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D H Cox

Publications and source records attributed to D H Cox.

At least 19 recordsLinked to original sources
PubMed1997

A comparison of subjective and objective measures of reduction of psoriasis with the use of ultrasound, reflectance colorimetry, computerized video image analysis, and nitric oxide production.

BACKGROUND: Studies of antipsoriatic therapy often rely on subjective scoring. Objective measures have been developed but have not previously been compared with subjective scoring. OBJECTIVE: Our purpose was to compare subjective and objective measures of reduction of psoriasis with topical therapy. METHODS: A 2-week, double-blind, left-to-right comparative trial of betamethasone valerate against white soft paraffin was performed in 12 patients. The subjective scores were erythema, elevation, scale, and a composite total. Objective measures were nitric oxide production measured by chemiluminescence; erythema reflectance; ultrasound scan for thickness, scale, and echo-poor zone; and computerized image analysis of video images. RESULTS: Subjective and objective measures had similar power to detect therapeutic effect. The subjective measures showed greater variation and relatively overestimated improvement. There was correlation between measures and estimates for area, redness, and thickness. Nitric oxide production was the most powerful objective measure. CONCLUSION: Thickness determined by ultrasound scan and nitric oxide production are useful measures of reduction of psoriasis, which lend themselves to more powerful statistical tests than subjective interval data.

Administration, Topical↗
PubMed1997

Separation of gating properties from permeation and block in mslo large conductance Ca-activated K+ channels.

In this and the following paper we have examined the kinetic and steady-state properties of macroscopic mslo Ca-activated K+ currents in order to interpret these currents in terms of the gating behavior of the mslo channel. To do so, however, it was necessary to first find conditions by which we could separate the effects that changes in Ca2+ concentration or membrane voltage have on channel permeation from the effects these stimuli have on channel gating. In this study we investigate three phenomena which are unrelated to gating but are manifest in macroscopic current records: a saturation of single channel current at high voltage, a rapid voltage-dependent Ca2+ block, and a slow voltage-dependent Ba2+ block. Where possible methods are described by which these phenomena can be separated from the effects that changes in Ca2+ concentration and membrane voltage have on channel gating. Where this is not possible, some assessment of the impact these effects have on gating parameters determined from macroscopic current measurements is provided. We have also found that without considering the effects of Ca2+ and voltage on channel permeation and block, macroscopic current measurements suggest that mslo channels do not reach the same maximum open probability at all Ca2+ concentrations. Taking into account permeation and blocking effects, however, we find that this is not the case. The maximum open probability of the mslo channel is the same or very similar over a Ca2+ concentration range spanning three orders of magnitude indicating that over this range the internal Ca2+ concentration does not limit the ability of the channel to be activated by voltage.

Animals↗
PubMed1997

Intrinsic voltage dependence and Ca2+ regulation of mslo large conductance Ca-activated K+ channels.

The kinetic and steady-state properties of macroscopic mslo Ca-activated K+ currents were studied in excised patches from Xenopus oocytes. In response to voltage steps, the timecourse of both activation and deactivation, but for a brief delay in activation, could be approximated by a single exponential function over a wide range of voltages and internal Ca2+ concentrations ([Ca]i). Activation rates increased with voltage and with [Ca]i, and approached saturation at high [Ca]i. Deactivation rates generally decreased with [Ca]i and voltage, and approached saturation at high [Ca]i. Plots of the macroscopic conductance as a function of voltage (G-V) and the time constant of activation and deactivation shifted leftward along the voltage axis with increasing [Ca]i. G-V relations could be approximated by a Boltzmann function with an equivalent gating charge which ranged between 1.1 and 1.8 e as [Ca]i varied between 0.84 and 1,000 microM. Hill analysis indicates that at least three Ca2+ binding sites can contribute to channel activation. Three lines of evidence indicate that there is at least one voltage-dependent unimolecular conformational change associated with mslo gating that is separate from Ca2+ binding. (a) The position of the mslo G-V relation does not vary logarithmically with [Ca]i. (b) The macroscopic rate constant of activation approaches saturation at high [Ca]i but remains voltage dependent. (c) With strong depolarizations mslo currents can be nearly maximally activated without binding Ca2+. These results can be understood in terms of a channel which must undergo a central voltage-dependent rate limiting conformational change in order to move from closed to open, with rapid Ca2+ binding to both open and closed states modulating this central step.

Animals↗
PubMed1997

Allosteric gating of a large conductance Ca-activated K+ channel.

Large-conductance Ca-activated potassium channels (BK channels) are uniquely sensitive to both membrane potential and intracellular Ca2+. Recent work has demonstrated that in the gating of these channels there are voltage-sensitive steps that are separate from Ca2+ binding steps. Based on this result and the macroscopic steady state and kinetic properties of the cloned BK channel mslo, we have recently proposed a general kinetic scheme to describe the interaction between voltage and Ca2+ in the gating of the mslo channel (Cui, J., D.H. Cox, and R.W. Aldrich. 1997. J. Gen. Physiol. In press.). This scheme supposes that the channel exists in two main conformations, closed and open. The conformational change between closed and open is voltage dependent. Ca2+ binds to both the closed and open conformations, but on average binds more tightly to the open conformation and thereby promotes channel opening. Here we describe the basic properties of models of this form and test their ability to mimic mslo macroscopic steady state and kinetic behavior. The simplest form of this scheme corresponds to a voltage-dependent version of the Monod-Wyman-Changeux (MWC) model of allosteric proteins. The success of voltage-dependent MWC models in describing many aspects of mslo gating suggests that these channels may share a common molecular mechanism with other allosteric proteins whose behaviors have been modeled using the MWC formalism. We also demonstrate how this scheme can arise as a simplification of a more complex scheme that is based on the premise that the channel is a homotetramer with a single Ca2+ binding site and a single voltage sensor in each subunit. Aspects of the mslo data not well fitted by the simplified scheme will likely be better accounted for by this more general scheme. The kinetic schemes discussed in this paper may be useful in interpreting the effects of BK channel modifications or mutations.

Animals↗
PubMed1996

Students with learning disabilities in Canadian colleges and universities: a primer for service provision.

The authors, both of whom are involved in providing support services to university students with learning disabilities, describe some of the current issues and challenges faced by students, staff, and faculty. Programs and initiatives in some Canadian institutions that have proven to be successful are described, such as a sequential five-step procedure model that directed the delivery of services at the university. Resource and reference lists are also provided.

Canada↗
PubMed1994

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

We have studied the inactivation of high-voltage-activated (HVA), omega-conotoxin-sensitive, N-type Ca2+ current in embryonic chick dorsal root ganglion (DRG) neurons. Voltage steps from -80 to 0 mV produced inward Ca2+ currents that inactivated in a biphasic manner and were fit well with the sum of two exponentials (with time constants of approximately 100 ms and > 1 s). As reported previously, upon depolarization of the holding potential to -40 mV, N current amplitude was significantly reduced and the rapid phase of inactivation all but eliminated (Nowycky, M. C., A. P. Fox, and R. W. Tsien. 1985. Nature. 316:440-443; Fox, A. P., M. C. Nowycky, and R. W. Tsien. 1987a. Journal of Physiology. 394:149-172; Swandulla, D., and C. M. Armstrong. 1988. Journal of General Physiology. 92:197-218; Plummer, M. R., D. E. Logothetis, and P. Hess. 1989. Neuron. 2:1453-1463; Regan, L. J., D. W. Sah, and B. P. Bean. 1991. Neuron. 6:269-280; Cox, D. H., and K. Dunlap. 1992. Journal of Neuroscience. 12:906-914). Such kinetic properties might be explained by a model in which N channels inactivate by both fast and slow voltage-dependent processes. Alternatively, kinetic models of Ca-dependent inactivation suggest that the biphasic kinetics and holding-potential-dependence of N current inactivation could be due to a combination of Ca-dependent and slow voltage-dependent inactivation mechanisms. To distinguish between these possibilities we have performed several experiments to test for the presence of Ca-dependent inactivation. Three lines of evidence suggest that N channels inactivate in a Ca-dependent manner. (a) The total extent of inactivation increased 50%, and the ratio of rapid to slow inactivation increased approximately twofold when the concentration of the Ca2+ buffer, EGTA, in the patch pipette was reduced from 10 to 0.1 mM. (b) With low intracellular EGTA concentrations (0.1 mM), the ratio of rapid to slow inactivation was additionally increased when the extracellular Ca2+ concentration was raised from 0.5 to 5 mM. (c) Substituting Na+ for Ca2+ as the permeant ion eliminated the rapid phase of inactivation. Other results do not support the notion of current-dependent inactivation, however. Although high intracellular EGTA (10 mM) or BAPTA (5 mM) concentrations suppressed the rapid phase inactivation, they did not eliminate it. Increasing the extracellular Ca2+ from 0.5 to 5 mM had little effect on this residual fast inactivation, indicating that it is not appreciably sensitive to Ca2+ influx under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Pharmacological discrimination of N-type from L-type calcium current and its selective modulation by transmitters.

GABA and norepinephrine inhibit high voltage-activated calcium current in chick sensory neurons. Using specific pharmacological tools, we have dissected this current into two components: the major one is omega-conotoxin sensitive and dihydropyridine resistant (N-type) while the minor one is dihydropyridine sensitively and omega-conotoxin resistant (L-type). The ability to selectively eliminate these two components has allowed us to determine whether the transmitters target the same or different channel types. Both GABA and norepinephrine modulate the N-type component as evidenced by their lack of effect on (1) omega-conotoxin-resistant current and (2) pure L-type tail current, prolonged by a dihydropyridine calcium channel agonist. This simple pharmacological profile will allow future tests of the significance of the two channel types in regulating sensory neuron functions.

Animals↗
PubMed1988

Heterogeneity of gamma-aminobutyric acid/benzodiazepine/beta-carboline receptor complex in rat spinal cord.

The properties of muscimol, beta-carboline (BC), and benzodiazepine (BZD) binding to crude synaptic membranes were studied in the spinal cord and cerebellum of rats. In cerebellar membranes, the density of high-affinity [3H]muscimol and [3H]6,7-dimethoxy-4-ethyl-beta-carboline ([3H]BCCM) binding sites is almost identical to that of [3H]flunitrazepam ([3H]FLU) or [3H]flumazenil (Ro 15-1788; ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1-4]benzodiazepine-3-carboxylate). In contrast to the cerebellum, the number of muscimol and BC binding sites in rat spinal cord is approximately 20-25% of the number of FLU or flumazenil binding sites. Moreover, in spinal cord membranes, BC recognition site ligands displace [3H]-flumazenil bound to those sites, with low affinity and a Hill slope significantly less than 1; the potency of the different BCs in displacing [3H]flumazenil is 20-50-fold lower in the spinal cord than in the cerebellum. [3H]Flumazenil is not displaced from spinal cord membranes by the peripheral BZD ligand Ro 5-4864 (4'-chlorodiazepam), whereas it is displaced with low affinity and a Hill slope of less than 1 (nH = 0.4) by CL 218,872 (3-methyl-6-(3-trifluoromethylphenyl)-1,2,4-triazolol[4,3-b] pyridazine). These data suggest that a large number of BZD binding sites in spinal cord (approximately 80%) are of the central-type, BZD2 subclass, whereas the BZD binding sites in cerebellum are predominantly of the central-type, BZD1 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Hydrogen selenide evolution-electrothermal atomic absorption method for determining nanogram levels of total selenium.

A hydrogen selenide (H2Se) evolution-electrothermal atomic absorption method is described for determining nanogram concentrations of total selenium (Se) in biological and environmental materials. A mixed acid digestion procedure is used to decompose organic material. Sodium borohydride, a redesigned hydride generator, and an electric-headed absorption tube are used for H2Se evolution and conversion to atomic Se. The method has a detection limit of 4 ng/mL and a sensitivity of 0.6 ng/mL, and is linear from 0 to 90 ng Se/mL. As determined on urine, water, and bovine liver, total and within-run precision had relative and standard deviation values of 5-17.2 and 5.5-12.6% respectively. Accuracy was established with 2 NBS and 3 EPA reference materials, and mean errors of 0 to +0.8 were obtained. Mean recoveries of 109 and 101% were obtained for 10 and 50 ng Se added to human urine.

Borohydrides↗
PubMed1979

Occupational lead poisoning in the United States: clinical and biochemical findings related to blood lead levels.

Dose-response relationships between blood lead levels and toxic effects have been evaluated in 160 lead workers in two smelters and a chemicals plant. Blood lead levels ranged from 0.77 to 13.51 mumol/litre (16-280 microgram/dl). Clinical evidence of toxic exposure was found in 70 workers (44%), including colic in 33, wrist or ankle extensor muscle weakness in 12, anaemia (Hgb less than 8.69 mumol/litre (Hb/4) or 14.0 gm/dl) in 27, elevated blood urea nitrogen (greater than or equal to 7.14 mmol/litre or 20 mg/dl) in 28, and possible encephalopathy in two. No toxicity was detected at blood lead levels below 1.93 mumol/litre (40 microgram/dl). However, 13% of workers with blood lead levels of 1.93 to 3.81 mumol/litre (40-79 microgram/dl) had extensor muscle weakness or gastrointestinal symptoms. Anaemia was found in 5% of workers with lead levels of 1.93-2.85 mumol/litre (40-59 microgram/dl), in 14% with levels of 2.90 to 3.81 mumol/litre (60-79 microgram/dl), and in 36% with levels greater than or equal to 3.86 mumol/litre (80 microgram/dl). Elevated blood urea nitrogen occurred in long-term lead workers. All but three workers with increased blood urea nitrogen had at least four years occupational lead exposure, and nine had received oral chelation; eight of this group had reduced creatinine clearance, and eight had decreased renal concentrating ability. These data support the establishment of a permissible biological limit for blood lead at a level between 1.93 and 2.90 mumol/litre (40-60 microgram/dl).

Air Pollutants, Occupational↗
PubMed1976

Increased lead absorption with anemia and slowed nerve conduction in children near a lead smelter.

Studies to evaluate the prevalence, sources, and health consequences of lead absorption were conducted among children living near a primary lead smelter. Lead levels in air, soil, and dust were highest at the smelter and decreased with distance. Ninety-nine percent of one- to nine-year-old children living within 1.6 kilometers had blood lead levels greater than or equal 40 mug/dl, indicating increased absorption, and 22% had levels greater than or equal 80 mug/dl. The prevalence of lead levels greater than or equal 40 mug/dl decreased with distance; at 72 kilometers from the smelter it was 1%. Erythrocyte protoporphyrin levels increased with blood lead levels: 17% of children with lead levels of greater than or equal 80 mug/dl were anemic. There was no overt neurologic toxicity. Significant negative correlation was found in 202 five- to nine-year-old children between blood lead levels and motor nerve conduction velocity (r = 0.38, p less than 0.02).

Air Pollutants↗
PubMed1975

Chronic lead absorption. Result of poor ventilation in an indoor pistol range.

Three cases of mild lead poisoning were discovered among instructors at an indoor pistol range. These cases were characterized by blood lead levels greater than 100 mug/100 ml, free erythrocyte protoporphyrin levels greater than 450 mug/100 ml of red blood cells, abdominal pain, and, in one instance, by slowing of motor and sensory nerve conduction velocity. Exposure to airborne lead produced during revolver-firing and bullet-molding accounted for the lead absorption. Ventilation in the range was inadequate.

Abdomen↗