myelinated retinal fibers are not rare in Italian patients with ARSACS. This finding may be the consequence of the thickening of the retina, as detected by OCT.

(E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid derivatives. A novel class of glycine site antagonists.

The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pKi = 6.70 +/- 0.03) analogues were the most active compounds of the series. Qualitative structure-activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pKi > or = 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (alpha = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.

Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia.

A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.

Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site.

A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.

Evaluating eye-body coordination during unrestrained functional activity in older persons.

BACKGROUND: Traditional paradigms for the study of ocular-motor control restrain subject motion and have not adequately quantified the sensorimotor strategies used by older persons to control gaze while performing activities of daily living. The purpose of our study was to describe eye-head-trunk coordination during a functional activity in freely moving community-dwelling older persons. METHODS: Thirty-five community-dwelling older persons (age range 71-92 years) participated in this study. Surface electro-oculography was used with an electromagnetic tracking device to measure vertical eye movement and linear and angular head position while each subject performed a stand-from-chair task. RESULTS: Standing from a chair involved low-frequency head motion (median z = 0.25 Hz; median pitch = 0.32 Hz). The distribution of phase for eyes versus vertical body motion were skewed toward head-trunk leading, suggesting that eye motion follows vertical body motion. Vertical gaze, however, was in phase with and moved in the same direction as head pitch. CONCLUSIONS: Gaze (eye position in space) was an active, integrated component of the standing motion. The results imply that both the oculomotor system and the head motor system in older persons are coordinated to direct gaze and, when necessary, work to suppress the vestibuloocular reflex. The interaction of eye-head-trunk motion provides a basis for understanding how a breakdown in the gaze control mechanisms in older persons might contribute to the risk of falling and fall-related injuries.

Lower extremity antagonist muscle response following standing perturbation in subjects with cerebrovascular disease.

The onset, amplitude, and relative timing of opposing muscle groups during forward and backward body sway were investigated in standing subjects with hemiplegia and a normal control group. The agonist was the first muscle stretched by platform perturbation and the antagonist was the opposing muscle passively shortened by the movement stimulus. Tibialis anterior (T), quadriceps (Q), gastrocnemius (G) and hamstrings (H) were simultaneously monitored bilaterally for burst activity. During rotational (toe up/down) and horizontal perturbations in normals, two distinct muscle responses were observed--an initial long-latency response (LLR) in the agonist and a subsequent response in the antagonist muscle group. Hemiplegics showed early activation of the antagonist response (AR) with respect to the initial LLR and frequent coactivation of synergists (T-Q or G-H). Although the AR was tightly coupled to the initial LLR in both hemiplegic lower limbs, initiation of the distal LLR-AR sequence was significantly delayed in the paretic extremity by 25-40 ms. In addition, the distal AR amplitude was suppressed in the paretic limb. The number of AR defaults in hemiplegics for all perturbation modes was significantly greater than normal. Therefore, unilateral cerebrovascular disease may reduce the occurrence of antagonist muscle activation and alter the latency, amplitude and phasing of passively shortened antagonist muscles.

Kinematic properties of voluntary postural sway in patients with unilateral primary hemispheric lesions.

The temporal and spatial characteristics of rapid voluntary body sway following unilateral cerebrovascular accident were assessed in single and combined planes of motion during a visually cued non-choice reaction time movement. Three distinct directions of intentional body sway were assessed: forward, toward the paretic, and toward the non-paretic lower extremity. Fluctuations in the center of foot pressure served as the basis for calculating body displacement and velocity by combining frontal and sagittal movement in an X-Y coordinate system (a bi-planar analysis). A linear regression analysis was used on individual force output channels to reduce the sway motion into separate component parts. The velocity profile in each direction of intended sway was calculated from the slope of the regression line (a single-plane analysis). Bi-planar velocity analysis showed that hemiplegics swayed as fast as normal subjects in any sway direction. In contrast, single plane analysis revealed a decrease in the velocity of hemiplegic sway when weight shifts were directed toward the paretic extremity. Response velocity in the non-paretic direction was similar to a comparison group of normal individuals. The apparent contradiction between single and bi-planar analyses was attributed to hemiplegic sway in extraneous planes of motion surrounding the intended sway path. During the course of body sway, hemiplegics showed a statistically larger range of extraneous movement away from the plane of intended movement. The directional deficits in sway velocity and excursion are compared to previously reported sway pathology associated with lesions of the human central nervous system.

Adapting human postural reflexes following localized cerebrovascular lesion: analysis of bilateral long latency responses.

The symmetry and adaptability of long latency stretch responses was studied in a group of 4 adult hemiplegics and 5 normals of similar age. Subjects stood on a moveable platform which directly rotated the ankles unexpectedly during a series of horizontal anterioposterior (AP) translations. When the platform was rotated toes-up, long latency discharge of gastrocnemius and hamstring muscles enhanced loss of balance by pulling the body backwards. Toes-down platform rotation elicited a reflex response from tibialis anterior and quadriceps which inappropriately pulled the body forward. Attenuation of these long latency responses was necessary to minimize functional destabilization. Normal and stroke subjects demonstrated appropriate suppression of long latency responses, but the magnitude of attenuation was not uniform in hemiplegics. Adaptation was decreased in the proximal synergists compared to normal. Latency of muscle activation in the paretic limb was prolonged, and a preference for initial non-paretic limb activation was evident. Both lower extremities in hemiplegics showed a disruption of timing between distal and proximal synergists. These results suggest that stroke victims retain or recover the ability to modulate stretch reflex activity for balance. Temporal and spatial response asymmetries surface as critical factors underlying disequilibrium associated with localized cerebrovascular lesion.

Postural supporting mechanisms during spontaneous single limb movement in the cat.

Patterns of postural adjustment accompanying spontaneous single limb movement in the cat were studied to examine qualitative and quantitative variations in support strategies. A multiple plate dynamometer and electromyograph were used to measure supporting actions during consecutive trials. Weight transfer involving primarily the forelimbs was dominant. A similar tripodal stance with increased bilateral hindlimb weight-bearing characterized a secondary support strategy. Both dominant and secondary balance behavior showed transient reversals to a bipodal postural pattern. Bipodal stance exhibited increased weight-bearing in the stabilizing forelimb and in the diagonally opposite hindlimb. Selection of different postural strategies for identical phasic limb movements could possibly result from modulation of lower level reflex inhibition.

Meta-analysis of the sensitivity and specificity of platform posturography.

OBJECTIVE: To compare the sensitivity and specificity of platform posturography with other vestibular tests for patients with peripheral vestibular deficits (PVD), Meniere's disease, benign paroxysmal positional vertigo (BPPV), and central nervous system-vestibular impairment (CNS). DATA SOURCES: A computed search was conducted using the Index Medicus database (1966-1994) and Current Contents Science Editions. STUDY SELECTION: Studies were selected for analysis if the article addressed the sensitivity and/or specificity of platform posturography, compared posturography with another objective test of vestibular function, identified the basis for abnormal test results, and reported the data with sufficient detail to calculate an effect size from a 2 x 2 contingency table. DATA EXTRACTION: A count of the normal and abnormal test results for posturography and the criterion standard were retrieved from each article, analyzed using a chi 2 statistic, and converted to an effect size. A positive effect size indicated that posturography identified abnormalities in patients who had normal tests on the criterion standard. DATA SYNTHESIS: Sensitivity and specificity of posturography were about 50%. The overall effect size was small (0.13) but positive. The diagnostic category had a significant influence on the predictive value of abnormal results (73% for Meniere's disease and BPPV, compared with 41% for PVD, and 44% for mixed CNS and PVD (F2,12 = 5.26, P = .02) and on the magnitude of the effect size (0.41 for mixed CNS and PVD compared with 0.22 for Meniere's disease and BPPV, and -0.10 for PVD (F2,12 = 13.95, P = .001). CONCLUSIONS: Platform posturography provides a measurable supplement to the standard vestibular examination. The enhancement was most notable when the target population included patients with CNS deficits.

Physical therapy for patients with TMD: a descriptive study of treatment, disability, and health status.

The purposes of this study were to compare disabilities and health status associated with temporomandibular disorders (TMD) to other musculoskeletal disorders, to describe the types of physical therapy administered to patients with TMD, and to evaluate health-related quality of life (HRQOL) as an index of clinical change following physical therapy treatment. Outcomes for 56 patients (mean age 40 years, SD 13 years; 89% female) were evaluated from a large database generated by the Focus on Therapeutic Outcomes network. A generic assessment of HRQOL--the Medical Outcomes Study (MOS) 17--was used to evaluate the physical and mental aspects of disability associated with TMD, and the results were compared descriptively to three groups of patients with different cervical pain syndromes. The results showed that patients with TMD had limitations in social function, emotional well-being, and energy level similar to patients with cervical disorders. Physical function (i.e., walking, carrying loads, or lifting), however, was much more limited in cervical disorder patients and bodily pain interfered more with daily work. Large positive effect sizes (> 0.80) in the areas of social function and bodily pain indicated clinical improvement for patients with TMD at the completion of physical therapy. The results suggest that the MOS-17 may be useful as one measure of clinical change for patients with TMD who receive physical therapy.

Reliability of computerized surface electromyography for determining the onset of muscle activity.

The reliability of a computerized analysis system (CAS) for determining muscle burst onset was compared with the subjective assessments of three trained examiners. A sample of 154 randomly selected, full-wave rectified and filtered electromyographic recordings was evaluated using a test-retest paradigm. Percentages of agreement, Pearson product-moment correlations, analyses of variance (ANOVAs), and intraclass correlation coefficients (ICCs) were used to measure the reliability. The between-rater agreement, which included the computerized EMG assessments, was only 23%. Within-rater agreement and Pearson correlation coefficients were perfect for CAS. The trained examiners' within-rater assessments averaged only 51% agreement, but test-retest correlations were high (r = .78 - r = .82). All ICCs were statistically significant, ranged from .46 to .60, and tended to be higher when the CAS onset determinations were deleted from the analysis. The ANOVAs revealed that trained examiners were more consistent among each other than when their assessments were compared with CAS assessments of EMG recordings. This finding, however, may be facility-specific in that any generalization to other examiners was limited. In contrast to trained examiners, the CAS was free of variations in judgment, ensured perfect reproducibility of trial assessments, and was highly useful for analyzing multi-channel EMG recordings. Although the CAS ensures perfect reliability, validity determinations require visual inspection of trial data.

Clinical assessment of manipulation and mobilization of the lumbar spine. A critical review of the literature.

The widespread use of manual therapy techniques suggests some degree of success in their application. In this article, I review the applied clinical research on the effectiveness of using manipulation or mobilization of the lumbar spine. The literature reviewed indicates highly equivocal results when the goal of therapy was to decrease pain and increase motion. Because of a high incidence of spontaneous recovery from low back syndromes, performance measures may appear to improve significantly when proper controls are not used. Evaluation of the therapeutic effects of manual therapy is complicated by potentially confounding variables when used with other physical therapy procedures. I discuss the need for further, well-designed studies.

Efficacy of manual therapy.

The use of manual therapy to treat somatic pain syndromes and associated disabilities is widespread. Yet, the efficacy of manual therapy has not been previously established because equivocal findings in the literature prevent definitive conclusions. The purposes of this article are (1) to establish objective criteria for judging the validity of manual therapy research, (2) to identify and discuss the results of those trials that were determined to be valid demonstrations of treatment efficacy or valid demonstrations of nonuseful therapy, and (3) to determine whether patients who benefit from manual therapy have common characteristics. The abstracts or full reports of 146 titles with appropriate key words were reviewed. Of these, 105 studies were not primary studies of manual therapy and were thus eliminated from review. In the 41 remaining studies, 18 did not utilize statistical comparisons or report blinded assessment of outcome measures. Nine controlled studies yielded negative results, but the statistical power or minimum sample size required to detect potential differences between manual therapy and control groups was not described. The 14 studies that met the efficacy criteria were categorized by the following factors: (1) the anatomical region of intervention, (2) pragmatic versus explanatory goals, and (3) primary intervention (manipulation, mobilization, combination). There was a paucity of valid explanatory research in all areas and a particular absence of controlled trials involving manual therapy applied to the peripheral joints. Manual therapy for low back pain, however, was studied extensively. The analysis of valid trials provided clear evidence that manual therapy, particularly manipulation, can be an effective modality when used to treat patients who have low back pain. A preliminary "profile" of the patient with low back pain who would likely benefit from manual therapy included acute symptom onset with less than a 1-month duration of symptoms, central or paravertebral pain distribution, no previous exposure to spinal manipulation, and no pending litigation or workers' compensation. Suggestions for future manual therapy research are discussed.

Efficacy of comprehensive rehabilitation programs and back school for patients with low back pain: a meta-analysis.

BACKGROUND AND PURPOSE: The use of back school as a treatment for low back pain is widespread, but determining the efficacy of this approach is complicated by variations in back schools and study methods across clinical trials. The purpose of this study was to conduct a meta-analysis to synthesize existing evidence on the efficacy of back school as either a primary intervention or a part of a comprehensive rehabilitation program for patients with low back pain. METHODS: The results of 19 prospective randomized controlled trials were evaluated. Quantitative reviewing procedures were used to calculate the effect sizes that compared patients receiving back school with those in a control or comparison group. Effect sizes were computed for 206 hypothesis tests involving 2,373 patients. RESULTS: The average effect size for comprehensive rehabilitation programs that included back school (d = 0.28) was larger than the average effect size for programs that offered back school as the primary intervention (d = -0.14). When effect sizes were stratified by program type and outcome, the comprehensive programs were superior to primary back school programs with respect to pain reduction, increased spinal mobility, and increased strength. Both types of programs showed reasonable success with education/compliance outcomes (d = 0.27-0.28). Lower effect sizes were found among the types of programs for disability and work/vocational outcomes (d < or = 0.20). CONCLUSIONS AND DISCUSSION: Back schools were most efficacious when coupled with a comprehensive rehabilitation program. Efficacy was supported for the treatment of pain and physical impairments and for education/compliance outcomes. Work/vocational and disability outcomes, however, were not improved substantially beyond control levels in comprehensive or primary back school programs. [Di Fabio RP. Efficacy of comprehensive rehabilitation programs and back school for patients with low back pain: a meta-analysis.

Sensitivity and specificity of platform posturography for identifying patients with vestibular dysfunction.

Sensitive and specific measures are needed to identify patients with vestibular impairments. The purpose of this clinical perspective is to describe the sensitivity and specificity of dynamic and static platform posturography for detecting vestibular disorders. The sensory organization test (SOT) of dynamic posturography (EquiTest), the motor "perturbation" test, and Romberg's tests on a static (fixed) force platform each had over 90% specificity. This finding means that nearly all of the subjects who should have tested negative, did test negative on each type of assessment. The sensitivity of the SOT was evaluated across five studies involving a total of 836 patients with peripheral vestibular deficits (PVDs). Abnormalities in the SOT were detected in only 40% (n = 338) of the cases. Static platform posturography sensitivity was evaluated across six studies involving a total of 571 patients with PVDs, and abnormalities were detected in 53% (n = 302) of these cases. Tests of spontaneous and positional nystagmus and the horizontal component of the vestibuloocular reflex (VOR), by comparison, detected PVDs in 48% of 798 patients with suspected vestibular impairment. For patients with vestibular deficits associated with central nervous system disease, a total of 389 cases were identified in five studies and SOT abnormalities were found in 54% (n = 209) of these cases. The motor perturbation test was abnormal in 35% (n = 41) of 119 patients with central vestibular disease. In conclusion, the sensitivity of static posturography appeared to be slightly better than that of dynamic posturography for detecting PVDs, but the level of sensitivity for each posturography test, as well as for tests of horizontal VOR function, was considered to be low. Combining either type of posturography with other tests of vestibular function, however, increased the overall sensitivity of detecting vestibular deficits to 61% to 89%. It was concluded that dynamic and static platform posturography as well as tests of VOR function lack adequate sensitivity to detect vestibular impairment when applied in isolation. Posturography appears to detect vestibular deficits in some patients who had normal VOR assessments and, therefore, provides supplemental rather than redundant information about vestibular dysfunction.

Manipulation of the cervical spine: risks and benefits.

Manipulation of the cervical spine (MCS) is used in the treatment of people with neck pain and muscle-tension headache. The purposes of this article are to review previously reported cases in which injuries were attributed to MCS, to identify cases of injury involving treatment by physical therapists, and to describe the risks and benefits of MCS. One hundred seventy-seven published cases of injury reported in 116 articles were reviewed. The cases were published between 1925 and 1997. The most frequently reported injuries involved arterial dissection or spasm, and lesions of the brain stem. Death occurred in 32 (18%) of the cases. Physical therapists were involved in less than 2% of the cases, and no deaths have been attributed to MCS provided by physical therapists. Although the risk of injury associated with MCS appears to be small, this type of therapy has the potential to expose patients to vertebral artery damage that can be avoided with the use of mobilization (nonthrust passive movements). The literature does not demonstrate that the benefits of MCS outweigh the risks. Several recommendations for future studies and for the practice of MCS are discussed.

Evaluation of eccentric exercise in treatment of patellar tendinitis.

The purpose of this study was to analyze the effects of a quadriceps femoris muscle eccentric training program on strength gain in patients with patellar tendinitis. The effect of an eight-week eccentric exercise program on quadriceps femoris muscle work was evaluated in four groups of subjects--two groups of "normal" (healthy) subjects and two groups of patients with patellar tendinitis. All four groups participated in a home muscle stretching exercise program, but only two groups--one group of normal subjects (N-A) and one group of subjects with tendinitis (T-A)--received additional eccentric training on an eccentric isokinetic dynamometer. The eccentric quadriceps femoris muscle work ratio (involved limb/uninvolved limb x 100) was used to quantify strength in the N-A and T-A Groups. Pain ratings were recorded for subjects with tendinitis before and after the eight-week experiment and were correlated with the dependent variable using a Spearman rank-order correlation coefficient. The N-A Group performed significantly better than all subjects with tendinitis (p less than .05). Subjects in the T-A Group, however, showed a trend toward increasing eccentric quadriceps femoris muscle work capacity over the eight-week training period. As pain ratings in the T-A Group increased, work ratios decreased. We concluded that eccentric exercise may be an effective treatment for patellar tendinitis, but that knee pain may limit optimal gains in strength.