Eye drop technique and patient-reported problems in a real-world population of eye drop users.

OBJECTIVE: To assess eye drop technique and patient-reported problems with eye drop instillation in a primary care sample of eye drop users. METHODS: Cross-sectional observational study in 136 community pharmacies in Belgium. Patient inclusion criteria were being age ≥ 18 years and using eye drops for ≥ 1 month (to ensure that patients were already familiar with eye drop instillation). Participants demonstrated their eye drop technique and completed a self-administered questionnaire. RESULTS: Participants (n = 678) had a mean age of 68.9 ± 12.4 years. During the demonstration, almost everyone (98.0%) successfully instilled at least one drop in the eye, although 14% required multiple attempts to achieve this. Only 3% of the sample exhibited perfect drop technique, meaning that they performed correctly all the steps. Most common deviations were touching the bottle to the eye or eyelid (40.7% of patients), and failing to close the eye (67.8%) and perform nasolacrimal occlusion for at least 1 min (94.7%) after drop instillation. Importantly, we found that 20% of ophthalmic suspensions were not shaken before use. Forty percent of patients reported ≥ 1 problem with eye drop instillation. Most common problems were difficulties with getting a drop in the eye (18.3% of patients), too many drops coming out of the bottle (14.6%), and difficulty squeezing the bottle (12.2%). About half of the sample recalled having had education in eye drop instillation technique. CONCLUSION: This study showed suboptimal eye drop technique in real-world clinical practice. A proactive role of community pharmacists in detecting and resolving these problems could be helpful.

Insights into levator muscle dysfunction in a cohort of patients with molecularly confirmed blepharophimosis-ptosis-epicanthus inversus syndrome using high-resolution imaging, anatomic examination, and histopathologic examination.

OBJECTIVE: To study the basis of defective levator palpebrae superioris (LPS) function in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an autosomal dominant eyelid malformation sometimes associated with ovarian dysfunction. METHODS: Eight patients with molecularly proved BPES underwent high-resolution surface-coil 3-T magnetic resonance imaging before surgical intervention. The features of LPS muscle and adjoining connective tissue were compared with an age-matched control subject. During LPS resection for ptosis repair, detailed anatomic examination of the LPS was performed. Histopathologic characteristics were compared with normal control samples from a cadaver and a patient with simple severe congenital ptosis. RESULTS: The most striking feature shown on magnetic resonance imaging was the thin, long anterior part of the LPS. During the operation, this consisted of a disorganized, thin, long aponeurosis. However, in the posterior part of the LPS, there was an organized thick structure suggestive of a muscle belly. Histopathologic examination revealed posteriorly well-formed striated muscle fibers in all patients with BPES but not in the control sample from the patient with simple severe congenital ptosis. These striated muscle fibers were comparable to those of the normal control tissue but were more intermixed with collagenous tissue and little fatty degeneration. CONCLUSIONS: The presence of striated muscle fibers in LPS of patients with BPES contrasts with the fatty degeneration in patients with simple severe congenital ptosis. To our knowledge, this is the first study providing novel insights into the pathogenesis of the eyelid malformation in BPES through extensive imaging, anatomic study, and histopathologic testing in a unique cohort of patients with molecularly proved BPES.

Restrictive extraocular myopathy: a presenting feature of acromegaly.

A 45-year-old man presented with binocular diplopia in primary gaze for 1 year. Orthoptic evaluation showed 10-prism diopter right eye hypotropia and 6-prism diopter right eye esotropia. The elevation and abduction of the right eye were mechanically restricted. This was associated with systemic features suggestive of acromegaly. Magnetic resonance imaging (MRI) of the brain demonstrated a pituitary macroadenoma. An elevated serum insulin-like growth factor I level and the failure of growth hormone suppression after an oral glucose load biochemically confirmed the diagnosis of acromegaly. Computed tomography (CT) of the orbit demonstrated bilateral symmetrical enlargement of the medial rectus and inferior rectus muscle bellies. All tests regarding Graves-Basedow disease were negative. Although rare, diplopia due to a restrictive extraocular myopathy could be the presenting symptom of acromegaly.

Increased levator muscle function by supramaximal resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

OBJECTIVE: To study the efficacy and clinical and anatomical results of supramaximal levator resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) with severe congenital ptosis with poor levator function (LF). METHODS: Eleven patients with molecularly proven BPES underwent supramaximal levator resection. Palpebral fissure height and LF were measured preoperatively and postoperatively. RESULTS: All patients showed an excellent reduction in ptosis with a single intervention resulting in a clear visual axis. Palpebral fissure height improved from mean (SD) 3.3 (0.7) mm preoperatively to 7.1 (0.9) mm postoperatively (P value <.001). Four patients underwent additional surgery because of cosmetic issues with eyelid height asymmetry. All patients showed a marked, consistent, and lasting improvement in LF, going from mean (SD) 1.9 (0.9) mm preoperatively to 7.4 (1.1) mm postoperatively (P value <.001). This improvement could be attributed to the presence of a very long and thin tendon, as well as a striated muscle belly. This elongated aponeurosis inhibits the levator muscle from having sufficient impact on the vertical eyelid excursion. CONCLUSIONS: We demonstrated that supramaximal levator resection performed in patients with BPES not only results in good cosmetic appearance in terms of ptosis reduction in the majority of cases but also in a significant increase of the levator palpebrae superioris function. An anatomical substrate was found to explain these findings. To our knowledge, this is the first study to provide evidence of a marked increase in LF in BPES due to resection of the elongated tendon with reinsertion of the muscle belly.

Intravitreal injection of microplasmin for treatment of vitreomacular adhesion: results of a prospective, randomized, sham-controlled phase II trial (the MIVI-IIT trial).

PURPOSE: Vitreomacular adhesion causing vitreomacular traction is a common indication for vitrectomy. It may be avoided by using enzymatic vitreolysis. The MIVI-IIT (traction) study evaluated the ability of a single or repeated injection of microplasmin to release vitreomacular traction. METHODS: This randomized, double-masked, Phase II trial with control sham injection enrolled 60 patients. Patients in each of the 4 cohorts were randomized (4:1) to active treatment or sham injection. In the first 3 cohorts, increasing doses of microplasmin (75, 125, and 175 microg) were administered. In the fourth cohort, an initial injection of 125 microg microplasmin or sham was administered followed 1 month later by an injection of 125 microg microplasmin if no release of adhesion occurred. A third dose was injected 4 weeks later if there was still no release of adhesion. RESULTS: Within 28 days of sham, 75, 125, and 175 microg microplasmin administration, nonsurgical resolution of vitreomacular adhesion was observed in 8, 25, 44, and 27% of the patients, respectively. When the 125 microg dose was repeated up to 3 times, adhesion release was observed in 58% of patients 28 days after the final injection. CONCLUSION: These results provide support for the potential of microplasmin as a nonsurgical treatment for vitreomacular adhesion.

Adenosine enhances the relaxing influence of retinal tissue.

Retinal tissue from different species continuously releases an as yet unidentified retinal relaxing factor (RRF) lowering tone of isolated arteries. The potential influence of adenosine on this relaxing influence was investigated using isometric tension recording of different isolated arteries. The presence of bovine retinal tissue or rat retinal tissue enhanced the vasorelaxing effect of adenosine on isolated bovine retinal artery. In isolated rat carotid artery adenosine elicited no relaxation. However, a small relaxation is observed in the presence of rat retinal tissue, but not in the presence of porcine retina. The fact that adenosine potentiates the effect of rat retinal tissue but not that of a similar piece of porcine retinal tissue indicates species differences. Neither a NO-synthase inhibitor (nitro-L-arginine, 0.1mM), a cyclooxygenase inhibitor (indomethacin, 10 microM) or an epoxygenase inhibitor (miconazole, 10 microM) influenced the enhanced vasodilating effect of adenosine on bovine retinal arteries in the presence of bovine retinal tissue. On the other hand, when the retinal arteries were contracted with 120 mM K(+), adenosine no longer induced relaxation of the preparation with bovine retinal tissue. This is in line with the concept that adenosine enhances the influence of RRF. Also, the fact that rat carotid artery is less sensitive to RRF than bovine retinal artery - corresponding with a less enhanced adenosine response in rat carotid artery - is in line with the potential involvement of the RRF in the enhanced adenosine response. However, experiments using a bioassay setup for RRF gave no evidence for an increased RRF-release from the retina, nor for an increased RRF-sensitivity of the retinal artery in the presence of adenosine. In conclusion, our findings indicate that adenosine potentiates the relaxing influence of bovine and rat retinal tissue. This effect is species dependent as it is not seen with porcine retinal tissue. Neither NO, cyclooxygenase metabolites or epoxyeicosatrienoic acids seem to be involved in this enhanced vasorelaxing response. The involvement of the RRF cannot be excluded.

Stereo vision enhances the learning of a catching skill.

The aim of this study was to investigate the contribution of stereo vision to the acquisition of a natural interception task. Poor catchers with good (N = 8; Stereo+) and weak (N = 6; Stereo-) stereo vision participated in an intensive training program spread over 2 weeks, during which they caught over 1,400 tennis balls in a pre-post-retention design. While the Stereo+ group improved from a catching percentage of 18% to 59%, catchers in the Stereo- group did not significantly improve (from 10 to 31%), this progress being indifferent from a control group (N = 9) that did not practice at all. These results indicate that the development and use of of compensatory cues for depth perception in people with weak stereopsis is insufficient to successfully deal with interceptions under high temporal constraints, and that this disadvantage cannot be fully attenuated by specific and intensive training.

The endothelium-derived hyperpolarising factor (EDHF) in isolated bovine choroidal arteries.

The present study reports of an endothelium-dependent and NO- and prostanoid-independent relaxation in isolated choroidal arteries, and evaluates the hypothesis of an endothelium-derived hyperpolarising factor (EDHF) playing a role in the choroidal circulation. Choroidal arteries were isolated from bovine eyes and mounted in a small vessel wire-myograph for isometric tension recording. Concentration-response curves for acetylcholine (0.1nM-10microM) were constructed in isolated choroidal arteries contracted with 10microM norepinephrine. Acetylcholine induced a concentration-dependent relaxation in the choroidal arteries. The presence of the NO-synthase inhibitor L-NA and the cyclo-oxygenase inhibitor indomethacin only had a limited effect on this relaxation. All further experiments were performed in the presence of L-NA and indomethacin, in order to study the NO- and prostanoid-independent part of the acetylcholine-relaxations. Both removal of the vascular endothelium or the presence of an increased K(+) concentration in the organ bath abolished the NO- and prostanoid-independent part of the acetylcholine-relaxations. The presence of TEA, a rather non-specific K(+) channel blocker, significantly reduced the acetylcholine-relaxations. Simultaneous application of apamin (an inhibitor of small-conductance Ca(2+)-activated K(+) channels) and charybdotoxin (an inhibitor of intermediate- and large-conductance Ca(2+)-activated K(+) channels) abolished the acetylcholine-induced relaxation and even resulted in a concentration-dependent contraction. Transmembrane potential recordings in isolated choroidal arteries revealed a clear membrane hyperpolarisation in the vascular smooth muscle cells of isolated choroidal arteries. It was therefore concluded that the acetylcholine-induced relaxation of choroidal arteries in the presence of NO-synthase and cyclo-oxygenase inhibitors is mediated by an endothelium-derived hyperpolarising factor. This EDHF seems to be of more importance than endothelium-derived NO or prostanoids.

Control of retinal arterial tone by a paracrine retinal relaxing factor.

Retinal blood flow is regulated by local factors. In vitro bioassay experiments give evidence that retinal tissue from different species (dogs, pigs, sheep, cows, rats, and mice) continuously releases a factor lowering tone of isolated retinal arteries. This factor is a general relaxant as it was effective in relaxing different types of vascular as well as nonvascular smooth muscle preparations. This factor is called the retinal relaxing factor (RRF) and its characteristics do not correspond with those of the many well-known vasorelaxants found in retina (i.e., NO, prostanoids, adenosine, ADP, ATP, lactate, glutamate, GABA, taurine, adrenomedullin, CGRP, ANP, BNP, and CNP). This unknown RRF is transferable, hydrophilic, and heat-stable. Its relaxing effect is independent of the presence of the vascular endothelium and of NO-synthase, adenylyl cyclase, guanylyl cyclase, and cyclooxygenase activity. RRF might have a role in hypoxic vasodilation in retinal arteries since hypoxia induces relaxation only when retinal tissue is present. Thus, the RRF pathway is sensitive to changes in oxygen tension and might be a sensitive mechanism for adjusting vascular diameter to retinal oxygen levels. Diminished RRF release might explain the decreased retinal circulation observed in disease with atrophic retina.

Clozapine directly relaxes bovine retinal arteries.

PURPOSE: It was suggested that clozapine might be helpful in the development of new antiglaucoma agents, as it combines lowering the intraocular pressure after topical instillation with vasodilation. This study aimed to evaluate and characterize the vasodilatory effect of clozapine in isolated bovine retinal arteries (BRAs). METHODS: Retinal arteries were isolated from bovine eyes and mounted in the organ bath of a small vessel myograph. RESULTS: Cumulative addition of clozapine (1 nM to 10 microM) caused a concentration-dependent relaxation of the BRAs. Removal of the endothelium, inhibition of nitric oxide synthase and of soluble guanylyl cyclase reduced the clozapine response, whereas cyclooxygenase inhibition had no influence. A Ca2+ channel activator, a 5-hydroxytryptamine receptor antagonist, and an adenosine receptor antagonist failed in affecting the clozapine-induced relaxations. CONCLUSIONS: Clozapine relaxes bovine retinal arteries. Endothelium-derived NO seems to be involved, whereas prostanoids, calcium entry blockade, 5-HT7 receptor stimulation, and adenosine receptor stimulation do not.

The vasorelaxing effect of CGRP and natriuretic peptides in isolated bovine retinal arteries.

PURPOSE: To study the vasorelaxing effect of calcitonin gene-related peptide (CGRP) and natriuretic peptides on isolated bovine retinal arteries (BRAs) and to evaluate the possibility of the unidentified retinal relaxing factor (RRF) being one of these peptides. METHODS: Retinal arteries were isolated from bovine eyes and mounted in a wire myograph for isometric tension recording. Concentration-response curves were generated by cumulative addition of the peptides to the organ bath. RESULTS: In BRAs, CGRP-induced relaxation was significantly reduced by removal of the endothelium or by application of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine (l-NA) or the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The nonselective K(+) channel blocker tetraethylammoniumchloride (TEA) and the voltage-dependent K(+) channel blocker 4-aminopyridine significantly reduced the CGRP response, whereas the Ca(2+) activated K(+) channel blockers apamin plus charybdotoxin, the inward rectifier K(+) channel blocker Ba(2+), and the adenosine triphosphate (ATP)-sensitive K(+) channel blocker glibenclamide had no effect. The CGRP receptor antagonist CGRP 8-37 caused a small, but not significant, rightward shift in the concentration-response curve for CGRP, whereas the AM-receptor antagonist AM 22-52 had no effect. The natriuretic peptides did not induce relaxation in isolated retinal arteries. CONCLUSIONS: Endothelium-derived NO, voltage-dependent K(+) channels, and possibly also CGRP(1) receptors are involved in the CGRP response in BRAs. The natriuretic peptides do not induce vasorelaxation in isolated BRAs. No evidence was found that CGRP or a natriuretic peptide is the as yet unidentified RRF.

Influence of adrenomedullin on tone of isolated bovine retinal arteries.

PURPOSE: To assess and characterize the vasorelaxing effect of adrenomedullin (AM) on isolated bovine retinal arteries (BRAs). METHODS: Retinal arteries were isolated from bovine eyes and mounted in a wire myograph for isometric tension recording. Concentration-response curves were generated by cumulative addition of AM (1 pM to 0.1 micro M) to the organ bath. RESULTS: AM caused a concentration-dependent relaxation of the BRAs. Removal of the endothelium of the BRAs, inhibition of nitric oxide synthase with -nitro-L-arginine (L-NA) or inhibition of soluble guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) significantly reduced the AM response. Cyclooxygenase inhibition with indomethacin or sodium diclofenac did not reduce, but rather increased, vasodilation. The AM-receptor antagonist AM 22-52 slightly, but significantly, reduced the AM response, whereas the CGRP-receptor antagonist CGRP 8-37 caused a more pronounced reduction. The adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (8-SPT) did not affect AM-induced vasorelaxation. Inhibition of several intracellular calcium ([Ca(2+)](i))-reducing mechanisms failed to block the relaxation induced by AM. Only inhibition of the plasma membrane Ca(2+)-adenosine triphosphatase (ATPase) with vanadate significantly attenuated the AM response. CONCLUSIONS: AM induces vasodilation in isolated bovine retinal arteries. Endothelium-derived NO and stimulation of CGRP- and AM-receptors appear to be involved in the AM response, whereas prostanoids and activation of adenosine receptors are not involved. Activation of Ca(2+)-extrusion by the plasma membrane Ca(2+)-ATPase may elicit the relaxation of BRAs in response to AM.

Rat retinal tissue releases a vasorelaxing factor.

PURPOSE: To investigate whether the retina of the rat exerts a vasodilatory influence by the release of a relaxing factor and to characterize the retinal relaxing factor (RRF). METHODS: The relaxing influence of the rat retina was investigated by placing the retina in close proximity with a precontracted isolated rat carotid artery ring segment, mounted for isometric tension measurements. RESULTS: Application of rat retina relaxed the artery in a reliable and reproducible way. The nitric oxide (NO)-synthase inhibitor N(omega)-nitro-L-arginine (L-NA), the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the removal of the endothelium of the artery all failed to affect the RRF response. The RRF response was not decreased; in contrast, it increased after treatment with a cyclooxygenase (COX) inhibitor (indomethacin or sodium diclofenac). Acute hypoxia largely enhanced retina-induced relaxation. Several potential mediators of hypoxia-induced vasodilation were excluded as candidates for the RRF or for mediating the enhanced response to RRF in hypoxia. Inhibition of the plasma membrane Ca(2+)-adenosine triphosphatase (ATPase) with vanadate significantly affected the RRF response. CONCLUSIONS: The release of an as yet unidentified relaxing factor(s) from the rat retina was demonstrated. Acute hypoxia profoundly enhances the RRF response. None of the known mediators of hypoxia-induced vasodilation nor NO, prostanoids, or endothelial factors mediate the RRF response. Activation of the plasma membrane Ca(2+)-ATPase seems to be involved in the RRF response.

A vasorelaxing factor is released from mouse retinal tissue.

The present study aimed to demonstrate the release of a retinal relaxing factor (RRF) from the retina of mice and to investigate the identity of the RRF. Ring segments of a mouse aorta were mounted in a small vessel myograph. The relaxing influence of mouse retinal tissue was assessed by placing a retina in close proximity to the precontracted aorta. This elicited reliable and reproducible relaxations in the aorta. Both the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine and the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one had no effect on the RRF response. Also the cyclooxygenase inhibitors indomethacin and sodium diclofenac failed to affect the retina-induced relaxations. Acute hypoxia largely enhanced retina-induced relaxations. It is concluded that mouse retinal tissue releases an RRF, that the mouse RRF response is not mediated by NO or prostanoids and that the mouse RRF response is profoundly influenced by hypoxia.