The brain and behavioral correlates of motor-related analgesia (MRA).

The human motor system has the capacity to act as an internal form of analgesia. Since the discovery of the potential influence of motor systems on analgesia in rodent models, clinical applications of targeting the motor system for analgesia have been implemented. However, a neurobiological basis for motor activation's effects on analgesia is not well defined. Motor-related analgesia (MRA) is a phenomenon wherein a decrease in pain symptoms can be achieved through either indirect or direct activation of the motor axis. To date, research has focused on (a) evaluating the pain-motor interaction as one focused on the acute protection from painful stimuli; (b) motor cortex stimulation for chronic pain; or (c) exercise as a method of improving chronic pain in animal and human models. This review evaluates (1) current knowledge surrounding how pain interferes with canonical neurological performance throughout the motor axis; and (2) the physiological basis for motor-related analgesia as a means to reduce pain symptom loads for patients. A proposal for future research directions is provided.

Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism.

Autosomal recessive ocular albinism (AROA) is a disorder characterized by reduced pigmentation of the retina and iris, hypoplastic fovea, variably reduced visual acuity and nystagmus. Pigmentation of the skin and hair is normal, but is usually slightly lighter than in unaffected sibs. We analysed 12 unrelated patients with AROA, and found that two had abnormalities of the tyrosinase (TYR) gene. These two patients were each a compound heterozygote for a different pathologic mutant allele and an allele containing a 'normal' polymorphism, Arg402Gln, which results in a tyrosinase polypeptide with reduced thermal stability. In these patients, AROA thus appears to represent a clinically mild form of OCA1, with a fixed visual deficit resulting from low tyrosinase activity during fetal development but with normal pigmentation of the skin and hair postnatally.

Biological and behavioral markers of pain following nerve injury in humans.

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system.

Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene.

We have cloned and sequenced the human KIT proto-oncogene, which contains 21 exons and spans more than 34 kb of DNA on chromosome segment 4q12. We also establish physical linkage between the KIT gene and the related PDGFRA gene. The organization of the KIT gene is virtually identical to that of the homologous FMS gene, located on chromosome 5. Together, these data suggest that the KIT and PDGFRA genes on chromosome 4 and the FMS and PDGFRB genes on chromosome 5 arose by duplication of a common ancestral gene, followed by duplication of a chromosome.

Novel mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism.

Piebaldism is an autosomal dominant genetic disorder of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Piebaldism results from mutations of the KIT proto-oncogene, which encodes the cellular receptor transmembrane tyrosine kinase for mast/stem cell growth factor. Here we describe two novel KIT mutations associated with human piebaldism. These amino acid substitutions, located in the most highly conserved sections of the KIT kinase domain, would be expected to dominant-negatively inhibit KIT-dependent signal transduction, resulting in aberrant melanocyte proliferation or migration during embryologic development.

Type I oculocutaneous albinism associated with a full-length deletion of the tyrosinase gene.

Type I oculocutaneous albinism is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes because of deficient activity of tyrosinase (EC 1.14.18.1). Type I oculocutaneous albinism is caused by mutations in the tyrosinase structural gene, TYR; however, no large TYR gene deletions have been identified previously in humans. Here we report a patient with type IB oculocutaneous albinism who is a compound heterozygote for TYR allele containing a mutation that is likely to affect pre-RNA splicing and a paternally inherited allele in which the TYR gene is completely deleted, the first such allele described to date. Aside from the albinism in the proband, his phenotype and that of his normally pigmented father is otherwise normal, suggesting that this TYR deletion does not involve other functionally important contiguous genes.

Selective modifiers of glutathione biosynthesis and 'repriming' of vascular smooth muscle photorelaxation.

Photorelaxation of vascular smooth muscle (VSM) is caused by the release of nitric oxide (NO) from a finite molecular store that can be depleted by irradiating pre-contracted arteries with visible light. The ability of an 'exhausted' vessel to respond to a further period of illumination is lost temporarily but then recovers slowly as the photosensitive store is reconstituted in the dark. The recovery process, termed repriming, displays an absolute requirement for endothelium-derived NO and is inhibited by pre-treating arteries with ethacrynic acid, a thiol-alkylating agent. Here we demonstrate that agents that up- or down-regulate glutathione (GSH) biosynthesis influence the extent to which the store is regenerated in the dark. Isolated rat tail arteries (RTAs) were perfused internally with Krebs solution containing phenylephrine (PE; mean [PE] +/- s.e.mean: 5. 78+/-0.46 microM) and periodically exposed to laser light (lambda=514.5 nm, 6.3 mW cm(-2) for 6 min). Photorelaxations of control RTAs were compared with those from either (a) vessels taken from animals previously injected i.p. with buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase (three injections, 100 mg kg(-1) at 8 h intervals); or (b) isolated RTAs that were perfused ex vivo with oxothiazolidine (OXO), a precursor of cysteine (10(-4) M OXO for 60 min). RTAs from BSO-treated animals exhibited attenuated photorelaxations: the mean (+/-s.e.mean) amplitude of the response recorded after 72 min recovery in the dark was 12.4+/-1.6% versus 21.4+/-2.9% for control arteries (n=5; P<0. 01). Conversely RTAs treated with OXO and allowed to recover for a similar period showed enhanced photorelaxations, 32.6+/-6.3% as compared to 21.4+/-2.9% for control arteries (n=5; P<0.01). A hyperbolic curve fit to repriming curves for BSO-treated and control arteries returned asymptote values (maximum photorelaxations) of (mean +/- s.e.mean) 24.2+/-3.2% and 55.2+/-8.5%, respectively. The level of GSH in RTA extracts was measured by high-pressure liquid chromatography (HPLC). Injecting animals with BSO decreased GSH to 85% of control levels (P<0.05) while treatment of isolated vessels with OXO resulted in a 31% increase above control levels (P<0.05). Thus, drug-induced changes in RTA GSH levels were positively correlated with altered photorelaxations. The results lead us to postulate that the photosensitive store in VSM is generated, at least in part, from intracellular GSH which becomes converted to S-nitrosoglutathione (GSNO) by nitrosating species that are formed ultimately from endothelium-derived NO. The possible physiological significance of a photolabile store of NO in VSM is discussed briefly.

Toward an objective interpretation of surface EMG patterns: a voluntary response index (VRI).

Individuals with incomplete spinal cord injuries (SCI) retain varying degrees of voluntary motor control. The complexity of the motor control system and the nature of the recording biophysics have inhibited efforts to develop objective measures of voluntary motor control. This paper proposes the definition and use of a voluntary response index (VRI) calculated from quantitative analysis of surface electromyographic (sEMG) data recorded during defined voluntary movement as a sensitive measure of voluntary motor control in such individuals. The VRI is comprised of two numeric values, one derived from the total muscle activity recorded for the voluntary motor task (magnitude), and the other from the sEMG distribution across the recorded muscles (similarity index (SI)). Calculated as a vector, the distribution of sEMG from the test subject is compared to the average vector calculated from sEMG recordings of the same motor task from 10 neurologically intact subjects in a protocol called brain motor control assessment (BMCA). To evaluate the stability of the VRI, a group of five healthy subjects were individually compared to the prototype, average healthy-subject vectors for all of the maneuvers. To evaluate the sensitivity of this method, the VRI was obtained from two SCI subjects participating in other research studies. One was undergoing supported treadmill ambulation training, and the other a controlled withdrawal of anti-spasticity medications. The supported treadmill training patient's VRI, calculated from pre- and post-training BMCA recordings, reflected the qualitative changes in sEMG patterns and functional improvement of motor control. The VRI of the patient followed by serial BMCA during medication withdrawal also reflected changes in the motor control as a result of changes in anti-spasticity medication. To validate this index for clinical use, serial studies using larger numbers of subjects with compromised motor control should be performed.

Equipment specifications for supported treadmill ambulation training.

Supported Treadmill Ambulation Training (STAT) is a mode of therapy for gait retraining for patients with spinal cord injuries or other upper motor neuron dysfunction. The STAT program involves simultaneously supporting a portion of the patient's weight while gait training on a treadmill. STAT has been successful in improving the gait of many research subjects, but has not been widely applied in clinical practice. The goal of this study was to acquire practical, clinically useful information regarding this therapeutic intervention in order to remove barriers to its use. This manuscript enumerates equipment specifications for the treadmill, body weight support (BWS) system, and harness. The ergonomics of the work space are also considered, since the therapist(s) will need access to the patient's legs during therapy. The specific recommendations were determined through prior clinical experience, consultation of anthropometric tables, and application of engineering principles. The guidelines listed are intended to facilitate safe and effective application of the therapy at minimum hardware cost.

Diagnosis and management of renal angioma.

Five patients with symptomatic renal angiomata are described. All presented with heavy haematuria and unilateral ureteric obstruction without evidence of a mass distorting the renal architecture. Renal angiomata are most easily diagnosed by selective renal angiography. They may be treated by intraarterial embolization, avoiding the need for major ablative surgery.

Renal conservation in the management of bilateral renal tumours.

We report five patients with bilateral tumours and review their management which include many of the therapeutic options that are available.

Neurophysiological examination of the corticospinal system and voluntary motor control in motor-incomplete human spinal cord injury.

This study employed neurophysiological methods to relate the condition of the corticospinal system with the voluntary control of lower-limb muscles in persons with motor-incomplete spinal cord injury. It consisted of two phases. In a group of ten healthy subjects, single and paired transcranial magnetic stimulation (TMS) of the motor cortex was used to study the behavior of the resulting motor evoked potentials (MEP) in lower-limb muscles. Interstimulus intervals (ISIs) of 15-100 ms were examined for augmentation of test MEPs by threshold or subthreshold conditioning stimuli. The second phase of this study examined eight incomplete spinal cord injured (iSCI) subjects, American Spinal Injury Association Impairment Scale C (n = 5) and D (n = 3) in whom voluntary motor control was quantified using the surface EMG (sEMG) based Voluntary Response Index (VRI). The VRI is calculated to characterize relative output patterns across ten lower-limb muscles recorded during a standard protocol of elementary voluntary motor tasks. VRI components were calculated by comparing the distribution of sEMG in iSCI subjects with prototype patterns collected from 15 healthy subjects using the same rigidly administered protocol, The resulting similarity index (SI) and magnitude values provided the measure of voluntary motor control. Corticospinal system connections were characterized by the thresholds for MEPs in key muscles. Key muscles were those that function as the prime-movers, or agonists for the voluntary movements from which the VRI data were calculated. Results include healthy-subject data that showed significant increases in conditioned MEP responses with paired stimuli of 15-50 ms ISI. Stimulus pairs of 75 and 100 ms showed no increase in MEP peak amplitude over that of the single-pulse conditioning stimulus alone, usually no response. For the iSCI subjects, 42% of the agonists responded to single-pulse TMS and 25% required paired-pulse TMS to produce an MEP. American Spinal Injury Association Impairment Scale component motor scores for agonist muscles, Quadriceps, Tibialis Anterior, and Triceps Surae, were significantly lower where MEPs could not be obtained (p < 0.05). VRI values were also significantly lower for motor tasks with agonists that had no resting MEP (p < 0.01). Therefore, the presence of a demonstrable connection between the motor cortex and spinal motor neurons in persons with SCI was related to the quality of post-injury voluntary motor control as assessed by the VRI.

Neurophysiological assessment of lower-limb voluntary control in incomplete spinal cord injury.

STUDY DESIGN: Cross-sectional retrospective study of a neurophysiological method of voluntary motor control characterization. OBJECTIVES: This study was undertaken to validate the surface electromyography (sEMG)-based voluntary response index (VRI) as an objective, quantitative, laboratory measure of spinal cord injury severity in terms of voluntary motor control disruption. SETTING: VA Medical Centers in Houston and Dallas Texas, USA. METHODS: A total of 67 subjects with incomplete spinal cord injury (iSCI), American Spinal Injury Association Impairment Scale (AIS)-C (n = 32) and -D (n = 35) were studied. sEMG recorded during a standardized protocol including eight lower-limb voluntary motor tasks was analyzed using the VRI method that relates multi-muscle activation patterns of SCI persons to those of healthy-subject prototypes (n = 15). The VRI is composed of a measure of the amount of the sEMG activity (magnitude) and the distribution of activity across muscle groups compared to that of healthy subjects for each motor task (similarity index, SI). These resulting VRI components, normalized magnitude and SI, were compared to AIS clinical findings in this study. Receiver operating characteristic analysis was performed to determine the SI values best separating AIS-C and AIS-D subjects. RESULTS: Magnitude and SI for AIS-C subjects had mean values of 0.27 +/- 0.32 and 0.65 +/- 0.21, respectively. Both parameters were significantly larger in the AIS-D subjects (0.78 +/- 0.43 and 0.93 +/- 0.06), respectively (P < 0.01). An SI value of 0.85 was found to separate AIS-C and AIS-D groups with a sensitivity of 0.89 and a specificity of 0.81. Further, the VRI of each leg strongly correlated with the respective AIS motor score (0.80, r < 0.01). CONCLUSIONS: In the domains of voluntary motor control, the sEMG-based VRI demonstrated adequate face validity and sensitivity to injury severity as currently measured by the AIS. SPONSORSHIP: Veterans Affairs Medical Center.

Management of complex renal calculi.

The treatment of small renal pelvic and ureteric calculi can be performed with relative safety and efficacy using lithotripsy or an endourological method. There remains however, a proportion of stones that are resistant to these methods because of their anatomical position, physical composition or sheer size. To these stones must be applied a treatment strategy using the variety of techniques to their maximum advantage. This article aims to review the accumulated experience on the management of these more complex urinary calculi.

Polymerase chain reaction detection of a novel human KIT (mast/stem cell growth factor receptor) gene polymorphism by single-strand conformation polymorphism analysis or by SmaI or BstNI cleavage.

We describe a common single-base polymorphism of the KIT gene that alters both SmaI and BstNI restriction sites, but is most easily detected as a single-strand conformation polymorphism (SSCP) using the polymerase chain reaction (PCR).

Arteriovenous fistula associated with adenocarcinoma of the kidney.

We present a case of a large renal arteriovenous fistula associated with an adenocarcinoma. The clinical and radiological findings are presented together with a brief review of the literature.

The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus.

Erectile impotence is more common in the diabetic than the general population, occurs at a younger age, and is often associated with ejaculatory problems. For these, and possibly for other more subtle reasons, fertility may be a problem for men with diabetes. The symptoms of erectile and ejaculatory dysfunction are frequently not discussed between patient and doctor. Psychological factors are important but the vast majority of diabetic patients have an organic basis for their impotence. Both neurogenic and vascular factors are important in the pathogenesis of erectile failure. Autonomic neuropathy is almost certainly the cause of the ejaculatory failure that may be present in up to 40% of men with diabetes. The final biochemical mediator of erection within the penile erectile tissue is nitric oxide and a key enzyme in its degradation is phosphodiesterase (type V). Drugs that affect the metabolism of this enzyme are being developed to treat erectile failure. At present, the self injection of intra-cavernosal erectogenic agents (such as prostaglandin E1) provide the main form of therapy for erectile failure. Vacuum devices are a simple alternative and venous ligation surgery may be effective for a properly selected cohort of patients. Prosthetic implants are a final option for patients in whom all else has failed. Fertility problems, particularly when associated with ejaculatory failure can be overcome with modern assisted reproductive techniques. Nowadays, these will frequently involve gamete micro-manipulation.

The use of small intestine in bladder reconstruction.

Reconstruction of the bladder is a treatment available to patients who have a diseased or damaged bladder, and small bowel is the most commonly used tissue. Augmentation cystoplasty increases the total bladder capacity, whereas substitution cystoplasty replaces the whole organ. This is either drained through a continent cutaneous stoma or is reanastomosed to the urethra as an orthotopic reconstruction. Although the treatment for invasive bladder cancer has not changed greatly in the last few decades, the use of orthotopic bladder reconstruction allows for a great improvement in the quality of life for patients who undergo cystectomy. These reconstructive techniques can also be offered to patients with other forms of pelvic malignancy that involve the bladder.