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Biomedical subjects

L Andrew Koman

Publications and source records attributed to L Andrew Koman.

At least 19 recordsLinked to original sources
PubMed2006

How muscles recover from paresis and atrophy after intramuscular injection of botulinum toxin A: Study in juvenile rats.

Botulinum toxin A (BoNT-A) is a potent biological toxin widely used for the management of skeletal muscle spasticity or dynamic joint contracture. Intramuscular injection of BoNT-A causes muscle denervation, paresis, and atrophy. This clinical effect of botulinum toxin A lasts 3 to 6 months, and injected muscle eventually regains muscle mass and recovers muscle function. The goal of the present study was to characterize the molecular and cellular mechanisms leading to neuromuscular junction (NMJ) regeneration and skeletal muscle functional recovery after BoNT-A injection. Fifty-six 1-month-old Sprague-Dawley rats were used. Botulinum toxin A was injected into the left gastrocnemius muscle at a dosage of 6 units/kg body weight. An equivalent volume of saline was injected into the right gastrocnemius muscle to serve as control. The gastrocnemius muscle samples were harvested from both hind limbs at 3 days, 7 days, 15 days, 30 days, 60 days, 90 days, 180 days, and 360 days after administration of toxin. In addition, the gastrocnemius muscles from 1-month-old rats with no injections were harvested to serve as uninjected control group. Muscle samples were processed and mRNA was extracted. Real-time polymerase chain reaction (PCR) and gene microarray technology were used to identify key molecules involved in NMJ stabilization and muscle functional recovery. More than 28,000 rat genes were analyzed and approximately 9000 genes are expressed in the rat gastrocnemius muscle. Seven days following BoNT-A injection, 105 genes were upregulated and 59 genes were downregulated. Key molecules involved in neuromuscular junction (NMJ) stabilization and muscle functional recovery were identified and their time course of gene expression following BoNT-A injection were characterized. This animal study demonstrates that following intramuscular injection of BoNT-A, there is a sequence of cellular events that eventually leads to NMJ stabilization, remodeling, and myogenesis and muscle functional recovery. This recovery process is divided into two stages (aneural and neural) and that the IGF-1 signaling pathway play a central role in the process.

Animals↗
PubMed2006

Fractures of the phalanges and interphalangeal joints in children.

Phalangeal fractures in children are common, and conservative treatment leads frequently to a good functional outcome. Articular or displaced fractures require early re-cognition and special attention, including surgery. In children, remodeling occurs primarily in the sagittal plane, and rotational deformities are often unacceptable.

Casts, Surgical↗
PubMed2005

Gene expression of nAChR, SNAP-25 and GAP-43 in skeletal muscles following botulinum toxin A injection: a study in rats.

PURPOSE: Botulinum toxin A (BoNT-A) is used to manage spasticity in cerebral palsy. BoNT-A cleaves SNAP-25 protein, blocking acetylcholine release and weakening the muscle. Nicotinic acetylcholine receptors (nAChR) including alpha, beta, delta, gamma, and epsilon subunits, and GAP-43 protein are associated with functional recovery of neuromuscular junctions (NMJ) following BoNT-A. To better understand the mechanism behind this functional recovery, this study attempted to (1) document changes in NMJ morphometry following BoNT-A, and (2) determine the gene expression of nAChR subunits, SNAP-25, and GAP-43 protein. METHODS: In this rat study (46 rats), 6 units/kg body weight of BoNT-A was injected into the gastrocnimus. NMJ morphometry and the time course of gene expression of nAChR subunits, SNAP-25, and GAP-43 were evaluated up to 1year post-injection. RESULTS: NMJ morphometry: gutter depth was reduced vs. the control side at two months, and normalizing by 6 months following BoNT. nAChR alpha mRNA and gamma mRNA increased by 3 days, peaked at 7 days and returned to control levels; delta mRNA peaked at 3 days. Epsilon mRNA peaked by 7 days. SNAP-25 mRNA increased from 60 to 90 days, returning to control levels by 6 months. GAP-43 mRNA was unchanged. CONCLUSIONS: Specific nAChR subunit mRNA expression up-regulates and then returns to normal within two weeks, preceding changes in NMJ morphometry. Although GAP-43 participates in nerve sprouting, no increase of GAP-43 mRNA occurred following BoNT-A. Delayed up-regulation of SNAP-25 mRNA might be associated with muscle functional recovery.

Animals↗
PubMed2005

Vascular changes of the hand in professional baseball players with emphasis on digital ischemia in catchers.

BACKGROUND: Repetitive trauma to the hand is a concern for baseball players. The present study investigated the effects of repetitive trauma and the prevalence of microvascular pathological changes in the hands of minor league professional baseball players. In contrast to previous investigators, we documented the presence of abnormalities in younger, asymptomatic individuals. METHODS: Thirty-six baseball players on active minor league rosters underwent a history and physical examination of both hands as well as additional specialized tests, including Doppler ultrasound, a timed Allen test, determination of digital brachial pressure indices, and ring sizing of fingers. Data were compared between gloved hands and throwing hands, hitters and nonhitters, and players at four different positions (catcher [nine subjects], outfielder [seven subjects], infielder [five subjects], and pitcher [fifteen subjects]). RESULTS: Digital brachial indices in the ring fingers of the gloved (p < 0.05) and throwing hands (p < 0.02) of catchers were significantly diminished compared with those in all other players. Doppler testing showed a significantly greater prevalence of abnormal flow in the ulnar artery at Guyon's canal when catchers were compared with other position players (p < 0.01). Doppler abnormalities were significantly more common in the gloved hand compared with the throwing hand (p < 0.05). Seven of nine catchers (and only catchers) were found to have index finger hypertrophy (average change, two ring sizes; p < 0.01); the hypertrophy occurred at the proximal phalanx and the proximal interphalangeal joint of the gloved hand. Catchers had a significantly higher prevalence of subjective hand symptoms (specifically, weakness in the gloved hand) compared with pitchers and infielders/outfielders (44% compared with 7% and 17%, respectively; p < 0.05). CONCLUSIONS: Microvascular changes are present in the hands of otherwise healthy professional baseball players in all positions, with a significantly higher prevalence in catchers, prior to the development of clinically important ischemia. Repetitive trauma resulting from the impact of the baseball also leads to digital hypertrophy in the index finger of the gloved hand of catchers. Gloves currently used by professional catchers do not adequately protect the hand from repetitive trauma.

Adult↗
PubMed2005

Complex regional pain syndrome.

Abnormal posttraumatic pain may delay recovery and severely impact health-related quality of life. The term complex regional pain syndrome describes abnormally intense and prolonged pain that is not related to tissue damage and is sometimes a sequela of injury. Various treatment strategies, including therapy, parental interventions, and peripheral surgery, are used to manage the condition.

Complex Regional Pain Syndromes↗
PubMed2005

Acute pain following musculoskeletal injuries and orthopaedic surgery: mechanisms and management.

The undertreatment of acute pain associated with musculoskeletal conditions and surgical procedures is a focus of growing concern to orthopaedic surgeons. Fortunately, the armamentarium now includes recent advances in the understanding of how undertreated acute pain can lead to chronic pain, the development of new therapeutic agents, and new approaches to pain management. The concept of neuronal plasticity (the ability of neurons to profoundly alter their structure, function, or biochemical profile in response to repeated afferent sensory input) is now central to the understanding of the development of chronic pain from acute pain. Local inflammation in injured tissue increases the sensitization of specialized peripheral sensory neurons (nociceptors), leading to repeated afferent input into the central nervous system. Resolving inflammation before these events occur may prevent modifications in the central nervous system that lead to chronic pain. Therefore, it is important to reduce pain and inflammation at both the central and peripheral level. In addition to traditional agents (aspirin, nonspecific nonsteroidal anti-inflammatory drugs, opioids, local anesthetics, and regional blocks), more recently developed agents, such as cyclooxygenase-2 specific inhibitors, are now available. Combinations of these agents, as well as combinations of pharmacologic and nonpharmacologic approaches, are being used as multimodal therapy to treat the multiple sources of acute pain. Clinical practice guidelines for the management of acute pain now emphasize the incorporation of new knowledge into solid, evidence-based practice. This knowledge, combined with further understanding of the anatomic, physiologic, cellular, and molecular basis of pain, will provide the basis forfuture approaches to the management of acute pain in orthopaedic practice.

Acute Disease↗
PubMed2004

Cerebral palsy.

Cerebral palsy, a range of non-progressive syndromes of posture and motor impairment, is a common cause of disability in childhood. The disorder results from various insults to different areas within the developing nervous system, which partly explains the variability of clinical findings. Management options include physiotherapy, occupational and speech therapy, orthotics, device-assisted modalities, pharmacological intervention, and orthopaedic and neurosurgical procedures. Since 1980, modification of spasticity by means of orally administered drugs, intramuscular chemodenervation agents (alcohol, phenol, botulinum toxin A), intrathecally administered drugs (baclofen), and surgery (neurectomy, rhizotomy) has become more frequent. Family-directed use of holistic approaches for their children with cerebral palsy includes the widespread adoption of complementary and alternative therapies; however, the prevalence of their use and the cost of these options are unknown. Traditional medical techniques (physiotherapy, bracing, and orthopaedic musculoskeletal surgery) remain the mainstay of treatment strategies at this time. This seminar addresses only the musculoskeletal issues associated with cerebral palsy and only indirectly discusses the cognitive, medical, and social issues associated with this diagnosis.

Cerebral Palsy↗
PubMed2004

Clinical usefulness of botulinum toxin in the lower extremity.

As the literature that pertains to botulinum toxin expands, the scope of treatment options broadens. Although initial uses of botulinum toxin focused around the head and neck, there are many uses for the toxin in the area of the foot and ankle; more possibilities are under investigation every day. We review the uses and techniques for botulinum toxin in the foot and ankle and present results of botulinum toxin treatment in 10 idiopathic toe walkers.

Ankle↗
PubMed2004

Complex regional pain syndrome (reflex sympathetic dystrophy).

The management of CRPS can be approached using objective criteria in a logical and systematic fashion. Frustration during treatment is common because: (1) the pathophysiology of CRPS is incompletely understood, (2) there is significant variation in presentation due to disparate premorbid anatomy and physiology, and (3) the natural history may be affected by incomplete treatment. Therapeutic efforts that should be effective may fail, and a trial-and-error approach to treatment is often mandatory. Early recognition of CRPS and prompt intervention, however, provide the best opportunity for clinical improvement.

Autonomic Nervous System↗
PubMed2004

Time course of recovery of juvenile skeletal muscle after botulinum toxin A injection: an animal model study.

OBJECTIVE: To study the effects of neuromuscular blockade using botulinum toxin A on juvenile muscles at a dosage of 6 units/kg body weight in a rat model. DESIGN: A total of 34 male Sprague-Dawley rats (1-mo old) were used. A small incision was made along the posterior aspect of the left hind leg with the exposure of the gastrocnemius. Botulinum toxin A was injected at a dosage of 6 units/kg body weight in the medial and lateral heads of the muscle. An equivalent volume of saline were injected into the right gastrocnemius (control). Motor evoked action potentials, muscle force generation, and muscle mass and neuromuscular junction morphometry were analyzed at different time intervals up to 1 yr after toxin injection. RESULTS: During the 1-2 wks after botulinum toxin A injection, muscle mass, electrophysiologic variables, and muscle force generation were significantly reduced but returned to nearly normal at 6 mos postinjection. In the study group, neuromuscular junction gutter depth became significantly shallower 2 mos after injection, then normalized at 1 yr. There was a nonsignificant trend toward larger neuromuscular junctions from the gastrocnemius injected with botulinum toxin A. CONCLUSION: Our findings provide scientific evidence to support the clinical situation in which the interinjection interval of 3-6 mos of botulinum toxin A at a similar dosage is used.

Animals↗
PubMed2004

Management of peripheral nerve defects: external fixator-assisted primary neurorrhaphy.

BACKGROUND: Controlled joint extension followed by gradual distraction with use of an external fixator may facilitate primary repair of peripheral nerve defects by permitting end-to-end repair without tension. The hypothesis of the present study was that gradual lengthening of nerve repairs with use of incremental distraction would provide superior results compared with grafting or repair under tension. METHODS: A median nerve segment measuring four times the diameter of the nerve was resected in thirty-six rabbits to create a 7-mm gap in the nerve. Neurorrhaphy was performed with use of one of three techniques. In Group 1 (cable graft), a tension-free medial antebrachial cutaneous graft was placed to allow full range of motion of the elbow postoperatively. In Group 2 (end-to-end repair without distraction), the elbow was externally fixed in hyperflexion and the nerve was repaired end-to-end. At fourteen days, the fixator was removed and unprotected elbow motion was permitted. In Group 3 (end-to-end repair with gradual distraction), the elbow was externally fixed in hyperflexion and primary neurorrhaphy was performed. At fourteen days, the elbow was extended 10 degrees every other day with use of the articulated external fixator until full extension was achieved. Median nerve amplitude, latency, and nerve-conduction velocity; flexor digitorum superficialis single-twitch force generation and maximum tetanic force generation; muscle mass; and elbow range of motion were measured at three or six months. In addition, histologic analysis of the median nerve distal to the repair site and the morphometry of the neuromuscular junction in the flexor digitorum superficialis were performed at six months. RESULTS: All rabbits regained full active and passive range of motion. At three months, the nerve-conduction velocities in Groups 2 and 3 were significantly greater than that in Group 1. At six months, the nerve-conduction velocities and amplitudes in Group 3 were significantly greater than those in Groups 1 and 2. At six months, the tetanic force in Group 3 was significantly greater than those in Groups 1 and 2. There were no significant differences in muscle mass among the groups. There were no significant differences in histological findings among the three groups, although there was a trend toward larger fiber size in Group 3 as compared with the other two groups. The neuromuscular junctions in Group 3 had a significantly larger surface area than did those in Group 1 (p = 0.002) and Group 2 (p = 0.034). CONCLUSION: The use of an articulated external fixator and controlled gradual distraction appears to facilitate the treatment of peripheral nerve defects.

Animals↗
PubMed2004

Longitudinal examination of health outcomes associated with botulinum toxin use in children with cerebral palsy.

A prospective cohort study with annual follow-up was conducted on 172 children with spastic type cerebral palsy receiving botulinum toxin type A (BTX) injections for spasticity management. A mixed modeling procedure was used to identify changes in both physical functioning outcomes for the child (using the WeeFIM measure) as well as quality of life of the parent caregiver (using the Stein and Reissman Impact on the Family Scale) with increasing utilization of BTX injections. The study found that each additional BTX injection administration was associated with a 2.3% improvement in the WeeFIM compared to the average baseline score (p < .01). Similarly, the study found an improvement of 2.5% compared to baseline in the parent's overall perception of the severity of the child's condition with each additional BTX injection administration (p < .001). These findings suggest that BTX injections may be associated with beneficial outcomes in childhood spasticity.

Adolescent↗
PubMed2003

Factors associated with self-esteem in pre-adolescents and adolescents with cerebral palsy.

Predictors of self-esteem were examined in 50 pre-adolescents and adolescents with cerebral palsy. On average, self-esteem was high, although 30% scored below a cut-point for low self-esteem. Self-esteem was bivariately associated with female gender, better physician-assessed functional ability, greater perception of the impact of the disability, and higher perceived parent overprotectiveness. In a multivariate model, only perceived impact of the disability remained significant.

Adolescent↗
PubMed2003

The acute effect of peripheral nerve transection on digital thermoregulatory function.

PURPOSE: This study tests the hypothesis that major peripheral nerves serve as important routes for adrenergic neural fibers and therefore peripheral nerve injury affects cutaneous perfusion within the nerve's sensory innervation territory. The specific aim of the study was to determine whether an acute isolated peripheral nerve injury would result in alteration of blood flow to a specific digit, digital pain, and/or cold sensitivity. METHODS: The influence of peripheral nerves on their dominant area of autonomic vasomotor function was evaluated in 9 patients who had primary neurorrhaphy after a single complete median or ulnar nerve transection. At a mean follow-up of 47 days the response of digital perfusion to a cold stress was examined in these patients by using isolated cold stress testing and laser Doppler fluxmetry. Patients also completed subjective questionnaires to evaluate their symptoms. RESULTS: The affected hands showed a decreased cutaneous perfusion when compared with the contralateral hands during all 3 phases of the cold stress test. In addition cutaneous perfusion patterns evaluated by laser Doppler perfusion imaging showed markedly decreased cutaneous perfusion patterns in the digits within the innervation territory of the injured nerve. There was no notable difference in digital baseline temperatures and temperature changes after an isolated cold stress test between the most affected digits of the injured hands and corresponding digits of the unaffected, contralateral hands. All 9 patients reported mild to severe digital numbness, 8 reported mild to severe pain, and 4 reported mild to moderate cold sensitivity of the upper extremity. CONCLUSIONS: This study documents that cutaneous perfusion and thermoregulatory function is altered after isolated peripheral nerve injury.

Adult↗
PubMed2003

Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin.

Botulinum A toxin produces selective and reversible chemodenervation that can be employed to balance muscle forces across joints in children with cerebral palsy (CP). Currently, there are two commercially available botulinum A toxin formulations (BOTOX) and Dysport). The amount of botulinum A toxin required depends upon the number of muscles that are targeted, and the size of the patient. In order to achieve adequate chemodenervation with botulinum A toxin, the following conditions must be met: (i) a sufficient number of units of toxin must be injected in order to neutralize neuromuscular junction (NMJ) activity; (ii) an appropriate drug volume is required in order to optimize the delivery of the toxin to the NMJs; and (iii) localization of the injecting needle through the fascia of the target muscle is necessary. Localization of the injection may be facilitated by active electromyography, ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks. Botulinum A toxin injections are indicated for use in pediatric patients with CP to: (i) improve motor function by balancing muscle forces across joints; (ii) improve health-related quality of life by decreasing spasticity and/or decreasing caregiver burden; (iii) decrease pain from spasticity; (iv) enhance self-esteem by diminishing inappropriate motor responses; and (v) provide a presurgical diagnostic tool. Following intramuscular injections of botulinum A toxin, short-term benefits of reduced spasticity are observed in approximately 70-82% of children. The intermediate term (1-2 years) efficacy rate is approximately 50%. The most common deformity treated with toxin injections in pediatric patients with CP is equinus foot deformity. However, efficacy of toxin injections for the management of crouched gait, pelvic flexion contracture, cervical spasticity, seating difficulties, and upper extremity deformity also has been documented. In addition, toxin injections have been shown to manage painful muscle spasticity associated with surgery or application of casts and painful cervical spasticity with or without dystonia. Toxin injections can also be used as a diagnostic tool to determine the appropriateness of other interventions by observing the muscle response to the injection in order to gain additional information for the development of a treatment plan. Botulinum A toxin, when used in appropriate doses, is well tolerated.

Botulinum Toxins↗
PubMed2003

Recurrence of equinus foot deformity in cerebral palsy patients following surgery: a review.

Although equinus deformity in children with cerebral palsy is often corrected with surgery, postsurgical recurrence of the deformity is not uncommon. In order to isolate factors that may be related to its recurrence, 31 studies were evaluated. Data from nine articles indicated that children younger than approximately 7 years of age at the time of surgery had a higher risk of recurrence than children who were older at the time of surgery. Recurrence rates may be understated in studies including less than a minimum of 4-5 years of patient follow-up. Lower recurrence rates are documented in diplegic patients compared with hemiplegic patients, and postoperative casting/splinting is stated, but not documented, to reduce recurrence. One study demonstrated that the use of chemodenervation delayed surgery and by inference theoretically would decrease recurrence after surgical release.

Adolescent↗
PubMed2002

Juvenile and adult rat neuromuscular junctions: density, distribution, and morphology.

Anatomical and physiological differences in neuromuscular junctions (NMJs) between juvenile and adult muscle may partially explain the variability in clinical results following chemodenervation with botulinum toxin or nerve repair in children and adults. We evaluated NMJ density, distribution, and morphometry in biceps brachii and gastrocnemius muscles from juvenile and adult rats. Motor endplates were stained with Karnovsky-Roots methods, and NMJ density (number/gram muscle tissue) was determined. The NMJ morphometry was quantitated with alpha-bungarotoxin labeling using confocal microscopy. Juvenile rats had a greater NMJ density in both muscles compared with adult rats. Juveniles and adult rats had a similar NMJ distribution in both muscles. In juvenile muscles NMJs occupied approximately 50% of the surface area and 70% of the length, width, circumference, and gutter depth compared with adult muscles. Our study demonstrates that although NMJs are smaller, juvenile muscles have a higher NMJ density than do adult muscles with similar distributions. If these age-dependent differences in NMJ density are obtained in humans, they may account, at least in part, for the better recovery that occurs in children than adults after nerve repair and also suggest that the dosage of botulinum toxin (units per kg) for chemodenervation may need to be increased in juveniles.

Aging↗