Potential pitfalls in the use of Glucoscan and Glucoscan II meters for self-monitoring of blood glucose.

We discovered that skilled nurses only casually trained in the use of a fingertip blood glucose reflectance meter (Glucoscan, Lifescan, Mountainview, California) had a 36% incidence of unacceptable results (greater than 15% from reference). A controlled study was undertaken and showed that with Glucoscan I (GI) 4 of 27 readings were unacceptable and with Glucoscan II (GII) 3 of 27 readings were unacceptable, a statistically nonsignificant difference. Minor deviations from the manufacturer's recommended technique had a significant effect on the results with GI. In contrast, GII was much less sensitive to variations in recommended technique. GI underestimated the reference glucose concentration by 11.7%, and GII overestimated by 6.5%, a statistically significant difference. We conclude that the health professional must be aware of interdevice and intradevice variability in self-monitoring of blood glucose (SMBG). Patients need careful training in the method of SMBG. The results of any single value should be interpreted with caution.

Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis.

We examined the toxicity of both single and multiple subcutaneous injections of recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, in doses ranging from 2 to 100 micrograms/kg. Adverse events were generally dose related and ranged from mild to severe. The tolerability of daily subcutaneous rhCNTF was equivalent to placebo at doses < or = 5 micrograms/kg/day. At higher doses, anorexia, weight loss, reactivation of herpes simplex virus (HSV1) labialis/stomatitis, cough, and increased oral secretions occurred.

Managing clinical research data: software tools for hypothesis exploration.

Data representation, data file specification, and the communication of data between software systems are playing increasingly important roles in clinical data management. This paper describes the concept of a self-documenting file that contains annotations or comments that aid visual inspection of the data file. We describe access of data from annotated files and illustrate data analysis with a few examples derived from the UNIX operating environment. Use of annotated files provides the investigator with both a useful representation of the primary data and a repository of comments that describe some of the context surrounding data capture.

Potentiation of rehabilitation: Medication effects on the recovery of function after brain injury and stroke.

In neurologic rehabilitation nothing is currently in clinical use that is effective in restoring lost neurologic function. This paper presents an overview of the various medicines that have been studied for their potential to facilitate recovery after brain injury. Early studies of acetylcholine and anticholinesterase drugs were reported favorably, but subsequent experience with them has not substantiated the initial enthusiasm. In the last two decades, data from work on rodents and cats suggest that certain drugs may facilitate or impede neurologic recovery after brain injury. Human studies on the effects of d-amphetamine and related compounds are sparse, and, although provocative, several problems make the results controversial. Data from studies in the laboratory suggest that clinicians may be impeding clinical outcome in stroke patients with some frequently used poststroke medications. A table lists (with references) the drugs that may impede recovery or reinstate deficits and drugs that may accelerate recovery.

Evaluation of a modified inverted walking stick as a treatment for parkinsonian freezing episodes.

We evaluated a modified inverted walking stick [visual cue (VC) stick] in Parkinson's disease patients with freezing episodes. Patients underwent baseline trials on a 60-ft track with four walking conditions: unassisted, with a straight walking stick, with the VC stick, and on the track with parallel lines spaced every 12 in. Patients completed three trials of each condition in a randomized order, with total course time and number of freezes recorded. Patients were given the VC stick to use at home until subjective maximum functional benefit was obtained and were then brought back for a follow-up objective evaluation. Eight patients completed the study. The straight stick and VC stick worsened patient performance as a group, while the parallel lines significantly improved group performance. However, two of the eight patients showed benefit from the VC stick. Improvement with parallel lines did not predict improvement with the VC stick. On follow-up trials, the two who initially showed improvement with the VC stick continued to show improvement, while none of the other patients showed additional benefit from a learning effect. We conclude that the VC stick will help a small subpopulation of Parkinson's disease patients with freezing, and this subpopulation can be identified with the initial office visit trial.

An object oriented user interface for analysis of biological data.

In a previous paper we described a self-documented file and a collection of general purpose programs or tools that facilitates the management and analysis of biological data. The tools can be specified in a pipeline to accomplish a specific analysis task. However, we found that it was difficult for investigators to learn the UNIX command language for specifying pipelines, specify selection tasks through a command language, and visualize the data as they were transformed and rearranged. To alleviate these problems we developed an object-oriented user interface for the pipeline programs. The system consists of four major programs for visualization: Vedit, Vgraf, Vscan, and V spread. Vedit is a simple text editor, Vgraf is a flexible graphics program, Vscan facilitates scanning graphically through large files, and Vspread provides spreadsheet-like capabilities. To demonstrate how the visualization programs are used together to accomplish the needed analysis we describe two case studies and then discuss how well the system accomplished the goals of visualization, short learning curve, and user adaptability.

A source of bias in the analysis of single channel data: assessing the apparent interaction between channel proteins.

A recent study of single sodium channel currents in neuroblastoma cells suggested interaction between ion channels in close proximity to one another (T. Kiss and K. Nagy, Eur. Biophys. J. 12, 13, 1985). The opening of one channel appeared to affect the likelihood that neighboring channels might open. Some of the conclusions were based on the analysis of observed channel openings that were segregated depending on whether one channel or more than one channel was open at the same time. We hypothesized that the longer one channel remained open, the more likely another channel operating independently, would open, thereby creating the impression of an apparent coupling of channel behavior. We performed simulations and measurements of single sodium channel currents to determine whether the technique of event segregation could account for apparent channel interactions. The simulations showed that the segregation of overlapping (more than one channel open at the same time) and nonoverlapping events led to a bias in the estimated open time and the derived closing rate. To avoid the bias, we found that random pairing of opening and closing events provided an unbiased estimate of the mean closing rate. Using this random assignment approach, we showed that the mean closing rate of single sodium channels in neonatal rat myocytes decreased with depolarization over a limited range of membrane potential. This suggested that the underlying closure mechanism(s) was voltage dependent. From the analysis of open times, we found no evidence for channel interaction in the time scale of tens of milliseconds. Depolarizing steps without events occurred in runs suggesting the existence of long-lived shut state(s). Double pulse experiments with the prepulse and test pulse above threshold showed significant inactivation of channels that did not open. The rate of inactivation of shut channels was substantially slower than the closure rate of open channels. The rate of inactivation of cardiac sodium channels appeared to be strongly dependent on the initial channel state.

Managing research data with self-documenting files.

Processing biomedical research data is frequently complex due to the evolutionary nature of experiments and the requisite modification of analysis software. For the past several years we have been evolving a set of software tools designed to improve our ability to respond to evolving experimental designs. These tools allow the investigator to easily manipulate the research data and specify desired data transformations at run time. Coupling of analysis software to research data files is dependent on data files that are commented in a manner similar to that used in programming languages. The resulting annotated data files are self-documenting, and their use facilitates visual interpretation of displayed data as well as automatic processing of subsets of data. Here we present a formal description of a self-documenting file and describe several software tools that facilitate processing of biomedical research data.

Blockade of cardiac sodium channels by lidocaine. Single-channel analysis.

The mechanism of interaction of lidocaine with cardiac sodium channels during use-dependent block is not well defined. We examined the blockade of single cardiac sodium channels by lidocaine and its hydrophobic derivative RAD-242 in rabbit ventricular myocytes. Experiments were performed in cell-attached and inside-out patches. Use-dependent block was assessed with trains of ten 200-msec pulses with interpulse intervals of 500 msec and test potentials of -60 to -40 mV. Single-channel kinetics sometimes showed time-dependent change in the absence of drug. During exposure to 80 microM lidocaine, use-dependent block during the trains was associated with a decrease in the average number of openings per step. At -60 mV, mean open time was not significantly changed (control, 1.4 +/- 0.6 msec; lidocaine, 1.2 +/- 0.3 msec, p greater than 0.05). Greater block developed during trains of 200-msec pulses compared with trains of 20-msec pulses at the same interpulse interval at test potentials during which openings were uncommon later than 20 msec (-50 and -40 mV). Prolonged bursts of channels showing slow-gating kinetics were observed both in control and the presence of 80 microM lidocaine. However, lidocaine may decrease the late sodium current by altering the kinetics of slow gating. The hydrophobic lidocaine derivative RAD-242, which has a 10-fold greater lipid solubility than lidocaine, decreased the peak averaged current during pulse train stimulation by 60% without a change in the mean open time. Our results suggest that the major effect of lidocaine during use-dependent block involves the interaction with a nonconducting state of the sodium channel followed by a failure to open during subsequent depolarization.

Clinical and pharmacokinetic aspects of high dose oral baclofen therapy.

Baclofen is a centrally acting muscle relaxant used for treatment of spasticity. Some patients, to experience adequate symptomatic relief, require dosages of baclofen that significantly exceed the conventional 80 mg daily maximum advocated by the 1992 Physicians' Desk Reference. In this pilot study of baclofen kinetics and dynamics in eleven patients, the safety and efficacy of high dose baclofen was confirmed. The data suggest that the pharmacokinetics of high dose baclofen may vary from those described previously. Time-to-peak plasma levels and plasma half-lives were noted to be substantially longer than prior reports indicate. Baclofen blood levels were observed to rise gradually over time in some patients on a stable dosing regimen, probably a result of impaired renal clearance. These findings may indicate that a change in pattern of prescription is warranted and that a reliable and practical measurement of systemic baclofen levels has a useful role in clinical practice, particularly for the patient with neurogenic bladder and potential renal insufficiency.

Characterization of the surface topography and putative tertiary structure of the human CD7 molecule.

The CD7 gp40 molecule is a member of the Ig gene superfamily and is expressed on T cell precursors before their entry into the thymus during fetal development. N-terminal amino acids 1-107 of CD7 are highly homologous to Ig kappa-L chains whereas the carboxyl-terminal region of the extracellular domain of CD7 is proline-rich and has been postulated to form a stalk from which the Ig domain projects. To define potential functional regions of CD7, we have studied the surface topography of the CD7 Ag by synthesizing peptides corresponding to linear sequences within the CD7 extracellular domains, by raising polyclonal anti-CD7 rabbit sera against these peptides, and by computer analysis of the primary CD7 amino acid sequence. Polyclonal anti-CD7 sera were studied using indirect immunofluorescence, RIA, radioimmunoprecipitation, and Western blot assays. Computer analysis was performed comparing the CD7 sequence with all other known protein sequences. We found that three CD7 epitopes defined by peptides CD7-1A (AA 1-38), CD7-4 (AA 48-74), and CD7-7 (AA 129-146) were available for binding antibody on the surface of the CD7 molecule. Using computer analysis, we transposed the amino acid sequence of the CD7 Ig kappa-like N-terminal domain of CD7 onto the spatial coordinates of REI, a previously reported Ig kappa-molecule highly homologous (48%) to the CD7 N-terminal Ig-like region. Based on computer analysis of this putative CD7 three-dimensional structure, both the CD7-1A and CD7-4 regions protruded from the surface of the N-terminal domain of the CD7 molecule. Finally, comparison of the CD7 transmembrane sequence with CD4 and HIV transmembrane sequences and with respiratory syncytial virus fusion sequences demonstrated similar sequence motifs among these molecules.