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PubMed2004

TRAIL-R as a negative regulator of innate immune cell responses.

TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R(-/-) mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R(-/-) mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-alpha, and IFN-gamma. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R(-/-) cells. The immediate-early TLR signaling events in TRAIL-R(-/-) macrophages and dendritic cells are normal, but I kappa B-alpha homeostatic regulation and NF-kappa B activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.

Amino Acid Sequence↗
PubMed2004

Total body centre of mass displacement estimated using ground reactions during transitory motor tasks: application to step ascent.

A double integration technique is presented that estimates whole body centre of mass (CoM) displacement from signals of a single force platform, compensating for the drift and low frequency noise inherent in the signals. The technique is composed of two different integration techniques, which may also be used separately, and is applied to transitory motor tasks with known initial and final conditions such as step ascent and descent, single step, etc. First, the lowest frequencies within the force platform signals and considered not to be associated with actual movement are filtered out. Second, a regular and a time-reversed double integration are performed and weighted against each other. The technique's accuracy was assessed using computer generated force platform signals that were artificially perturbed. Experimental data were used to compare the estimated CoM displacement to that obtained from a regular double integration and from segmental analysis performed on stereophotogrammetric data. It was shown that the proposed technique's CoM displacement estimates were more repeatable and up to 50% more accurate than those of a regular double integration. Moreover, the CoM displacement estimated using a single force platform and the proposed technique was found to be not statistically different from that obtained with more demanding measurement and processing techniques such as stereophotogrammetry and segmental analysis.

Adult↗
PubMed2006

Synthesis and two-dimensional correlation infrared spectroscopy study of an organic-inorganic hybrid compound constructed by [Mo(5)P(2)O(23)] and Cu-imidazole components.

A novel compound, (Himi)(H(3)O) [Cu(imi)(2)](2)[P(2)Mo(5)O(23)].H(2)O 1 (imi=imidazole), was synthesized by hydrothermal method and characterized by X-ray single analysis, ESR spectrum, one-dimensional (1D) infrared spectroscopy and two-dimensional (2D) correlation infrared spectroscopy under thermal and magnetism perturbation. Crystal data for the compound 1: orthorhombic system, space group Pnma, a = 14.580(3)A, b = 21.073(4)A, c = 16.664(3)A, Z = 4. It consists of the Mo-Cu building-blocks [Cu(imi)(4)](2)[P(2)Mo(5)O(23)](2-), protonated imidazole cations and water molecules. In the Mo-Cu building-blocks, [Mo(5)P(2)O(23)](6-) clusters are linked by {Cu(imi)(4)}(2+) group to form a two-dimension parallelogram griddling structure. From the 2D IR correlation spectroscopy analyses, it is discovered that the intensity changes of Mo=O and P-O band are sensitive to the temperature variation, whereas the Mo-O bond linking to Cu(2+) can be remarkably affected by the magnetism variation. Furthermore, the intensity changes of P-O bands occur prior to that of the Mo=O band during the temperature elevation.

Chemistry, Inorganic↗
PubMed2006

Precision mapping of the metabolome.

The global study of the structure and dynamics of metabolic networks has been hindered by a lack of techniques that identify metabolites and their biochemical relationship in complex mixtures. The recent application of Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) to metabolomic analysis suggests a way to tackle the problem. A lower-cost alternative to high-field FTICR-MS, the Orbitrap mass analyzer, promises accelerated activity in this area. Here, we show how the ultra-high mass accuracy and resolution provided by this new generation of mass spectrometers can help to identify metabolites and connect them into metabolic networks. Data from perturbation studies and isotope-tracking experiments can complement this information to create metabolic maps de novo and chart unexplored areas of metabolism.

Algorithms↗
PubMed2000

Reduction of gait data variability using curve registration.

Timing in peak gait values shifts slightly between gait trials. When averaged, the standard deviation (S.D.) in gait data may increase due to this inter-trial variability unless normalization is carried out beforehand. The objective of this study was to determine how curve registration, an alignment technique, can reduce inter-subject variability in gait data without perturbing the curve characteristics. Twenty young, healthy men participated in this study each providing a single gait trial. Gait was assessed by means of a four-camera high-speed video system synchronized to a force plate. A rigid body three-segment model was used in an inverse dynamic approach to calculate three-dimensional muscle powers at the hip, knee and ankle. Curve registration was applied to each of the 20 gait trials to align the peak powers. The mean registered peak powers increased by an average of 0.10 +/- 0.13 W/kg with the highest increases in the sagittal plane at push-off. After performing curve registration, the RMS values decreased by 13.6% and the greatest reduction occurred at the hip and knee, both in the sagittal plane. No important discontinuities were reported in the first and second derivatives of the unregistered and registered curves. Curve registration did not have much effect on the harmonic content. This would be an appropriate technique for application prior to any statistical analysis using able-bodied gait patterns.

Adult↗
PubMed2002

N-terminus of the photosystem II manganese stabilizing protein: effects of sequence elongation and truncation.

The importance of the N-terminal domain of manganese stabilizing protein in binding to photosystem II has been previously demonstrated [Eaton-Rye and Murata (1989) Biochim. Biophys. Acta 977, 219-226; Odom and Bricker (1992) Biochemistry 31, 5616-5620]. In this paper, we report results from a systematic study of functional and structural consequences of N-terminal elongation and truncation of manganese stabilizing protein. Precursor manganese stabilizing protein is the unprocessed wild-type protein, which carries an N-terminal extension of 84 amino acids in the form of its chloroplastic signal peptide. Despite its increased size, this protein is able to reconstitute O(2) evolution activity to levels observed with the mature, processed protein, but it also binds nonspecifically to PSII. Truncation of wild-type manganese stabilizing protein by site-directed mutagenesis to remove three N-terminal amino acids, resulting in a mutant called DeltaG3M, causes no loss of activity reconstitution, but this protein also exhibits nonspecific binding. Further truncation of the wild-type protein by ten N-terminal amino acids, producing DeltaE10M, limits binding of manganese stabilizing protein to 1 mol/mol of photosystem II and decreases activity reconstitution to about 65% of that obtained with the wild-type protein. Because two copies of wild type normally bind to photosystem II, amino acids in the domain (4)K-(10)E must be involved in the binding of one copy of manganese stabilizing protein to photosystem II. Spectroscopic analysis (CD and UV spectra) reveals that N-terminal elongation and deletion of manganese stabilizing protein influence its overall conformation, even though secondary structure content is not perturbed. Our data suggest that the solution structure of manganese stabilizing protein attains a more compact solution structure upon removal of N-terminal amino acids.

Amino Acid Sequence↗
PubMed2000

Protein spray-freeze drying. Effect of atomization conditions on particle size and stability.

PURPOSE: To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein. METHODS: Atomization variables were explored for excipient-free (no zinc added) and zinc-complexed bovine serum albumin (BSA). Particle size was measured by laser diffraction light scattering following sonication in organic solvent containing poly(lactide-co-glycolide) (PLG). Powder surface area was determined from the N2 vapor sorption isotherm. Size-exclusion chromatography (SEC) was used to assess decrease in percent protein monomer. Fourier-transform infrared (FTIR) spectroscopy was employed to estimate protein secondary structure. PLG microspheres were made using a non-aqueous, cryogenic process and release of spray-freeze dried BSA was assessed in vitro. RESULTS: The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N2 relative to that for liquid feed). Particle size was inversely related to specific surface area and the amount of protein aggregates formed. Zinc-complexation reduced the specific surface area and stabilized the protein against aggregation. FTIR data indicated perturbations in secondary structure upon spray-freeze drying for both excipient-free and zinc-complexed protein. CONCLUSIONS: Upon sonication, spray-freeze dried protein powders exhibited friability, or susceptibility towards disintegration. For excipient-free protein, conditions where the mass flow ratio was > -0.3 yielded sub-micron powders with relatively large specific surface areas. Reduced particle size was also linked to a decrease in the percentage of protein monomer upon drying. This effect was ameliorated by zinc-complexation, via a mechanism involving reduction in specific surface area of the powder rather than stabilization of secondary structure. Reduction of protein particle size was beneficial in reducing the initial release (burst) of the protein encapsulated in PLG microspheres.

Biocompatible Materials↗
PubMed1995

The relative distribution of T cell subsets is altered in Jamaican children infected with human T cell lymphotropic virus type I.

Early childhood infection with human T cell lymphotropic virus type I (HTLV-I) has been suggested to be involved in the pathogenesis of infective dermatitis and adult T cell leukemia/lymphoma. Since only a very small percentage of HTLV-I-infected children develop disease later in life, identification of early interim markers for persons at risk for developing disease would enable monitoring and might provide insight into the pathophysiology of the various diseases associated with HTLV-I infection. A cross-sectional study analyzed T cell subsets in 35 HTLV-I-seronegative and 16 HTLV-I-seropositive Jamaican children 11-31 months old. HTLV-I seropositivity was associated with an increase in the mean percentage of CD4 cells expressing HLA-DR, a marker for T cell activation (P = .02). This increase was positively correlated with duration of infection (r = .74, P = .009). These data demonstrate perturbation of regulatory cells of the immune system in HTLV-I-infected children.

Breast Feeding↗
PubMed1998

Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII.

Bursts of free radicals produced by ionization of water in close vicinity to DNA can produce clusters of opposed DNA lesions and these are termed multiply damaged sites (MDS). How MDS are processed by the Escherichia coli DNA glycosylases, endonuclease (endo) III and endo VIII, which recognize oxidized pyrimidines, is the subject of this study. Oligonucleotide substrates were constructed containing a site of pyrimidine damage or an abasic (AP) site in close proximity to a single nucleotide gap, which simulates a free radical-induced single-strand break. The gap was placed in the opposite strand 1, 3 or 6 nt 5' or 3' of the AP site or base lesion. Endos III and VIII were able to cleave an AP site in the MDS, no matter what the position of the opposed strand break, although cleavage at position one 5' or 3' was reduced compared with cleavage at positions three or six 5' or 3'. Neither endo III nor endo VIII was able to remove the base lesion when the gap was positioned 1 nt 5' or 3' in the opposite strand. Cleavage of the modified pyrimidine by endo III increased as the distance increased between the base lesion and the opposed strand break. With endo VIII, however, DNA breakage at the site of the base lesion was equivalent to or less when the gap was positioned 6 nt 3' of the lesion than when the gap was 3 nt 3' of the lesion. Gel mobility shift analysis of the binding of endo VIII to an oligonucleotide containing a reduced AP (rAP) site in close opposition to a single nucleotide gap correlated with cleavage of MDS substrates by endo VIII. If the strand break in the MDS was replaced by an oxidized purine, 7,8-dihydro-8-oxoguanine (8-oxoG), neither endo VIII cleavage nor binding were perturbed. These data show that processing of oxidized pyrimidines by endos III and VIII was strongly influenced by the position and type of lesion in the opposite strand, which could have a significant effect on the biological outcome of the MDS lesion.

Base Sequence↗
PubMed1994

Resuscitation from hypovolemia in swine with intraosseous infusion of a saturated salt-dextran solution.

Prehospital fluid resuscitation of traumatic injury is limited by difficulty in delivering large volumes of fluid in the field and time delays associated with gaining vascular access. We addressed these limitations in 14 anesthetized swine by evaluating a highly efficient volume expander, a near-saturated salt-dextran solution (SSD) administered through a new device, which gains vascular access via intraosseous (IO) infusion into the sternal bone marrow. After a steady-state baseline was achieved, all animals were hemorrhaged to 45 mm Hg for one hour. Half of the hemorrhaged animals were infused intraosseously with either normal saline (NS) or SSD until cardiac output was restored to the baseline value. No further infusion was given and animals were monitored for 2 hours. Both regimens were able to restore cardiac output to the baseline value, but only 1.3 +/- 0.1 mL/kg of SSD was required vs. 31.6 +/- 6.3 mL/kg for NS. In addition, cardiac output was better sustained after 2 hours with SSD than with NS. No deleterious effects of IO infusion of SSD were observed. From the improvement in cardiovascular variables and the lack of significant sternal or pulmonary pathologic perturbations, these data suggest that IO infusion of SSD can effectively treat hypovolemia and may allow field treatment when logistic considerations make conventional resuscitation impractical.

Animals↗
PubMed2001

Chloroplast DNA methylation and inheritance in Chlamydomonas.

When Chlamydomonas reinhardtii cells mate, a zygotic maturation program is activated, part of which leads to destruction of chloroplast DNA (cpDNA) from the mating type minus (mt-) parent, and, therefore, to uniparental inheritance of mating type plus (mt+) cpDNA. A long-standing model that explains the selective destruction of mt(-) cpDNA in zygotes invokes a methylation-restriction system. We tested this model by using the potent methylation inhibitor 5-aza-2'-deoxycytidine (5adc) to hypomethylate parental cpDNA and found that the pattern of cpDNA inheritance is altered by 5adc in a manner that is consistent with the model. Surprisingly, however, hypomethylated mt+ cpDNA is not destroyed in zygotes as the methylation-restriction model predicts it should be. Destruction of mt- cpDNA is also unaffected when the parental mt+ cpDNA is hypomethylated. Instead, loss of methylation affects the relative rates of replication of residual mt- cpDNA and mt+ cpDNA in germinating zygotes. The mode of action for 5adc on cpDNA replication in germinating zygotes may be via hypomethylation of mt+ cpDNA, but is also consistent with its action as a DNA-damaging agent. Interestingly, 5adc causes reduced cpDNA replication only in germinating zygotes, not in vegetatively grown cells, indicating that cpDNA replication is qualitatively different in these two stages of the life cycle. Our results demonstrate that methylation is not necessary for protection of the mt+ cpDNA in early zygotes and uncover a novel stage of the Chlamydomonas life cycle when replication of cpDNA is highly susceptible to perturbation. Our data support a model in which differential cpDNA replication in germinating zygotes is used as a mechanism to selectively amplify intact and properly methylated cpDNA molecules.

Animals↗
PubMed1993

In vivo cytokine expression in normal and perturbed murine skin--analysis by competitive quantitative polymerase chain reaction.

Although cells from both epidermis and dermis have been shown to produce a variety of soluble mediators in vitro, it is not clear whether this reflects the in vivo situation. To study in vivo cytokine expression, whole skin as well as dispase-separated epidermis and dermis from normal adult mice were prepared and snap-frozen immediately. RNA was then extracted and analyzed both by conventional and by competitive quantitative polymerase chain reaction. Molecular analysis showed that murine skin in vivo constitutively expresses several cytokine genes at moderate (e.g., interleukin-1 alpha) or low (e.g., interleukin-6 and granulocyte-macrophage colony-stimulating factor) abundance. A striking, rapid upregulation was observed for some of these cytokines in the process of tissue separation. Of interest, the epidermal and dermal compartments exhibited different induction patterns: interleukin-1 alpha, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha expression were detected preferentially in the epidermis, whereas upregulation of interleukin-6 was found to be most prominent in the dermis. This pattern of cytokine expression was also reflected in supernatants generated from the respective single-cell suspensions. Thus, this study determines the baseline in vivo cytokine expression in the skin and the occurrence of immediate, compartment-specific alterations on perturbation. These data should contribute to our understanding of both skin homeostasis and the host-defense mechanisms initiated following injury to this organ.

Amino Acid Sequence↗
PubMed2003

Cholesterol depletion of human immunodeficiency virus type 1 and simian immunodeficiency virus with beta-cyclodextrin inactivates and permeabilizes the virions: evidence for virion-associated lipid rafts.

Recent evidence suggests that human immunodeficiency virus type 1 (HIV-1) particles assemble and bud selectively through areas in the plasma membrane of cells that are highly enriched with glycosylphosphatidylinositol-anchored proteins and cholesterol, called lipid rafts. Since cholesterol is required to maintain lipid raft structure and function, we proposed that virion-associated cholesterol removal with the compound 2-hydroxy-propyl-beta-cyclodextrin (beta-CD) might be disruptive to HIV-1 and simian immunodeficiency virus (SIV). We examined the effect of beta-CD on the structure and infectivity of cell-free virions. We found that beta-CD inactivated HIV-1 and SIV in a dose-dependent manner and permeabilized the viral membranes, resulting in the loss of mature Gag proteins (capsid, matrix, nucleocapsid, p1, and p6) without loss of the envelope glycoproteins. SIV also lost reverse transcriptase (RT), integrase (IN), and viral RNA. IN appeared to be only slightly diminished in HIV-1, and viral RNA, RT, matrix, and nucleocapsid proteins were retained in HIV-1 but to a much lesser degree. Host proteins located internally in the virus (actin, moesin, and ezrin) and membrane-associated host proteins (major histocompatibility complex classes I and II) remained associated with the treated virions. Electron microscopy revealed that under conditions that permeabilized the viruses, holes were present in the viral membranes and the viral core structure was perturbed. These data provide evidence that an intact viral membrane is required to maintain mature virion core integrity. Since the viruses were not fixed before beta-CD treatment and intact virion particles were recovered, the data suggest that virions may possess a protein scaffold that can maintain overall structure despite disruptions in membrane integrity.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2004

Beta-cell function and islet morphology in normal, obese, and obese beta-cell mass-reduced Göttingen minipigs.

Herein, we bridge beta-cell function and morphology in minipigs. We hypothesized that different aspects of beta-cell dysfunction are present in obesity and obesity with reduced beta-cell mass by using pulsatile insulin secretion as an early marker. Measures for beta-cell function (glucose and arginine stimulation plus baseline and glucose-entrained pulsatile insulin secretion) and islet morphology were studied in long-term (19-20 mo) obese (n = 5) and obese beta-cell-reduced [nicotinamide + streptozotocin (STZ), n = 5] minipigs and normal controls, representing different stages in the development toward type 2 diabetes. Acute insulin response (AIR) to glucose and arginine were, surprisingly, normal in obese (0.3 g/kg glucose: AIR = 246 +/- 119 vs. 255 +/- 61 pM in control; 67 mg/kg arginine: AIR = 230 +/- 124 vs. 214 +/- 85 pM in control) but reduced in obese-STZ animals (0.3 g/kg glucose: AIR = 22 +/- 36, P < 0.01; arginine: AIR = 87 +/- 92 pM, P < 0.05 vs. control). Baseline pulsatile insulin secretion was reduced in obese (59 +/- 16 vs. 76 +/- 16% in control, P < 0.05) and more so in obese-STZ animals (43 +/- 13%, P < 0.01), whereas regularity during entrainment was increased in obese animals (approximate entropy: 0.85 +/- 0.14 vs. 1.13 +/- 0.13 in control, P < 0.01). Beta-cell mass (mg/kg body wt) was normal in obese and reduced in obese-STZ animals, with pancreatic fat infiltration in both groups. In conclusion, obesity and insulin resistance are not linked with a general reduction of beta-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of beta-cell dysfunction, with the three groups representing stages in the progression from normal physiology to diabetes, and assessment of pulsatility as the single most sensitive marker of beta-cell dysfunction.

Animals↗
PubMed1996

Dilution acidosis: evidence for a role of intracellular pH in the control of ventilation.

Acute hyperosmolality results in an extracellular dilution acidosis and hypercarbia that does not stimulate ventilatory compensation. The osmotic stress is also associated with shifts in water and electrolyte balance and an increase in intracellular pH. The alkaline intracellular pH was hypothesized to have a role in preventing a normal respiratory response to the extracellular acidosis and hypercarbia. Therefore, this study examined the effect of ion-exchange blockade on intra- and extracellular pH and ventilation during acute hyperosmolality in the Pekin duck (Anas platyrhynchos) by using 31P-nuclear magnetic resonance spectroscopy. Both 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and amiloride inhibited the development of the intracellular alkalosis that normally develops in muscle during acute hyperosmolality. Instead, exposure to hyperosmotic stress during ion-exchange blockade resulted in a significant acidosis both intracellularly and extracellularly. Arterial pH decreased 0.10 +/- 0.04 pH unit with a sucrose infusion after either blocker, and intracellular pH decreased 0.11 +/- 0.06 and 0.16 +/- 0.04 pH units with a sucrose infusion after DIDS and amiloride, respectively. Ventilation increased 79 +/- 28 and 122 +/- 100%, respectively, during acute hyperosmolality after ion-exchange blockade with either DIDS or amiloride. The results suggest that intracellular pH may play a role in the ventilatory response to acid-base perturbations. The data also indicate that both Cl-/HCO3- and Na+/H+ exchanges are involved in the development of the intracellular alkalosis during hyperosmotically induced extracellular acidosis.

Acidosis↗
PubMed1983

Response to sudden torques about ankle in man: V effects of peripheral ischemia.

Sudden dorsiflexions and plantar flexions of the foot were imposed by a torque motor while blood flow to the lower leg was occluded by a sphygmomanometer cuff. Seated subjects were instructed to resist the torques and restore the foot to its original position as rapidly as possible. Measurements of the first two electromyographic (EMG) responses were made in the soleus (SOL) and anterior tibial (TA) muscles. These are the myotatic reflex at about 40 ms and the postmyotatic response at about 120 ms. In the anterior tibial muscle, the myotatic component often occurs at 60- to 90-ms latency and is continuous with the postmyotatic component. After about 20 min of ischemia, there is a rapid and eventually complete loss of the myotatic component of the response in the stretched muscle. Concurrent with the loss of the myotatic reflex there is usually a reduction of the postmyotatic component. The latency of postmyotatic component remains unchanged, even after the myotatic reflex is abolished. Voluntary restoration of the foot to its original position in opposition to the motor torque is delayed and slowed by the time that the myotatic reflex has vanished. By measuring electromyographic responses to visually triggered reactions, we demonstrate that the reduction of the postmyotatic response is not due to failure of the efferent pathway. On this basis we discuss the possible contributions made by myotatic mechanisms to the tasks of load compensation and maintenance of muscle tone. Hoffmann reflexes were evoked in similar experiments with stimulation of the posterior tibial nerve at the popliteal fossa, distal to the cuff. The maximal direct motor response and muscle twitch are unaffected by loss of the H-reflex. Myotatic and Hoffmann reflexes were both evoked with torque perturbations and with a stimulating electrode proximal to a below-the-knee cuff. In this case, the myotatic reflex failed while the maximal H-reflex was slightly facilitated. The loss of the myotatic reflex was accompanied by a modest reduction in the direct motor response to electrical stimulation and a somewhat greater reduction in the postmyotatic response to torque perturbation. The data are interpreted to support a dual role for the primary afferent pathway in the control of voluntary movements. It provides the fastest path for the activation of a stretched muscle to initiate a load-compensating contraction. It also provides a form of servo assistance in modulating descending control signals. The degree of this assistance is estimated. In this simple experimental paradigm, functional contributions of the reflex arc are demonstrated.

Ankle Joint↗
PubMed1987

Point spread functions and detail detection.

Point spread functions, intended to characterize local spatial transfer of the visual system, can be obtained psychophysically using a perturbation technique. Data of such point spread functions are shown for three experimental conditions: foveally at adaptation levels of 1200 and 10 Td, and in the parafovea at an eccentricity of 2 deg using a 1200 Td adaptation level. The results are consistent with earlier findings (Blommaert, F. J.J. and Roufs, J.A.J. 1981, Vision Res. 21, 1223-1233). On the basis of such point spread functions a simplified multiple unit model was constructed, the parameters of which were fitted to thresholds of discs with varying diameter. Threshold predictions from this model for annuli, thin lines and broad lines were found to be in fair quantitative agreement with experimental results. It is argued that for a certain class of slender stimuli, including alphanumeric characters, thresholds can be described with a single channel model containing only the experimentally determined point spread function as a basic component.

Humans↗
PubMed2004

Magnetic resonance imaging study of current and ion delivery into the eye during transscleral and transcorneal iontophoresis.

PURPOSE: The objectives were to determine by nuclear magnetic resonance imaging (MRI) the target sites of ion delivery in the eye during iontophoresis, compare transscleral and transcorneal ocular iontophoresis, and monitor the distribution of a probe ion in the anterior chamber and vitreous after iontophoretic delivery. METHODS: Thirty-minute 2-mA anodal constant current transscleral and transcorneal iontophoresis (current density, 10 mA/cm(2)) was performed on three New Zealand White rabbits in vivo. Intravitreal injection and passive delivery were the controls. Transscleral and transcorneal iontophoresis experiments were conducted with the electrode device placed in the superior cul-de-sac away from the limbus and on the cornea adjacent to the limbus, respectively. During iontophoresis, the current delivered into the eye was monitored using a probe ion (Mn(2+)) with MRI. The distributions of the ion in the aqueous and vitreous humor after iontophoresis, passive delivery, and intravitreal injection were also determined by MRI. RESULTS: With the short application time, passive diffusion did not deliver a significant amount of the ion into the eye. Whereas transscleral iontophoresis delivered the ion into the vitreous, transcorneal iontophoresis delivered the ion into the anterior chamber. The current pathways during iontophoresis were mainly from the electrode into the eye, perpendicular to the electrode-eye interface beneath the electrode. Electric current along the surface of the globe was relatively minimal. With the present transscleral iontophoresis protocol, the ion penetrated the sclera and traveled as far as 1.5 mm from the electrode-conjunctiva interface into the vitreous. For transcorneal iontophoresis, the ion penetrated the cornea and filled the entire anterior chamber. CONCLUSIONS: MRI can be a useful technique in the study of the penetration of probe compounds in the eye during and after iontophoresis, such as in iontophoresis protocol and device testing. Ocular pharmacokinetic studies using MRI are noninvasive and provide real-time data without perturbation and compound redistribution that can occur during dissection and assay in traditional pharmacokinetic studies. With MRI, it was shown that transscleral iontophoresis, transcorneal iontophoresis, and intravitreal injection deliver ions to different parts of the eye.

Animals↗