Defective neurogenesis in citron kinase knockout mice by altered cytokinesis and massive apoptosis.

Citron-kinase (Citron-K) has been proposed by in vitro studies as a crucial effector of Rho in regulation of cytokinesis. To further investigate in vivo its biologic functions, we have inactivated Citron-K gene in mice by homologous recombination. Citron-K-/- mice grow at slower rates, are severely ataxic, and die before adulthood as a consequence of fatal seizures. Their brains display defective neurogenesis, with depletion of specific neuronal populations. These abnormalities arise during development of the central nervous system due to altered cytokinesis and massive apoptosis. Our results indicate that Citron-K is essential for cytokinesis in vivo but only in specific neuronal precursors. Moreover, they suggest a novel molecular mechanism for a subset of human malformative syndromes of the CNS.

The design of and chronic tissue response to a composite nerve electrode with patterned stiffness.

OBJECTIVE: As neural interfaces demonstrate success in chronic applications, a novel class of reshaping electrodes with patterned regions of stiffness will enable application to a widening range of anatomical locations. Patterning stiff regions and flexible regions of the electrode enables nerve reshaping while accommodating anatomical constraints of various implant locations ranging from peripheral nerves to spinal and autonomic plexi. APPROACH: Introduced is a new composite electrode enabling patterning of regions of various electrode mechanical properties. The initial demonstration of the composite's capability is the composite flat interface nerve electrode (C-FINE). The C-FINE is constructed from a sandwich of patterned PEEK within layers of pliable silicone. The shape of the PEEK provides a desired pattern of stiffness: stiff across the width of the nerve to reshape the nerve, but flexible along its length to allow for bending with the nerve. This is particularly important in anatomical locations near joints or organs, and in constrained compartments. We tested pressure and volume design constraints in vitro to verify that the C-FINE can attain a safe cuff-to-nerve ratio (CNR) without impeding intraneural blood flow. We measured nerve function as well as nerve and axonal morphology following 3 month implantation of the C-FINE without wires on feline peripheral nerves in anatomically constrained areas near mobile joints and major blood vessels in both the hind and fore limbs. MAIN RESULTS: In vitro inflation tests showed effective CNRs (1.93 ± 0.06) that exceeded the industry safety standard of 1.5 at an internal pressure of 20 mmHg. This is less than the 30 mmHg shown to induce loss of conduction or compromise blood flow. Implanted cats showed no changes in physiology or electrophysiology. Behavioral signs were normal suggesting healthy nerves. Motor nerve conduction velocity and compound motor action potential did not change significantly between implant and explant (p > 0.15 for all measures). Axonal density and myelin sheath thickness was not significantly different within the electrode compared to sections greater than 2 cm proximal to implanted cuffs (p > 0.14 for all measures). SIGNIFICANCE: We present the design and verification of a novel nerve cuff electrode, the C-FINE. Laminar manufacturing processes allow C-FINE stiffness to be configured for specific applications. Here, the central region in the configuration tested is stiff to reshape or conform to the target nerve, while edges are highly flexible to bend along its length. The C-FINE occupies less volume than other NCEs, making it suitable for implantation in highly mobile locations near joints. Design constraints during simulated transient swelling were verified in vitro. Maintenance of nerve health in various challenging anatomical locations (sciatic and median/ulnar nerves) was verified in a chronic feline model in vivo.

Modeling the postural disturbances caused by upper extremity movements.

This paper describes the design, validation, and application of a dynamic, three-dimensional (3-D) model of the upper extremity for the purpose of estimating postural disturbances generated by movements of the arms. The model consists of two links representing the upper and lower arms, with the shoulder and elbow modeled as gimbal joints to allow three rotational degrees of freedom. With individualized segment inertial parameters based on anthropometric measurements, the model performs inverse dynamic analysis of recorded arm movements to calculate reaction forces and moments acting on the body at the shoulder in three dimensions. The method was validated by comparing the output of the model to estimates obtained from ground reaction loads during stereotypical and free form unilateral movements at various velocities and with different loads carried by human subjects while seated on biomechanical force platforms. The correlation between predicted and measured reaction forces and moments was very good under all conditions and across all subjects, with average rms errors less than 8% of measured peak-to-peak values. The model was then applied to bimanual activities representative of functional movements that would typically be performed while standing at a counter. The resulting estimates were consistent and adequate for the purpose of evaluating postural disturbances caused by upper extremity movements.

Architecture of the rectus abdominis, quadratus lumborum, and erector spinae.

Quantitative descriptions of muscle architecture are needed to characterize the force-generating capabilities of muscles. This study reports the architecture of three major trunk muscles: the rectus abdominis, quadratus lumborum, and three columns of the erector spinae (spinalis thoracis, longissimus thoracis and iliocostalis lumborum). Musculotendon lengths, muscle lengths, fascicle lengths, sarcomere lengths, pennation angles, and muscle masses were measured in five cadavers. Optimal fascicle lengths (the fascicle length at which the muscle generates maximum force) and physiologic cross-sectional areas (the ratio of muscle volume to optimal fascicle length) were computed from these measurements. The rectus abdominis had the longest fascicles of the muscles studied, with a mean (S.D.) optimal fascicle length of 28.3 (4.2)cm. The three columns of the erector spinae had mean optimal fascicle lengths that ranged from 6.4 (0.6)cm in the spinalis thoracis to 14.2 (2.1)cm in the iliocostalis lumborum. The proximal portion of the quadratus lumborum had a mean optimal fascicle length of 8.5 (1.5)cm and the distal segment of this muscle had a mean optimal fascicle length of 5.6 (0.9)cm. The physiologic cross-sectional area of the rectus abdominis was 2.6 (0.9)cm(2), the combined physiologic cross-sectional area of the erector spinae was 11.6 (1.8)cm(2), and the physiologic cross-sectional area of the quadratus lumborum was 2.8 (0.5)cm(2). These data provide the basis for estimation of the force-generating potential of these muscles.

The theoretical development of a multichannel time-series myoprocessor for simultaneous limb function detection and muscle force estimation.

This paper details the theoretical development and simulation of a complete time-series myoprocessor which provides reliable and economical predictions of both the magnitude and direction of limb motion from the spectral content of the surface EMG. Treating multiple channels of surface EMG as a vector-valued autoregressive process incorporates spatially distributed information which extends the operating range of parallel filtering limb function classifiers and reduces their sensitivity to modeling conditions. Active joint moment is estimated simultaneously from the pooled variance of the prewhitened EMG generated during the classification procedure. Estimation from the prewhitened sequence imposes no additional computational requirements and extends optimal myoprocessors to include multiple channels of serially dependent data. Such a system may be applied to the control of actively powered prostheses or orthoses.

The experimental demonstration of a multichannel time-series myoprocessor: system testing and evaluation.

A multichannel time-series myoprocessor which combines the advantages of the parallel filtering limb function classifiers of Doerschuk et al. and the "optimal myoprocessor" muscle force estimators described by Hogan et al. have been developed and evaluated experimentally. Magnitudes and directions of knee movements were identified accurately and robustly from EMG sites intermediate to the major thigh muscles of intact individuals. Electrode placement criteria were tested, and system performance and sensitivity to contraction level as functions of channel number were computed. By including spatially distributed information into the structure of the processor, gains in accuracy and reliability over systems with fewer channels were demonstrated. Operating range increased with the number of channels included in the processor. Joint moment was estimated from multiple channels of temporally correlated data, extending and generalizing previously reported techniques. Identifying the parameters of AR models of the EMG at low levels of contraction resulted in more robust classification and joint moment estimation. Optimal electrode position could not be predicted a priori. The system may be applicable to the proportional control of myoelectric prostheses.

Tetanic responses of electrically stimulated paralyzed muscle at varying interpulse intervals.

The influence of stimulus interpulse interval (IPI) on torque output during electrically-evoked contractions was investigated for the knee extensor muscles of paralyzed subjects. The parameters measured were the rise time, magnitude, and relaxation time of the contraction at stimulus IPI's ranging from 62 to 7 ms. Torque output increased as IPI's were decreased from 62 to 15 ms. Peak torques were recorded at IPI's of 12-15 ms; IPI's less than these resulted in an insignificant loss of torque. Rise times decreased as IPI's were decreased. Relaxation time generally increased as IPI's were decreased with the longest relaxation times occurring with stimulation at an IPI of 12 ms. To demonstrate the influence of IPI on muscle fatigue, the effect of prolonged stimulation at short (12 ms) and long (50 ms) IPI's was also compared. After 30 s of stimulation with an IPI of 12 ms, mean torque had declined to 5 +/- 3 percent and after 30 s of stimulation with an IPI of 50 ms, mean torque had declined to 82 +/- 4 percent of the initial value. Knowledge of how stimulus IPI influences the response of paralyzed muscle to electrical stimulation may assist in the development of rehabilitation devices which utilize these technologies.

A reusable, self-adhesive electrode for intraoperative stimulation in the lower limbs.

A suction-based stimulating electrode was designed and fabricated to allow intraoperative testing of lower-limb muscles during routinely scheduled surgical procedures. The suction device can adhere to a small exposure of muscle surface with reproducible contact forces and can maintain its geometric relationship to the underlying tissue for sufficient time to grade the resulting muscle contraction before removal and repositioning. When operated with a 10-cc syringe, the device can generate between 0 and 23 N of contact force; correlation between measured contact forces and those analytically predicted was 0.989. Preliminary animal testing indicates that the reusable device maintains its position over the nerve entry point even during vigorous active contractions of the stimulated muscle. Thus, it may be a valuable useful tool for locating the optimal site for a permanent electrode for functional electrical stimulation (FES) applications, as well as an ideal means of providing accurate and repeatable stimulation in various locations.

Selectivity of intramuscular stimulating electrodes in the lower limbs.

Intramuscular (IM) electrodes have been used safely and effectively for decades to activate paralyzed muscles in neuroprosthetic systems employing functional electrical stimulation (FES). However, the response to stimulation delivered by these and any type of electrode can be limited by a phenomenon known as spillover, in which the stimulus intended to produce a contraction in a particular muscle inadvertently activates another muscle, causes adverse sensation, or triggers undesired reflexes. The purpose of this retrospective study was to determine the selectivity of monopolar intramuscular stimulating electrodes implanted in the lower limbs of individuals with motor and sensory complete paraplegia secondary to spinal cord injury (SCI) and to catalog the most common electrode spillover patterns. The performance records of 602 electrodes from 10 subjects who participated in a program of standing and walking with FES in our laboratory over the past decade were examined. Sixty percent (358) of these electrodes were "stable" (i.e., stimulated responses were consistent during the first 6 months postimplant), and 32% of all stable electrodes (113) exhibited spillover as noted in clinical and laboratory records. Common spillover patterns for eight muscle groups were tabulated and analyzed in terms of their functional implications. The beneficial (activation of synergistic muscles) or deleterious (activation of compromising reflexes, antagonists, or adverse sensation) effects of spillover were highly context dependent, with several potentially useful spillover patterns in certain phases of gait becoming undesirable and limiting in others. Knowledge of the selectivity of intramuscular electrodes and the patterns of spillover they exhibit should guide surgeons and rehabilitationists installing lower-limb neuroprostheses during the implantation process and allow them to better predict the ultimate functional usefulness of the electrodes they choose.

Effects of stimulated hip extension moment and position on upper-limb support forces during FNS-induced standing--a technical note.

This study explores the effects of active hip extension moment produced by electrical stimulation on the support forces the arms must exert through an assistive device during quiet erect standing with functional neuromuscular stimulation (FNS) in individuals with spinal cord injuries (SCI). A static sagittal plane biomechanical model of human standing was developed to predict the effects of stimulated hip extension moment and sagittal plane hip angle on the arm support necessary to maintain an upright posture. Two individuals with complete thoracic SCI were then tested while they stood with continuous stimulation to the knee and trunk extensors. The steady-state active extension moment exerted at the hip was varied by activating different combinations of hip extensor muscles with continuous stimulation while steady-state support forces applied to the arms and feet during standing were measured. The steady-state support forces imposed on the arms during quiet standing decrease with increased stimulated hip extension moment and are highly dependent upon hip flexion angle, as predicted by the biomechanical simulations. Experimentally, the combination of gluteus maximus and semimembranosus stimulation produced three times more steady-state hip extension moment than did stimulation of the gluteus maximus and adductor magnus. This resulted in a ten-fold decrease in body weight supported on the arms. More vertical postures (smaller hip flexion angles) improve the effectiveness of the hip extensor muscles in reducing the support forces placed on the arms. A single Newton-meter of stimulated hip extension moment with the hips fixed at 5 degrees of flexion results in almost five times the reduction in arm support forces as with the hips at 20 degrees. To minimize the forces applied by the arms on an assistive device for support while standing with FNS, these preliminary results suggest that (1) efforts should be made to assume the most erect postures possible and (2) muscles and stimulation paradigms that maximize active hip extension moment should be chosen.

Challenges to clinical deployment of upper limb neuroprostheses.

The technology for functional neuromuscular stimulation (FNS) as a means of providing upper limb function to people with tetraplegia has been under development by three clinical research groups for almost two decades. This paper presents the current status of the clinical trials of three FNS systems: a noninvasive system built into a cosmetic forearm splint, a 30-channel percutaneous system, and an 8-channel implantable system. The complexity of FNS systems and the unique characteristics of the individuals to whom they are applied combine to create many clinical and technical challenges that must be addressed before the devices can be deployed. The emerging challenges to widespread clinical introduction of FNS systems for hand and arm function are identified and analyzed. In addition to the demands of designed and conducting the clinical trials to satisfy regulatory requirements, the lack of knowledge, skepticism, and the complacency on the part of potential FNS recipients, as well as of rehabilitation professionals, must be overcome through education and careful consideration of economic and societal factors in the design of clinical systems.

Preliminary performance of a surgically implanted neuroprosthesis for standing and transfers--where do we stand?

This paper describes the preliminary performance of a surgically implanted neuroprosthesis for standing and transfers after spinal cord injury (SCI) in an initial group of 12 volunteers with longstanding paralysis. The CWRU/VA standing neuroprosthesis consists of an 8-channel implanted receiver-stimulator, epimysial and surgically implanted intramuscular electrodes, and a programmable wearable external controller. After reconditioning exercise and rehabilitation with the system, most individuals with paraplegia or low tetraplegia were able to stand, transfer, and release one hand from a support device to manipulate objects in the environment or to perform swing-to ambulation in a walker. The effort and assistance required for transfers were reduced for users with mid-level tetraplegia, although the maneuvers were not independent. Neuroprosthesis users with tetraplegia and paraplegia alike benefited from the improvements in their general health derived from exercise, including reduced risk of decubiti and self-reported modulation of spasticity. Stimulated responses are stable and sufficiently strong for function, and implanted components are reliable with a 90% probability of epimysial electrode survival at 4 years post-implant. The techniques employed are repeatable and teachable, and suitable for multi-center clinical trial.

Characterization of the bone mineral density of children with spinal cord injury.

The purpose of this study was to compare the bone mineral density in children with spinal cord injury (SCI) with age- and sex-matched controls in three anatomic areas of the proximal hip. In addition, post hoc analysis looked for differences in bone density between sub-groups considering several factors associated with spinal cord injury: the presence or absence of spasticity, the level of injury and the presence or absence of pathologic fractures. Fifty-one pediatric patients with spinal cord injury between the ages of 3 and 20 underwent bone density measurements using dual photon absorptiometry. Before pooling the data across age groups, all measurements were normalized to age- and sex-matched controls because of increasing bone density with growth and higher bone density in males. The results revealed lower bone densities in subjects with SCI as compared with their non-disabled peers, ranging from 56 percent to 65 percent of normal across the three anatomic regions. On the average, subjects who had a previous history of fractures had significantly lower bone density measurements than those without fractures. At the intertrochanteric region, a 10.6 percent difference was noted between subjects with tetraplegia versus those with paraplegia. At the femoral neck and Ward's Triangle, an 8.5 percent difference was noted between subjects with and without spasticity. No conclusions could be drawn from the analyses at the other sites. Together these results begin to characterize bone density levels of the pediatric SCI population.

Inter-rater reliability of a clinical test of standing function.

The Functional Standing Test (FST) has been proposed and described as an evaluative tool to assess a person's ability to perform one-handed reaching tasks while standing. The test items, several of which are identical to those in the Jebson Test of Hand Function, require the manipulation of objects on a counter top and on simulated kitchen shelves while the person is standing. The purpose of this study was to assess the inter-rater reliability of FST when it is administered to adolescents with spinal cord injuries who stand with braces, and to able-bodied young adults. Two testers administered the FST separately to three individuals with spinal cord injuries (SCI) below T-2 who stood with knee-ankle-foot orthoses (KAFOs) and to 10 able-bodied people who stood unassisted. The order in which the testers operated was randomized and the Intraclass Correlation Coefficient (ICC (2,1)) was used to analyze inter-rater reliability. Eighty percent of the subtests were found to be moderately to very reliable when applied to either group on the same day. Half of the test items were categorized as having the same level of inter-rater reliability between the two sample populations. A modified version of the test eliminating unreliable components could serve as a valuable and inexpensive means of evaluating the effectiveness of various therapies and technologies to provide or assist standing function. Validity and specificity of the test remain the focus of future research.

Functional neuromuscular stimulation in spinal cord injury.

With recent advances in clinical medicine and biomedical engineering, functional neuromuscular stimulation (FNS) can now be added to the psychiatric armamentarium to decrease the debilitating effects of traumatic spinal cord injury. In this article, the components of FNS systems and their evolution in design are presented. The clinical implications of FNS are discussed with respect to upper and lower extremities and bladder applications, and perspectives on future developments and directions are reviewed.

[Hepatorenal syndrome]. / La sindrome epatorenale.

The term "hepatorenal syndrome" is used to bring together a variety of syndromes whose common feature is liver and kidney parenchymal distress. For this reason, its use has been questioned by many workers. A subdivision into acute and chronic forms is proposed and emphasis is placed on the common physiopathogenetic processes, together with the notable importance of DIC. This approach is supported by reference to a series of 36 chronic and 6 acute cases.

[Goodpasture's syndrome. Observations on a case]. / Sindrome di Goodpasture. Considerazioni su di un caso.

Following a review of the most recent aetiopathogenetic theories and therapeutic records of Goodpasture's syndrome, a personal case is reported. Stress is laid on the extreme clinical variability of the disease and on the role which disseminated intravascular clotting can have on its course.

[Renal tubular acidosis during a course of liver cirrhosis]. / Acidosi renale tubulare in corso di cirrosi epatica.

In a group of 23 patients suffering from liver cirrhosis, metabolic acidosis was always observed, in most cases corrected by respiratory alkalosis. In 8,6% of cases a tubular renal acidosis (type I), in 8,6% (type II) and 8,6% a loss of urinary bicarbonate without acidosis were observed.

Selective activation of the human tibial and common peroneal nerves with a flat interface nerve electrode.

OBJECTIVE: Electrical stimulation has been shown effective in restoring basic lower extremity motor function in individuals with paralysis. We tested the hypothesis that a flat interface nerve electrode (FINE) placed around the human tibial or common peroneal nerve above the knee can selectively activate each of the most important muscles these nerves innervate for use in a neuroprosthesis to control ankle motion. APPROACH: During intraoperative trials involving three subjects, an eight-contact FINE was placed around the tibial and/or common peroneal nerve, proximal to the popliteal fossa. The FINE's ability to selectively recruit muscles innervated by these nerves was assessed. Data were used to estimate the potential to restore active plantarflexion or dorsiflexion while balancing inversion and eversion using a biomechanical simulation. MAIN RESULTS: With minimal spillover to non-targets, at least three of the four targets in the tibial nerve, including two of the three muscles constituting the triceps surae, were independently and selectively recruited in all subjects. As acceptable levels of spillover increased, recruitment of the target muscles increased. Selective activation of muscles innervated by the peroneal nerve was more challenging. SIGNIFICANCE: Estimated joint moments suggest that plantarflexion sufficient for propulsion during stance phase of gait and dorsiflexion sufficient to prevent foot drop during swing can be achieved, accompanied by a small but tolerable inversion or eversion moment.

Selective stimulation of the human femoral nerve with a flat interface nerve electrode.

In humans, we tested the hypothesis that a flat interface nerve electrode (FINE) placed around the femoral nerve trunk can selectively stimulate each muscle the nerve innervates. In a series of intraoperative trials during routine vascular surgeries, an eight-contact FINE was placed around the femoral nerve between the inguinal ligament and the first nerve branching point. The capability of the FINE to selectively recruit muscles innervated by the femoral nerve was assessed with electromyograms (EMGs) of the twitch responses to electrical stimulation. At least four of the six muscles innervated by the femoral nerve were independently and selectively recruited in all subjects. Of these, at least one muscle was a hip flexor and at least two were knee extensors. Results from the intraoperative experiments were used to estimate the potential for the electrode to restore knee extension and hip flexion through functional electrical stimulation. Normalized EMGs and biomechanical simulations were used to estimate joint moments and functional efficacy. Estimated knee extension moments exceed the threshold required for the sit-to-stand transition.