Kari Krootila

Calcitonin gene-related peptide (CGRP) immunoreactive sensory nerves in the human and guinea pig uvea and cornea

The presence of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the uvea and cornea of human and guinea pig eyes was evaluated using immunohistochemical techniques. CGRP immunoreactivity was found in thin, varicose nerve fibers in both species. Most of the fibres were localized in the ciliary body, and were mainly associated with blood vessels. In the human ciliary body, a moderate number of CGRP immunoreactive nerves were also seen in the ciliary muscle. In the iris and cornea, CGRP immunoreactive fibres were relatively uncommon. In the iris, they were mostly found associated with blood vessels, while in the cornea they were seen sub-epithelially or as free nerve endings in the epithelium. In the trigeminal ganglion, small sized ganglion cells displayed CGRP immunoreactivity. About 40% of all ganglion cells were immunoreactive nerves in the guinea pig, while sympathetic denervation did not change the staining pattern of CGRP immunoreactivity. The present findings, together with previous physiological data, suggest that CGRP might play a role in the regulation of the blood flow, aqueous humour dynamics, and neurogenic inflammation, not only in experimental animals but also in man.

Cost-utility of routine cataract surgery.

BackgroundIf decisions on health care spending are to be as rational and objective as possible, knowledge on cost-effectiveness of routine care is essential. Our aim, therefore, was to evaluate the cost-utility of routine cataract surgery in a real-world setting.MethodsProspective assessment of health-related quality of life (HRQoL) of patients undergoing cataract surgery. 219 patients (mean (SD) age 71 (11) years) entering cataract surgery (in 87 only first eye operated, in 73 both eyes operated, in 59 first eye had been operated earlier) filled in the 15D HRQoL questionnaire before and six months after operation. Direct hospital costs were obtained from a clinical patient administration database and cost-utility analysis performed from the perspective of the secondary care provider extrapolating benefits of surgery to the remaining statistical life-expectancy of the patients.ResultsMean (SD) utility score (on a 0–1 scale) increased statistically insignificantly from 0.82 (0.13) to 0.83 (0.14). Of the 15 dimensions of the HRQoL instrument, only seeing improved significantly after operation. Mean utility score improved statistically significantly only in patients reporting significant or major preoperative seeing problems. Of the subgroups, only those whose both eyes were operated during follow-up showed a statistically significant (p < 0.001) improvement. Cost per quality-adjusted life year (QALY) gained was €5128 for patients whose both eyes were operated and €8212 for patients with only one eye operated during the 6-month follow-up. In patients whose first eye had been operated earlier mean HRQoL deteriorated after surgery precluding the establishment of the cost per QALY.ConclusionMean utility gain after routine cataract surgery in a real-world setting was relatively small and confined mostly to patients whose both eyes were operated. The cost of cataract surgery per quality-adjusted life year gained was much higher than previously reported and associated with considerable uncertainty.

Effect of neurogenic irritation and calcitonin gene-related peptide (CGRP) on ocular blood flow in the rabbit

The effects of sensory nerve stimulation (topical neutral formaldehyde, 1%) and intracameral injection of calcitonin gene-related peptide (CGRP) on regional ocular blood flow, intraocular pressure (IOP), the blood-aqueous barrier, pupil size, and blood pressure were studied in the rabbit. Sensory nerve stimulation elicited a typical irritative response in the rabbit eye, with vasodilation in the ciliary body (from 128 +/- 31 to 363 +/- 105 mg/min, p less than 0.05) accompanied with a breakdown of the blood-aqueous barrier, rise in the IOP, and miosis. CGRP caused similar, but not identical, changes in the eye: vasodilation in the ciliary body (from 60 +/- 14 to 258 +/- 75 mg/min, p less than 0.05), breakdown of the blood-aqueous barrier and rise in the IOP, accompanied with systemic hypotension. Miosis was not observed after CGRP. In the present study, the vasodilatory action of CGRP on the rabbit eye has been shown. This makes our understanding of the mechanism of the ocular irritative response after sensory nerve stimulation more complete. Thus, CGRP through vasodilation disrupts the blood-aqueous barrier and raises the IOP. The more intense increase in the IOP after sensory nerve stimulation than after CGRP is probably caused by a CGRP-induced vasodilation and breakdown of the blood-aqueous barrier, enhanced by a miosis-induced pupillary block.

CGRP in relation to neurogenic inflammation and cAMP in the rabbit eye

The effects of topical application of neutral formaldehyde (1%) and intracameral administration of calcitonin gene-related peptide (CGRP, 0.5- or 2.0 micrograms) on the intraocular pressure (IOP), blood-aqueous barrier, pupil size, blood pressure and cyclic AMP (cAMP) content in the aqueous humour of a rabbit were studied. Topical chemical irritation with 1% formaldehyde caused a typical irritative response in the eye with a rise in the IOP, breakdown of the blood-aqueous barrier and miosis. The cAMP content in the aqueous humour was also increased (88.5 +/- 35.0 pmol ml-1, P less than 0.05) when compared with the control group (16.3 +/- 3.6 pmol ml-1). Intracameral administration of CGRP caused a rise in the IOP, breakdown of the blood-aqueous barrier and also systemic hypotension. Miosis was not observed after intracameral CGRP but an increase in the cAMP content in the aqueous humour was seen (130.5 +/- 30.3- and 158.7 +/- 48.1 pmol ml-1, both P less than 0.01, after 0.5 or 2.0 micrograms, respectively). The cAMP concentration in the aqueous humour after topical chemical irritation and intracameral CGRP correlated with the intensity of the breakdown of the blood-aqueous barrier. CGRP seems to cause most, but not all, of the ocular changes after sensory nerve stimulation elicited by topical neutral formaldehyde. Of these CGRP-induced changes, only the breakdown of the blood-aqueous barrier is related to an increase in the cAMP content in the aqueous humour. Contralateral responses after sensory nerve stimulation were similar to contralateral responses to intracameral CGRP.

Treatment of postoperative keratoplasty astigmatism using femtosecond laser-assisted intrastromal relaxing incisions.

PURPOSE To investigate the effectiveness of femtosecond laser-assisted intrastromal relaxing incisions for astigmatism management and establish laser treatment parameters. METHODS Sixteen eyes of 16 patients had regular astigmatism after penetrating keratoplasty. All sutures had been removed and the refraction was stabilized. Paired arcuate intrastromal incisions were made 180° apart within the graft stroma with a femtosecond laser preserving the epithelium. Follow-up examinations were performed at 1 week, 2 weeks, 1 month, and 3 months. RESULTS The logMAR corrected distance visual acuity (CDVA) improved from 0.50 ± 0.29 to 0.32 ± 0.23 (Snellen 20/63 to 20/40). Refractive and topographic anterior cylinders decreased from 6.8 ± 2.2 diopters (D) to 3.7 ± 1.7 D and from 9.5 ± 4.8 D to 4.4 ± 2.1 D, respectively. Stabilization of topographic cylinder was observed 1 month postoperatively. The worse the preoperative CDVA was and the higher the preoperative values for the refractive and topographic cylinders were, the higher the surgically induced changes were. Anterior side cut angles at 90° and 120° produced similar results. A bulge of incision occurred in one eye requiring compression sutures. CONCLUSIONS Significant improvement in CDVA and refractive and topographic cylinders indicated a good effect of femtosecond laser-assisted intrastromal relaxing incisions in reducing astigmatism. No advantage between 90° and 120° anterior side cut angles was found. No infections were recorded and no patient expressed discomfort.

Treatment of Pseudomonas aeruginosa keratitis with combined corneal cross-linking and human amniotic membrane transplantation

0.01) compared with vehicle treatment (14.13 ± 1.73%, n = 14, Fig. 1A, B). By contrast, the ratio of normal vascularized area is higher in the animals treated with VAP-1 inhibitor (94.69 ± 0.82%, n = 18, p < 0.01) than those treated with vehicle (83.56 ± 1.56%, n = 14, Fig. 1C), indicating that VAP-1 blockade did not affect physiological vascular development in OIR model. The present data demonstrated that VAP-1 blockade selectively prevents pathological retinal neovascularization without inhibiting physiological neovascularization. Previous data demonstrated that VAP-1 blockade attenuated the angiogenic response via suppression of recruitment of monocyte lineage cells (Noda et al. 2008; Nakao et al. 2011). As it has been elucidated that monocyte lineage cells are involved in the pathological neovascularization in OIR model (Ishida et al. 2003), it is likely that VAP-1 blockade attenuates the pathological neovascularization through suppression of macrophage recruitment. Interestingly, the current data also demonstrated that physiological neovascularization was not inhibited and rather increased in VAP-1 inhibitortreated group compared with vehicletreated group. It was reported that VAP-1 is expressed from embryonic day 14 in mouse retina, which may indicate that VAP-1 plays a role for vascularization during eye development (Valente et al. 2008). However, the current data showed that VAP-1 blockade did not suppress physiological neovascularization in OIR model and therefore suggested that the role of VAP-1 might not be identical in physiological and pathological angiogenesis. In the treatment of ROP, the therapeutic agents that suppress pathological, but not physiological, neovascularization are ideal. Further studies to evaluate the effect of VAP-1 blockade in OIR model are warranted.

Recovery of the blood-aqueous barrier after topical chemical irritation in the rabbit eye.

An acute irritative response in the rabbit eye, taking the form of a rise in the intraocular pressure (IOP), miosis, and breakdown of the blood-aqueous barrier, was elicited by topical application of 1% neutral formaldehyde. The peak rise in IOP was 22.1 ± 2.5 mmHg and occurred within 14.2 ± 1.9 min, after which IOP returned to normal values in 45.4 ± 5.2 min. An increased amount of i.v.-injected Evans Blue was found in the aqueous humour when injected 15 min after the irritation (119.0 ± 21.2 μg/ml, compared with 2.1 ± 1.4 μg/ml in intact eyes;P < 0.001), and the protein concentration in the aqueous humour was also increased, to 11.3 ±1.4 mg/ml (P < 0.001). When Evans Blue was injected 60 min after the irritation, no statistically significant difference was found from normal in the amounts (13.7 ± 7.8 μg/ml) in the aqueous humour, although the protein concentration in the aqueous humour was again found to be elevated (7.9 ± 1.6 mg/ml,P < 0.01). Histologically, the Evans Blue was shown to leak through both the ciliary and the iris barriers at 15 min. At 60 min only occasional Evans Blue leakage was demonstrated between the nonpigmented epithelial cells and only minor fluorescence was seen in iris stroma. The histological findings were in good agreement with Evans Blue analyses in the aqueous humour. The miosis lasted over 60 min in the formaldehyde-treated eyes. After sympathectomy the rise in IOP was more rapid at the beginning of the response, suggesting greater sensitivity of the sympathectomized eyes to the irritative stimuli. However, the miosis had recovered by 60 min after irritation in the sympathectomized eyes. In the contralateral eyes changes in IOP and in the integrity of the blood-aqueous barrier were observed. The present results suggest that the breakdown of the blood-aqueous barrier after sensory nerve stimulation is transient and recovery rapid.

Effect of α-adrenergic and serotonergic blockers on the acute irritative response in the rabbit eye

The effect of alpha-adrenergic and serotonergic (5-HT) blockers on the acute irritative response in the rabbit eye elicited by topical, neutral formaldehyde (1%), was studied. In the control animals, the peak rise in the intraocular pressure (delta IOP) after irritation was 29.5 +/- 5.7 mm Hg, and the perfusion pressure of the eye at 1 min after irritation was 50.1 +/- 2.8 mm Hg. The peak rise in the IOP was inhibited by phentolamine (alpha- and 5-HT-antagonist, delta IOP = 6.6 +/- 2.1 mm Hg, P less than 0.01), methysergide (5-HT-antagonist, delta IOP = 10.6 +/- 4.4 mm Hg, P less than 0.05), and prazosin (alpha 1-antagonist, delta IOP = 12.8 +/- 3.7 mm Hg, P less than 0.05). Perfusion pressures of the eyes were decreased after pretreatment with phentolamine or prazosin, and were 35.2 +/- 4.8 mm Hg (P less than 0.05) and 25.7 +/- 3.7 mm Hg (P less than 0.01), respectively. Perfusion pressure in the methysergide group remained unchanged (75.4 +/- 14.2 mm Hg). Yohimbine (alpha 2-antagonist) and ketanserin (5-HT2-antagonist) did not inhibit the IOP response. None of the antagonists could inhibit the miosis or disruption of the blood-aqueous barrier induced by topical neutral formaldehyde. In the contralateral eyes, the changes in the IOP, in the integrity of the blood-aqueous barrier, and also in the pupil size, were enhanced by ketanserin. The present study demonstrates the inhibitory actions of methysergide, phentolamine, and prazosin on the neurally mediated, acute irritative response in the rabbit eye. Methysergide seems to inhibit the response, probably acting via the 5-HT1-receptors. A part of the effect of phentolamine might be explained by an inhibitory action via 5-HT1-receptors. The effect of phentolamine and prazosin on the alpha 1-receptors seems to create an inhibitory action on the irritative response by lowering the perfusion pressure of the eye.

Mast cells in the anterior uvea of the rabbit. Intraocular effects of compound 48/80 in the rabbit

In the present study, the presence and localization of mast cells and the intraocular effects of compound 48/80 have been studied in detail in the rabbit eye using histochemical and physiological methods. In histochemical studies mast cells were localized in the anterior uvea, especially in the ciliary and iridial processes. Intracamerally injected, compound 48/80 caused an increase in the intraocular pressure, disruption of the blood-aqueous barrier and an increase in the cAMP content in the aqueous humour. Miosis was observed only after higher doses of compound 48/80 (greater than 100 micrograms) and even then only one-half of the eyes responded. The intraocular effects, excluding miosis, of compound 48/80 resembled an on/off-type of response, where 20 micrograms caused only minor changes, if any, and 50 micrograms gave a maximal response. The ocular hypertensive reaction developed a tachyphylaxis so that the second and third consecutive dose of compound 48/80 (100 micrograms) produced no significant change in IOP. The results indicate that mast cells, which are present in the anterior uvea in an extent not known previously, might be involved in certain inflammatory reactions in the rabbit eye. The inconsistent and slight miosis after the intracameral application of compound 48/80 indicates that the mechanism is different from that caused by sensory nerve stimulation. The rapid development of tachyphylaxis after consecutive application of compound 48/80 suggests that mast cells are easily depleted which might be useful for further studies to evaluate the functional role of mast cells in different pathophysiological conditions in the rabbit eye.

Penetrating Keratoplasty for Corneal Amyloidosis in Familial Amyloidosis, Finnish Type

PURPOSE To analyze the outcome of penetrating keratoplasty (PK) to the first eye for corneal amyloidosis in familial amyloidosis, Finnish type (FAF). DESIGN Single-center, retrospective, nonrandomized, interventional, noncomparative case series. PARTICIPANTS Thirty-one eyes of 31 patients with FAF. INTERVENTION All patients with FAF who had their first PK in Helsinki University Eye Hospital between January 1, 1990, and August 1, 2011, were identified and a retrospective analysis of the patient charts was performed. MAIN OUTCOME MEASURES Best spectacle-corrected visual acuity (BCVA), intraoperative and postoperative complications, graft survival, reason for graft failure, and frequency of regrafting. RESULTS The median follow-up period was 32 months (range, 5-114). After 24 months, the median BCVA was 1.15 on a logarithm of the minimum angle of resolution scale (20/280; mean, 1.1; SD, 0.5) in comparison with the preoperative median BCVA of 1.3 (20/400; mean, 1.3; SD, 0.4). At 24 months, 3 of 18 eyes (17%) had a visual acuity of ≥0.5 (20/63) and 13 of 18 grafts (72%) were clear. Rejection occurred in 6 of 31 primary grafts (19%). Graft failure occurred in 16 of 31 eyes and resulted from surface complications in 11 eyes and additionally from rejection in 5 eyes. Seven eyes needed regrafting (twice in 1 eye). Complications were frequent in the early and late postoperative periods. Presence of preoperative corneal or graft neovascularization was an indicator of a high risk of graft failure and poor visual outcome. CONCLUSIONS In a minority of FAF patients, PK improves vision. Owing to the high failure risk and guarded visual prognosis after PK, it is important that both the surgeon and the patient have realistic expectations. It may be reasonable to limit PK to cases with bilateral advanced disease. It seems reasonable to optimize ocular surface health and to delay PK.