Controlled and tuneable drug release from electrospun fibers and a non-invasive approach for cytotoxicity testing.

Electrospinning is an attractive method to generate drug releasing systems. In this work, we encapsulated the cell death-inducing drug Diclofenac (DCF) in an electrospun poly-L-lactide (PLA) scaffold. The scaffold offers a system for a sustained and controlled delivery of the cytotoxic DCF over time making it clinically favourable by achieving a prolonged therapeutic effect. We exposed human dermal fibroblasts (HDFs) to the drug-eluting scaffold and employed multiphoton microscopy and fluorescence lifetime imaging microscopy. These methods were suitable for non-invasive and marker-independent assessment of the cytotoxic effects. Released DCF induced changes in cell morphology and glycolytic activity. Furthermore, we showed that drug release can be influenced by adding dimethyl sulfoxide as a co-solvent for electrospinning. Interestingly, without affecting the drug diffusion mechanism, the resulting PLA scaffolds showed altered fibre morphology and enhanced initial DCF burst release. The here described model could represent an interesting way to control the diffusion of encapsulated bio-active molecules and test them using a marker-independent, non-invasive approach.

Physiologic and clinical monitoring of spastic hypertonia.

Spasticity has been defined as "a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome." Increased motor neuron excitability and enhanced stretch-evoked synaptic excitation of motor neurons are potential neurophysiologic mechanisms to explain this phenomenon. The relative contribution of these two distinct mechanisms likely varies depending on the location of the lesion in the central nervous system. The patient history is an important component of the clinical evaluation focusing on potential nociceptive inputs that can worsen spasticity (e.g., urinary tract infections, skin breakdown). Assessment of the impact of the spasticity on function (positive and negative), position, care of the patient, and pain should be pursued. Clinical examination of spasticity is performed using methods to evoke and quantify spastic reflex responses to muscle stretch stimuli and to observe the patient performing functional tasks to note the impact of spasticity on their performance. Treatment is based on the negative impact of the spasticity on the patient, severity of the problems, and whether the hypertonicity is focal or diffuse in distribution (see article by Elovic elsewhere in this issue). First-line treatments include elimination of nociceptive stimuli, range of motion, seating and positioning, and other physical modalities. If additional intervention is necessary, oral medications are implemented for widespread spasticity, whereas focal problems are treated with prolonged stretching and splinting or casting to maintain muscle stretch and optimal positioning. In more severe cases, invasive procedures may be needed to supplement other treatments. Neurolytic procedures are pursued for focal tone problems. For generalized hypertonicity, intrathecal pump administration of medications or surgical interruption of reflex pathways has been helpful. Ultimately, the clinician must systematically approach the evaluation and treatment of spasticity. As decisions regarding moving from less to more invasive treatments are discussed, the potential risks and side effects of treatment options must be weighed versus the potential benefits that the patient might receive to maintain a rational approach to the management of spasticity.

Evidence-based practice: methods to evaluate individual patient improvement.

The expectations and demands associated with evidence-based practice in medical rehabilitation require the use of research procedures that are practice based and practitioner oriented. Traditional research methods, including randomized clinical trials, are powerful techniques for determining the efficacy of rehabilitation interventions; however, randomized clinical trials have some practical and ethical limitations when applied to many research questions important to the field of medical rehabilitation, and alternative methods are needed to fully examine the effectiveness of treatment techniques for individual patients and to document clinical accountability. This paper examines the use of single-system designs and N of 1 research strategies. The advantages and limitations of single-system methods are described, and examples relevant to the documentation of clinical outcomes in medical rehabilitation are presented.

Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.

Correlation between weakness and axonal loss in patients with CMT1A.

We have developed a protocol to measure the progression of disability in patients with Charcot Marie Tooth (CMT) disease, particularly CMT1 over a several year period. Because CMT1 is a chronic disease, the natural history of changes occurring in such a brief period are not well understood, making clinical trials for CMT1 patients difficult to evaluate. We hypothesize that weakness in CMT1 correlates with axonal loss secondary to the abnormalities in Schwann cell myelin gene expression, which cause the disease. To test this hypothesis, we elected to carefully evaluate CMT patients by various modalities to measure strength, sensory loss, and axonal loss and demyelination and to compare these modalities to determine whether they correlated with findings on clinical examination. As suspected, patient weakness correlates more with secondary axonal loss than with demyelination, even though the primary abnormality in CMT1 is demyelination.

Functional outcome measures to assess interventions for spasticity.

PURPOSE: Clinicians use functional loss as a criterion to treat spasticity, but the connection between function and severity of spasticity is not well established for monitoring spasticity treatment effect. Studies were reviewed which have implemented outcome measures to assess functional changes relative to changes in spasticity. Criteria for review included the reliability and internal validity of the functional measures used and the strengths/weaknesses of the study designs that likely affected the external validity of the measures for this application. Guidelines are provided for the use and development of functional outcome measures in futures studies of spasticity treatment based on this review. DATA IDENTIFICATION: An English-language literature search using MEDLINE and bibliographies of published articles and textbooks was conducted. RESULTS: Very few functional measures demonstrated changes concurrent to a reduction in spasticity. There were multiple potential confounding factors in study protocols, reporting of results, and data analysis that might account for the limited number of measures shown to be valid for this application. Selected standardized ordinal functional outcome scales (the PECS and PEDI) and specific functional tasks were identified as measures that show promise for assessing changes concurrent with altered spasticity level. CONCLUSION: Based on a review of previous studies, functional measures involving posture, positioning, balance, and certain mobility skills have potential, with further test development, to provide needed information regarding the impact of spasticity on functional outcome.

Practically perfect planning.

Planning is a routine human activity performed daily that often challenges confident professionals. The nursing process, adapted as a planning tool, provides the means to achieve institutional goals. The application of the nursing process to planning in one operating room setting resulted in the preparation of more than 1,500 surgical case supply preference lists in 5 weeks' time. The achievement facilitated timely implementation of an automated charging system for surgical cases through practically perfect planning.

Rehabilitation in joint and connective tissue diseases. 1. Systemic diseases.

This self-directed learning module highlights new advances in this topic area. It is part of the chapter on rehabilitation in joint and connective tissue diseases in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses treatment and outcome in rheumatoid arthritis, musculoskeletal involvement in human immunodeficiency virus infection, scleroderma, systemic lupus erythematosus, and intraarticular injection of corticosteroids.

Rehabilitation in joint and connective tissue diseases. 2. Inflammatory and degenerative spine diseases.

This self-directed learning module highlights new advances in this topic area. It is part of the chapter on rehabilitation in joint and connective tissue diseases in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses ankylosing spondylitis and spinal stenosis, including differential features, diagnostic strategy, rehabilitation management, spinal complications of ankylosing spondylitis, and pathophysiology of spinal stenosis.

Rehabilitation in joint and connective tissue diseases. 3. Limb disorders.

This self-directed learning module highlights new advances in this topic area. It is part of the chapter on rehabilitation in joint and connective tissue diseases in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses the following: differential features, diagnostic strategy, and rehabilitation management of hip, knee, foot, and shoulder pain; indications, contraindications, and postsurgical management for joint arthroplasty; management of gout and chondrocalcinosis; and rehabilitation issues related to hip and shoulder fracture.

Measurement standards for interdisciplinary medical rehabilitation.

Rehabilitation must address problems inherent in the measurement of human function and health-related quality of life, as well as problems in diagnosis and measurement of impairment. This educational document presents an initial set of standards to be used as guidelines for development and use of measurement and evaluation procedures and instruments for interdisciplinary, health-related rehabilitation. Part I covers general measurement principles and technical standards, beginning with validity, the central consideration for use of measures. Subsequent sections focus on reliability and errors of measurement, norms and scaling, development of measures, and technical manuals and guides. Part II covers principles and standards for use of measures. General principles of application of measures in practice are discussed first, followed by standards to protect persons being measured and then by standards for administrative applications. Many explanations, examples, and references are provided to help professionals understand measurement principles. Improved measurement will ensure the basis of rehabilitation as a science and nourish its success as a clinical service.

[Administration of prostaglandin E1 in diabetics and non-diabetic patients with severe Fontaine stage IIb arterial occlusive disease]. / Einsatz von Prostaglandin E1 bei Diabetikern und Nicht-Diabetikern mit schwerer arterieller Verschlusskrankheit im Stadium IIb--IV nach Fontaine.

The success in therapy of prostaglandin E1 intra-arterially and intravenously applied to diabetics and non-diabetics with PAOD, stages IIb-IV according to Fontaine, was scrutinized in a city hospital primarily concerned with geriatrics, metabolism, and angiology. All the patients included were examined in retrospective studies with regard to the improvement of their situations during their stays in hospital and--in addition to that--a part of them prospectively some time after their stays in hospital. In all, 99 patients were included in the retrospective examination of which there were 60 diabetics and 39 non-diabetics. Of the 60 diabetics 53 were in stage IV, 5 in stage III, and 2 in stage IIb while in case of non-diabetics 26 were in stage IV, 10 in stage III, and 3 in stage IIb. 50 of the diabetics and 27 of the non-diabetics were treated intra-arterially. The prospectively orientated post-observation included 38 diabetics and 24 non-diabetics. The results of the retrospective examination revealed a significantly superior efficiency of intra-arterially applied PGE1 compared with the intravenous application, both, with regard to the reduction of needed analgesics and the improvement of the clinical situation. A comparison between intra-arterially treated diabetics and non-diabetics showed a significantly higher rate of success of the diabetics regarding to the improvement of the clinical situation. Concerning the prospective post-examination: due to their PAOD the diabetics took significantly more often analgesics at the time of their post-examination than the non-diabetics. Also concerning the development of their clinical situations the diabetics turned out to have worse results than the non-diabetics, however, the differences were not significant in this case.

Spasticity in spinal cord injured persons: quantitative effects of baclofen and placebo treatments.

Spasticity commonly occurs after a spinal cord injury and is characterized by increased resistance to passive movement of peripheral joints. This study examined the effect of an antispasticity medication on stiffness from the myotatic reflex response generated by passive sinusoidal ankle motion. A repeated measures, multiple base-line, single-subject, double-blind design was employed. The independent variable was spasticity medication treatment, where the levels were 40 mg/day and 80 mg/day of baclofen v placebo treatment. Viscous and elastic stiffness measurements were taken at the ankle joint during a placebo base-line phase and during treatment with baclofen for five adult males with traumatic spinal cord injuries. Ankle sinusoidal oscillation frequencies were from 3 to 12 Hz during test sessions. Mean viscous and elastic stiffness scores for all frequencies were calculated for each phase of the study. Randomization tests of mean changes in stiffness measurements between each treatment phase of the study failed to provide any convincing evidence of a significant treatment effect for reduction of spasticity in the traumatic spinal cord injured subjects studied. Further testing is needed to exclude potential confounding factors before this conclusion can be confirmed. The results suggest that baclofen is not a universal treatment of choice for all individuals with spasticity resulting from traumatic spinal cord injury.

The supraspinal anxiolytic effect of baclofen for spasticity reduction.

Recent studies in the psychiatric literature indicate that baclofen has an anxiolytic action in certain psychopathologic conditions. Clinical observation has shown that manifestations of spasticity are increased in anxious individuals, implicating a supraspinal site of mediation for these responses. The purposes of this study were to determine if baclofen reduced anxiety in individuals with traumatic spinal cord lesions and whether that reduction was correlated with decreased spasticity from the baclofen. Five adult males with traumatic spinal cord injury were randomly assigned to the study protocol. A double-blind, repeated measures, multiple base-line, single-case research design was employed. The independent variable was dose of medication with the three levels being placebo, 40 mg/day of baclofen and 80 mg/day of baclofen, in four evenly divided doses. The dependent variable was the score obtained on the Beck Inventory-A anxiety scale (BIA). The subjects were administered the BIA twice per week for a nine-week period of time, during which they received the doses of medication as described. Quantitative measurements of spasticity were also taken at each session. Visual inspection analysis of the data showed that two subjects had no measurable anxiety of the BIA throughout the study. Three subjects had measurable anxiety on the BIA during the base-line/placebo phase. They showed a decreased level of their BIA scores with 40 mg/day of baclofen, and a further level reduction with 80 mg/day of baclofen. The reduction in BIA scores was statistically significant using the standard deviation band test in one of these subjects. These data indicate that BIA probably has an anxiolytic effect for individuals status post-traumatic spinal cord injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiatric therapeutics. 2. Therapeutic heat and cold, electrotherapy, and therapeutic exercise.

This self-directed learning module highlights the general concepts and advances in therapeutic heat and cold, electrotherapy, and therapeutic exercise. This article is part of the chapter on physiatric therapeutics for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. Special advances include lasers in medicine and the description of the appropriate type of exercise for weight control.

Physiatric therapeutics. 4. Transfers and mobility/community reentry.

This self-directed learning module highlights advances in transfer and mobility skills, and community reentry. It is part of the chapter on physiatric therapeutics for the Self-Directed Medical Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This section contains essential information on bed mobility, dependent or assisted bed transfers, assisted and independent wheelchair transfers, advanced wheelchair skills, mobility in the community, activities of daily living and advanced living skills, communication, social support, adjustment to disability, prevocational and vocational issues, options for community living, and public policies regarding people with disabilities.

Spasticity: quantitative measurements as a basis for assessing effectiveness of therapeutic intervention.

Spasticity, a common problem in upper motor neuron lesions, frequently results in uncontrolled involuntary motion that interferes with function. A quantifiable method related to the mechanical output of the muscle is needed to test and improve therapeutic intervention. A sinusoidal displacement of 5 degrees was used to measure elastic and viscous stiffness around the ankle at frequencies from 3 to 12Hz. To isolate viscoelastic response, the influences of inertia and equipment drag were eliminated. Test-retest correlation values were 0.953 for elastic and 0.992 for viscous stiffness. The elastic stiffness in 13 spastic subjects under nerve block was significantly higher than that of 13 healthy subjects (p less than or equal to 0.05), indicating early changes associated with contracture. Elastic and viscous response is expressed by the total stiffness vector containing both components, the Nyquist diagram. This diagram's pathlength from 3 to 12Hz was calculated and showed high test-retest reliability in healthy subjects. The median pathlength value for the spastic group was 98 Newton-meters/radian (N-m/rad) and, for the normal group, 24N-m/rad, a statistically significant difference (p less than or equal to 0.0001). A mathematical model of the spastic response shows that the Nyquist diagram's pathlength relates to reflex loop gain and is independent of the shift in passive properties. The model predicts a shift in passive properties during spastic responses relative to responses measured during nerve block. Thus, subtraction of passive responses measured during nerve block may not isolate the remaining reflex response, but the pathlength measure relating to the reflex response gain was unaffected, allowing evaluation of therapeutic intervention effectiveness.

Urea secretion into the colon of sheep and goat.

Total urea entry rate into the body pool and urea hydrolysis rate (transfer of endogenous urea into the total gastrointestinal (g.i.) tract) were obtained after single intravenous injections of [14C]urea and from renal urea excretion in sheep and goat. Secretion of endogenous urea into the colon was estimated from the appearance of urea N in the temporarily isolated and perfused colon. Rate of urea secretion into the colon was rather small (0.10-0.31 mmol . h-1). It was only 0.3-1.1% of urea entry rate, or 0.4-7% of urea hydrolysis rate. Urea secretion into the colon increased linearly with increase of plasma urea concentration. Dietary conditions and short-chain fatty acid concentrations in colonic contents had no significant effect on the permeability of the colonic epithelium for urea.