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PubMed2005

Antiangiogenic and vascular-targeting activity of the microtubule-destabilizing trans-resveratrol derivative 3,5,4'-trimethoxystilbene.

Neovascularization plays an important role in neoplasia and angioproliferative diseases. Two major modalities have been developed so far to affect neovascularization: its prevention by antiangiogenic compounds, and immature vessel disruption by vascular-targeting agents. trans-Resveratrol, found in grapes and wine, exerts antioxidant, antineoplastic, and antiangiogenic activities. Here, among various synthetic trans-resveratrol derivatives tested, 3,5,4'-trimethoxystilbene was an antiangiogenic agent 30 to 100 times more potent than parent compound in inhibiting endothelial cell proliferation, sprouting, collagen gel invasion, and morphogenesis (ID50 = 0.3-3.0 microM). In addition, 3,5,4'-trimethoxystilbene acts as a vascular-targeting agent by causing microtubule disassembling and tubulin depolymerization and by impairing the repositioning of the microtubule organization center and the formation of membrane ruffles in migrating endothelial cells. In keeping with a vascular-targeting ability, 3,5,4'-trimethoxystilbene induced apoptosis only in subconfluent endothelial cells and apoptotic regression of immature vessels in the ex vivo rat aorta ring assay. In vivo, 3,5,4'-trimethoxystilbene caused the rapid stasis of blood flow and regression of intersegmental vessels in the trunk of zebrafish embryos. In addition, it inhibited blood vessel growth and caused the disappearance of pre-existing blood vessels in the area vasculosa of the chick embryo. In conclusion, 3,5,4'-trimethoxystilbene associates an antiangiogenic profile to a significant vascular-targeting activity.

Angiogenesis Inhibitors↗
PubMed2006

Enhancing the survival of tunneled haemodialysis catheters using an antibiotic lock in the elderly: a randomised, double-blind clinical trial.

BACKGROUND: Tunneled-cuffed catheters (TCC) are often used among the elderly to commence and carry out haemodialysis (HD). Complications like infection and thrombosis frequently reduce the lifespan of TCC. The role of an antibiotic heparin 'lock' in the prevention of thrombotic and infectious complications and enhancement of TCC survival in the elderly has not been investigated previously. METHODS: In this prospective, double-blind clinical trial, TCC (n = 119, placed among 113 elderly patients requiring HD during March 2002 - February 2003) were randomised to either group I having TCC (n = 59, placed in 58 elderly patients) locked with cefotaxime (10 mg/mL) and heparin (5000 U/mL), or group II with TCC (n = 60, placed in 55 elderly patients) having catheter-restricted filling of heparin (5000 U/mL) alone. Symptomatic catheter-related blood stream infections (CRBSI) and catheter thrombosis were the primary end points in this study. Thrombosis was defined as an inability to use the catheter at a blood flow of 200 mL/min that did not respond to catheter repositioning and/or intraluminal thrombolysis. The incidence of catheter thrombosis, CRBSI and percentage of catheter survival were estimated and statistically compared between the two groups. RESULTS: Kaplan-Meier survival analysis using log rank test showed higher thrombosis-free TCC survival (84.7%vs 63.3%, P = 0.021), infection-free survival (68.7%vs 31.3%, P < 0.001) and infection and thrombosis-free survival (65.0%vs 35.0%, P = 0.006) at 365 days in group I compared with group II. CONCLUSION: Cefotaxime and heparin locks safely and effectively enhance the lifespan of TCC by lowering the incidence of thrombotic and infectious complications among elderly end-stage renal failure (ESRD) patients.

Aged↗
PubMed2002

Utility of percutaneous intervention in the management of tunneled hemodialysis catheters.

A variety of interventional techniques have been developed to restore function to dysfunctional tunneled hemodialysis catheters (THC). The relative efficacies of these techniques were evaluated retrospectively to determine which therapy might be most beneficial. The records of malfunctioning THCs referred to interventional radiology between November 1995 and December 1999 were retrospectively reviewed. Dysfunctional THCs were studied using DSA images obtained while injecting contrast through the lumens of the THCs. The interventions performed were categorized into 1 of 5 groups: no treatment or conservative measures such as vigorous flushing; advancing a guidewire through the THC to reposition the catheter tip or to dislodge a small thrombus; catheter exchange over a guidewire; fibrin stripping of the THC using a loop snare; or prolonged (4 or more hr) direct thrombolytic infusion. A Cox Proportional Hazards model was developed to compare the rate of failure among the procedures. There were 340 THC studies. The catheters were managed as follows: 93 patients received conservative management only, 15 had a guidewire advanced through the catheter, 147 underwent catheter exchange, 62 were treated with a fibrin stripping procedure, and 23 received a thrombolytic infusion. Estimated 30-day patency rates for THCs were 38.2% for conservative management, 30.9% for guidewire manipulation of catheter tip, 53.6% for catheter exchange, 76.1% for fibrin stripping, and 69.8% for thrombolytic infusion. Differences among the treatments were observed (p < 0.01) and pairwise comparisons were made among the treatment groups. Failure rates were significantly higher in the catheter exchange (p <0.01) and guidewire manipulation at catheter tip (p <0.01) groups when compared with the fibrin stripping group. The catheter exchange and guidewire manipulation groups also experienced higher rates of failure when compared with the thrombolytic infusion group, although the differences were not statistically significant (p = 0.08, p = 0.17, respectively). Four procedure-related complications requiring hospitalization or other intervention occurred. Three of these were in the catheter exchange group with one incidence of sepsis, one drug reaction, and one hematoma. Fibrin stripping and thrombolytic infusion provided the greatest efficacy in the treatment of poorly functioning THCs, but all therapies demonstrated wide-ranging results. Central line exchanges did not provide a superior secondary patency and experienced more complications.

Adolescent↗
PubMed2002

The role of the hydrophobic distal heme pocket of CooA in ligand sensing and response.

CooA from Rhodospirillum rubrum is a heme-containing transcriptional activator that becomes activated only upon binding CO. The basis for this specificity has been probed in a CooA variant, termed DeltaP3R4 CooA, lacking two residues adjacent to the Pro(2) heme ligand, which weakens that ligand. DeltaP3R4 CooA can bind imidazole and CN(-), as well as CO, and form a 6-coordinate low spin adduct with each. However, in contrast to the case with CO, imidazole and CN(-) do not stimulate the DNA binding activity of DeltaP3R4 CooA. This result indicates that the CO-specific activation of CooA is not merely the result of creation of a 6-coordinate CooA adduct but that there must be another element to this response. One feature of CooA activation is modest repositioning of the C-helices upon CO binding, so we altered a portion of the C-helix (residues Ile(113) and Leu(116)) located near the heme-bound CO in wild type CooA, and we investigated the effect on CO-specific activation. Surprisingly, the sizes of Ile(113) and/or Leu(116) positions are not critical for CooA activation by CO, disproving a precise interaction between these residues and the CO-bound heme as a basis for the CO activation mechanism and CO ligand specificity. In contrast, hydrophobic residues at these positions contribute to the activation. Some CooA variants altered at these positions in the background of DeltaP3R4 were also found to show low but reproducible activation in response to imidazole binding to the heme. A model for the role of hydrophobicity in CooA activation and specificity is suggested.

Bacterial Proteins↗
PubMed2006

D1 and D2 receptor antagonist injections in the prefrontal cortex selectively impair spatial learning in mice.

The prefrontal cortex (PFC) is a cortical area involved in selecting and retaining information to produce complex behaviors. Within the PFC, the dopaminergic system plays an important role in information processing. Thus, the objective of this study was to test whether bilateral administration of the D1 and D2 receptor antagonists in the prelimbic region of the PFC influenced the performance of mice in a non-associative spatial learning task. CD1 mice were bilaterally microinjected in the PFC with either the D1 receptor antagonist, SCH23390 (SCH 6.25; 12.5; 50 ng), or the D2 receptor antagonist, sulpiride (SULP 12.5; 50; 100 ng) and placed into an open field containing five different objects. After three sessions of habituation two objects were repositioned (spatial change) and in the subsequent session one of the objects was substituted (non-spatial change). No significant alteration was observed in the habituation pattern of the animals after D1 or D2 receptor blockade. When two of the objects were displaced, control mice explored the displaced objects far more than the non-displaced ones, while mice treated with SCH or SULP spent a comparable amount of time re-exploring the two object categories. Conversely, DA antagonists had no effects on the discrimination of the new object. Thus, the administration of both SCH and SULP selectively impaired the ability of mice to discriminate a spatial change, without affecting any other behavioral parameter. These findings could provide a model to study the role of the PFC dopaminergic system in spatial learning and to study the neural mechanisms underlying cognitive and attention deficits often observed in psychiatric disorders.

Afferent Pathways↗
PubMed1996

Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity.

BACKGROUND: Thymidylate synthase (TS) catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) by 5, 10-methylenetetrahydrofolate (CH2H4folate) to form deoxythymidine monophosphate (dTMP) and dihydrofolate (H2folate). The essential role of TS in the cell life cycle makes it an attractive target for the development of substrate and cofactor-based inhibitors that may find efficacy as anticancer and antiproliferative drugs. Antifolates that compete specifically with the binding of CH2H4 folate include the cofactor analog CB3717 (10-propargyl-5,8-dideazafolate). However, the development of potent cofactor analog inhibitors of TS, such as CB3717, as drugs has been slowed by their toxicity, which often becomes apparent as hepatic and renal toxicity mediated by the specific chemistry of the compound. Attempts to abolish toxicity in human patients while preserving potency against the target enzyme, have led to the development of ZD1694, which has already shown significant activity against colorectal tumours. RESULTS: The three dimensional crystallographic structure of ZD1694 in complex with dUMP and Escherichia coli TS has been determined to a resolution of 2.2 . This was used to evaluate the specific structural determinants of ZD1694 potency and to correlate structure/activity relationships between it and the closely related ligand, CB3717. ZD1694 binds to TS in the same manner as CB3717 and H2 folate, but a methyl group on its quinazoline ring, its thiophene ring and the methyl group at N10 are compensated for by plastic accommodation of the enzyme active site coupled with specific rearrangement in the solvent structure. A specific hydrogen bond between the protein and the inhibitor CB3717 is absent in the case of ZD1694 whose monoglutamate tail is reoriented and more well ordered. CONCLUSIONS: The binding mode of ZD1694 to thymidylate synthase has been determined at atomic resolution. ZD1694 forms a ternary complex with dUMP and participates in the multi-step TS reaction through the covalent bond formation between dUMP and Cys146 thereby competing with CH2H4 folate at the active site. Analysis of this inhibitor ternary complex structure and comparison with that of CB3717 reveals that the enzyme accommodates the differences between the two inhibitors with small shifts in the positions of key active site residues and by repositioning an active site water molecule, thereby preserving a general binding mode of these inhibitors.

Antimetabolites, Antineoplastic↗
PubMed2002

Comparison of Diaket and MTA when used as root-end filling materials to support regeneration of the periradicular tissues.

AIM: The objective of this study was to evaluate on a comparative basis the potential for mineral trioxide aggregate (MTA) and Diaket to promote periradicular tissue regeneration when used as surgical root-end filling materials. METHODOLOGY: Seven dogs weighing between 15 and 25 kg were anesthetized prior to having the root canals of their mandibular premolars accessed, cleaned, shaped and obturated. Coronal access cavities were restored with IRM. Surgical access to the root ends was established and the root ends were resected and prepared with ultrasonic tips. Root-end fillings of either MTA or thickly mixed Diaket were randomly assigned to the preparations. Reflected tissues were repositioned and sutured with 4-0 vicryl sutures. Sixty days postsurgery, the animals were killed, perfused with 10% neutral buffered formalin and the third and fourth premolars removed in block sections. The specimens were demineralized and sectioned at 6-microm intervals for histological assessment. Sections were stained with either haematoxylin and eosin or Gomori's one step trichrome stain and examined under the light microscope. All evaluations were made by two calibrated examiners and gradings were scored based on established criteria. The raw data was evaluated statistically using anova after adjusting for the animal block effect. RESULTS: Statistical evaluation indicated that there were no statistical differences between the observed regenerative responses of the tissues to the two root-end filling materials. CONCLUSIONS: Both Diaket and MTA can support almost complete regeneration of the periradicular periodontium when used as root-end filling materials in periradicular surgery on noninfected teeth.

Aluminum Compounds↗
PubMed1996

Structure of HIV-1 TAR RNA in the absence of ligands reveals a novel conformation of the trinucleotide bulge.

Efficient transcription from the human immunodeficiency virus (HIV) promoter depends on binding of the viral regulatory protein Tat to a cis-acting RNA regulatory element, TAR. Tat binds at a trinucleotide bulge located near the apex of the TAR stem-loop structure. An essential feature of Tat-TAR interaction is that the protein induces a conformational change in TAR that repositions the functional groups on the bases and the phosphate backbone that are critical for specific intermolecular recognition of TAR RNA. We have previously determined a high resolution structure for the bound form of TAR RNA using heteronuclear NMR. Here, we describe a high resolution structure of the free TAR RNA based on 871 experimentally determined restraints. In the free TAR RNA, bulged residues U23 and C24 are stacked within the helix, while U25 is looped out. This creates a major distortion of the phosphate backbone between C24 and G26. In contrast, in the bound TAR RNA, each of the three residues from the bulge are looped out of the helix and U23 is drawn into proximity with G26 through contacts with an arginine residue that is inserted between the two bases. Thus, TAR RNA undergoes a transition from a structure with an open and accessible major groove to a much more tightly packed structure that is folded around basic side chains emanating from the Tat protein.

Antiviral Agents↗
PubMed2002

Beta(2)-microglobulin clearance decreases with Renalin reuse.

The HEMO study revealed that beta(2)-microglobulin clearance decreases over time with Renalin reuse in the high-flux group. It was suggested that the reuse of polysulfone or cellulose triacetate high-flux dialyzers with Renalin (without bleach) results in degradation of the high-flux capacity. At our haemodialysis unit (Vila Real, Portugal) we reused dialyzers until January 2000 (limited to 10 reuses), with an automatic machine Renatron (Renal Systems, Minntech. All of our 31 patients who started with postdilution haemodiafiltration on-line (HDFol) were always dialyzed with F-80 polysulfone (Fresenius). The reposition rate was 10 litres/session until 1998 and 20 litres/session thereafter. Reuse techniques were abandoned in our country in January 2000 following an EEC directive. Thereafter, we have decided to maintain HDFol with the same dialyzers without reuse. The mean beta(2)-microglobulin predialysis values did not decrease over time until reuse was terminated (1995 with low-flux haemodialysis: 25.4 +/- 6.4 microg/l; 1997: 24.7 +/- 6.6 microg/l; 1998: 29.2 +/- 8.9 microg/l; 1999: 33.7 +/- 4.7 microg/l) whereas beta(2)-microglobulin clearances were reasonable with HDFol (1998: 56.4 +/- 25.9 ml/min; 1999: 47.9 +/- 16.4 ml/min). After stopping reuse we have noticed that predialysis beta(2)-microglobulin values decreased (2000: 23.0 +/- 3.9 microg/l) in accordance with beta(2)-microglobulin clearance duplication (2000: 84.1 +/- 25.0 ml/min; p < 0.01). It is our opinion that the reuse of polysulfone dialyzers with Renalin should be abandoned in the field of high-flux haemodialysis. It causes deterioration in the beta(2)-microglobulin clearance and probably interferes with the high-flux haemodialysis benefits, namely the reduction of dialysis-related amyloidosis.

Acetic Acid↗
PubMed2002

Design of thyroid hormone receptor antagonists from first principles.

It is desirable to obtain TR antagonists for treatment of hyperthyroidism and other conditions. We have designed TR antagonists from first principles based on TR crystal structures. Since agonist ligands are buried in the fold of the TR ligand binding domain (LBD), we reasoned that ligands that resemble agonists with large extensions should bind the LBD, but would prevent its folding into an active conformation. In particular, we predicted that extensions at the 5' aryl position of ligand should reposition helix (H) 12, which forms part of the co-activator binding surface, and thereby inhibit TR activity. We have found that some synthetic ligands with 5' aryl ring extensions behave as antagonists (DIBRT, NH-3), or partial antagonists (GC-14, NH-4). Moreover, one compound (NH-3) represents the first potent TR antagonist with nanomolar affinity that also inhibits TR action in an animal model. However, the properties of the ligands also reveal unexpected aspects of TR behavior. While nuclear receptor antagonists generally promote binding of co-repressors, NH-3 blocks co-activator binding and also prevents co-repressor binding. More surprisingly, many compounds with extensions behave as full or partial agonists. We present hypotheses to explain both behaviors in terms of dynamic equilibrium of H12 position.

Animals↗
PubMed1985

The effects of single doses of muzolimine upon urinary solute and fluid excretion.

The natriuretic effect of many loop diuretics is followed by an important decrease - rebound undershoot - in renal Na+ excretion, which is accompanied by thirst and fluid reposition. Also most loop diuretics increase K+ and Mg2+ urinary outputs, thus leading to somatic depletion of these cations and subsequent cardiac arrhythmias. The objectives of the present study were to describe the urinary outputs and flows of several solutes after various doses of muzolimine. Experiments were carried out in ten healthy adult volunteers given monodoses of placebo and of muzolimine 20, 30 and 40 mg on separate days and in random order. Urine collected at 3, 6, 9, 12 and 24 h after dosing was analysed for solutes. Muzolimine 20 mg did not increase mean 24 h urinary Na+ output significantly with respect to placebo. Muzolimine 30 mg exerted maximal diuretic, chloriuretic and natriuretic effects, while not affecting the mean 24 h urinary outputs of K+ and Mg2+ significantly. Muzolimine 30 mg caused a small undershoot in urinary Na+ flow after completion of its natriuretic effect. Muzolimine 30 mg should be considered a first choice loop diuretic since it only causes a mild post-natriuretic undershoot and does not increase urinary Mg2+ output significantly.

Adolescent↗
PubMed1985

Role of uptake in gamma-aminobutyric acid (GABA)-mediated responses in guinea pig hippocampal neurons.

Intracellular recordings were obtained from hippocampal pyramidal neurons maintained in vitro. Measurements were made of the conductance change induced by iontophoretically applied gamma-aminobutyric acid (GABA) and, using voltage-clamp techniques, of inhibitory postsynaptic currents resulting from activation of inhibitory pathways. Analysis of GABA iontophoretic charge-response curves indicated that there was considerable variation among neurons with respect to the slope of this relation. The placement of the GABA-containing pipette did not appear to be responsible for the observed variation, since vertical repositioning of the pipette did not alter the slope of the charge-response relationship. Steady iontophoresis of GABA from one barrel of a double-barreled pipette markedly affected the charge-response relation obtained when short pulses were applied to the other barrel. The curve was shifted to the left, and the slope was decreased. Concomitantly, the enhanced GABA-induced responses were prolonged. Similar alterations in GABA responsiveness were observed when the uptake blocker, nipecotic acid, was iontophoretically applied. Furthermore, bath application of saline containing a reduced sodium concentration (25% of control) also produced a prolongation of GABA-mediated responses. Under voltage clamp, inhibitory postsynaptic currents were observed to have biphasic decays. The initial, fast decay was prolonged by an average of 18% by nipecotic acid, whereas the later, slow phase was prolonged by 23%. The results of these studies support the hypothesis that a saturable GABA uptake system is responsible for the observed variation in the charge-response curves and, in turn, underlies the apparent sensitizing effect of excess GABA application. The results also suggest that a reduction of transmitter uptake affects the time course of inhibitory postsynaptic currents in the hippocampus.

Animals↗
PubMed1999

The hind paw edema produced by staphylococcal enterotoxin B in female mice is modulated by sex hormones.

This paper describes the involvement of sex hormones in the edematogenic response produced by staphylococcal enterotoxin B (SEB) in the mouse hindpaw. Both the paw weight variation and the protein exudate produced by the intraplantar administration of SEB (12.5 micrograms/paw) to intact, randomly cycling female (IRCF) mice were significantly attenuated when the animals were ovariectomized (OVX). The attenuation of SEB-induced paw swelling produced by OVX was not reversed by estradiol (OE2) reposition. Thus, 4 h after the injection of SEB the increase in paw weight in OVX-mice treated with OE2 (10 micrograms/kg in corn oil) was 15.0 +/- 0.9 mg, while the exudation corresponded to 2.1 +/- 0.3 micrograms of Evans blue dye/g of tissue. Neither of these values differed significantly from those obtained 4 h after the intraplantar injection of SEB (12.5 micrograms/paw) in non-treated OVX-mice (paw swelling, 14.0 +/- 0.8 mg; dye exudation, 2.0 +/- 0.3 micrograms/g, N = 6). Pretreating IRCF mice once a day for three days with human chorionic gonadotrophin (40 IU/kg, i.m.) reduced the paw edema produced by the toxin, thus indicating an involvement of gonadotrophins in this event. A pronounced decrease in paw weight variation (about 45%) and dye exudation (61%) was detected when IRCF mice were previously treated every 72 h with three injections of OE2 (10 micrograms/kg in corn oil, i.m.). Similar situations were also seen when the animals were pretreated at 72 h intervals with three injections of testosterone (10 mg/kg in corn oil, i.m.). We conclude that the paw edema induced by SEB in female mice is hormonally regulated. Our results also indicate that the HPA-immune axis is involved in this phenomenon.

Animals↗
PubMed2002

Dramatic 5'-residue effect on conformer distribution of short oligonucleotide retro models of the cisplatin-DNA cross-link: implications for the Lippard and cross-link distorted base pair steps present in cisplatin-DNA duplex adducts.

The cisplatin anticancer drug preferentially attacks the GG sequence of DNA duplexes. Virtually all DNAs containing the key G*G* lesion (G* = N7 platinated G) have large distortions in the cross-link (G*G*) base pair (bp) step and also in the adjacent Lippard (XG*) bp step, making the adducts very different from B-form DNA in the XG*G* region. The XG*G* strand in duplexes also differs in several ways from single-strand (ss) models with G*G* and XG*G* sequences. In the duplex, the X residue has an N sugar, the 5'-G* and 3'-G* bases have slight "R" canting (3'-G* H8 atom toward the 5'-G* base), and there is no or weak H-bonding by the NH3 ligands. In most XG*G* ss models, X has an S sugar, the 5'-G* base normally cants strongly toward the 3'-G* base (L canting), and the NH3 forms an H-bond. Well-defined ss models exist in the solid state, but dynamic motion obscures the properties of the ss models in solution. In this work, we employ retro models (better defined, less dynamic ss models) to understand the differences between duplex and ss models. The retro models in this study lack carrier ligand NH's, thus eliminating H-bonding. To correlate previous ss solid-state models with our solution work, we constructed hybrid molecules by overlaying parts of known structures. The combined model and experimental information indicates that the X N-pucker is not favorable in L-canted ss models, that X residue steric effects (not H-bonding) favor L canting in ss models, that X N-pucker is needed for favorable WC hydrogen bonding and stacking interactions in duplexes, and that X N-pucker minimizes X base clashes with bases in the complementary strand in duplexes. The R canting minimizing clashes between the X and G* residues of the Lippard bp step (independent of X pucker) and the repositioning of the X residue base caused by the change from S-pucker to N-pucker together lead to the unusual features of the Lippard bp step in the duplex.

Base Pairing↗
PubMed2001

Two-year outcomes of intrastromal corneal ring segments for the correction of myopia.

OBJECTIVE: To evaluate the safety and efficacy of Intrastromal Corneal Ring Segments (ICRS) for the correction of myopia. DESIGN: Nonrandomized, comparative trial. PARTICIPANTS: Patients enrolled in the United States Food and Drug Administration phase II and phase III clinical trials of the ICRS had best spectacle-corrected visual acuity (BSCVA) of 20/20 or better, myopia of -1.00 to -3.50 diopters (D), and a cylindrical correction of 1.00 D or less as measured by manifest refraction. INTERVENTION: Surgical correction of myopia with an ICRS. MAIN OUTCOME MEASURES: Efficacy was assessed by predictability of refractive outcome (deviation from predicted cycloplegic refraction spherical equivalent), stability of refractive effect, and postoperative uncorrected visual acuity. Safety was assessed by adverse events, maintenance or loss of preoperative BSCVA, and induced manifest refraction cylinder. RESULTS: Four hundred fifty-two patients were enrolled at 11 investigational sites in both studies. Of the 454 surgical attempts, 449 received an ICRS in one eye (0.25, 0.30, and 0.35 mm in 148, 151, and 150 eyes, respectively). First surgeries were attempted in 452 patients. An ICRS was successfully implanted in 447 initial eyes, and 5 surgeries were discontinued. Of the five discontinued surgeries, three patients subsequently exited from the study, and two patients went on to have the ICRS implanted in the second eye, bringing the total number of successful implants to 449 patient eyes. Month 24 postoperative follow-up was completed on 358 patients (80%). At month 24, 328 of 354 eyes (93%) were within +/-1.00 D of predicted refractive outcome. Refraction changed by 1 D or less in 97% of eyes (421/435) between 3 and 6 months after implantation and in 99% (343/348) between months 18 and 24. Before surgery, 87% of eyes (390/448) saw worse than 20/40 uncorrected; 24 months after surgery, 55% of eyes (196/358) saw 20/16 or better, 76% (271/358) saw 20/20 or better, and 97% (346/358) saw 20/40 or better. Although two eyes (2/358; 0.5%) lost two or more lines of BSCVA at 24 months; visual acuity in both was 20/20 or better. Intraoperative complications included anterior corneal surface perforation (three eyes) and anterior chamber perforations (two eyes, one during an attempted exchange procedure); all healed spontaneously without suturing and without loss of BSCVA. The ICRS was repositioned in five eyes to increase correction. Postoperative complications in one eye each were infectious keratitis, shallow segment placement, and loss of two lines of BSCVA at two or more consecutive examinations (subsequently regained). CONCLUSIONS: The ICRS safely, predictably, and effectively reduced or eliminated myopia of -1.00 to -3.50 D. The refractive effect was stable over time.

Adult↗
PubMed1982

Induction of dark-adaptive retinomotor movement (cell elongation) in teleost retinal cones by cyclic adenosine 3','5-monophosphate.

In the teleost retina, the photoreceptors and retinal pigment epithelium (RPE) undergo extensive movements (called retinomotor movements) in response to changes in light conditions and to an endogenous circadian rhythm. Photoreceptor movements serve to reposition the light-receptive outer segments and are effected by changes in inner segment length. Melanin granule movements within the RPE cells provide a movable melanin screen for rod outer segments. In the dark (night), cones elongate, rods contract, and pigment granules aggregate to the base of the RPE cell; in the light (day), these movements are reversed. We report here that treatments that elevate cytoplasmic cyclic adenosine 3',5'-monophosphate (cAMP) provoke retinomotor movements characteristic of nighttime dark adaptation, even in bright light at midday. To illustrate this response, we present a quantitative description of the effects of cyclic nucleotides on cone length in the green sunfish, Lepomis cyanellus. Cone elongation is induced when light-adapted retinas are exposed to exogenous cAMP analogues accompanied by phosphodiesterase (PDE) inhibitors (either by intraocular injection or in retinal organ culture). Cone movements is not affected by cyclic GMP analogies. Dose-response studies indicate that the extent, but not the rate, of cone elongation is proportional to the concentration of exogenous cAMP and analogue presented. As has been reported for other species, we find that levels of cAMP are significantly higher in dark- than in light-adapted green sunfish retinas. On the basis of these observations, we suggest that cAMP plays a role in the light and circadian regulation of teleost cone length.

Animals↗
PubMed2002

[Laser epithelial keratomileusis (LASEK): histological investigation for vitality of corneal epithelial cells after alcohol exposure].

BACKGROUND: Laser epithelial keratomileusis (LASEK) is a new surgical procedure to treat myopia. An epithelial flap is created after the exposure to 20 % alcohol and following the laser ablation the epithelium is repositioned to its original location. The advantage of LASEK is that the ablated corneal surface is covered by a full thickness epithelium immediately after surgery. It is hypothesised that this epithelial coverage inhibits the wound healing response of the cornea. However, this concept will only work if the epithelial cells are still vital after the exposure to alcohol. MATERIAL AND METHODS: The vitality of the corneal epithelial cells was investigated in 6 human cadaver eyes after the exposure to 20 % alcohol over 15 to 60 s. The vitality of the corneal epithelial cells was assessed by soaking the specimen in a 0.1 % trypan blue solution and incubated at 37 degrees C for 2 min. After a wash with BSS the specimen were re-incubated at 37 degrees C for 30 min in culture medium. After one more wash with BSS the cells were observed with a standard light microscope. Cells which retained the blue colour would be dead and vital cells would appear clear. Light microscopy and transmission electron microscopy was used to detect morphological changes. RESULTS: Mainly vital corneal epithelial cells were seen for an alcohol exposure time of up to 30 s. In particular the basal epithelial cells appeared alive. With a exposition time of 60 s most cells were dead. CONCLUSION: In LASEK the exposure time of 20 % alcohol is between 20 and 30 s. Based on our results we can conclude that after such exposure time most cells are alive, which is essential for the postoperative wound healing response.

Cell Count↗
PubMed1999

Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists, and residual agonist activity of antagonists, for glucocorticoid receptor-regulated gene expression.

A distinguishing, but unexplained, characteristic of steroid hormone action is the dose-response curve for the regulation of gene expression. We have previously reported that the dose-response curve for glucocorticoid induction of a transfected reporter gene in CV-1 and HeLa cells is repositioned in the presence of increasing concentrations of glucocorticoid receptors (GRs). This behavior is now shown to be independent of the reporter, promoter, or enhancer, consistent with our proposal that a transacting factor(s) was being titrated by added receptors. Candidate factors have been identified by the observation that changes in glucocorticoid induction parameters in CV-1 cells could be reproduced by varying the cellular levels of coactivators [transcriptional intermediary factor 2 (TIF2), steroid receptor coactivator 1 (SRC-1), and amplified in breast cancer 1 (AIB1)], comodulator [CREB-binding protein (CBP)], or corepressor [silencing mediator for retinoid and thyroid-hormone receptors (SMRT)] without concomitant increases in GR. Significantly, the effects of TIF2 and SMRT were mutually antagonistic. Similarly, additional SMRT could reverse the action of increased levels of GRs in HeLa cells, thus indicating that the effects of cofactors on transcription may be general for GR in a variety of cells. These data further indicate that GRs are yet an additional target of the corepressor SMRT. At the same time, these cofactors were found to be capable of regulating the level of residual agonist activity displayed by antiglucocorticoids. Finally, these observations suggest that a novel role for cofactors is to participate in processes that determine the dose-response curve, and partial agonist activity, of GR-steroid complexes. This new activity of cofactors is disconnected from their ability to increase or decrease GR transactivation. An equilibrium model is proposed in which the ratio of coactivator-corepressor bound to either receptor-agonist or -antagonist complexes regulates the final transcriptional properties.

Cell Line↗