Benedetto Ricci

Oxygen-induced retinopathy in the rat model.

Identification of a suitable animal model is essential for the continued study of retinopathy of prematurity (ROP). Since 1984 we have used the newborn rat for the study of oxygen-induced retinopathy (OIR). The rat retina is highly immature at birth. Like those of humans, the retinal vessels arise from mesenchymal precursors, but contrary to that which occurs in humans, canalization of the rats inner retinal vessels is not related to the presence of cystoid spaces. In addition, only immature Stage I photoreceptors are present around the optic disk at birth. This extreme immaturity makes the rat retina highly susceptible to direct damage from oxygen.Oxygen-induced retinopathy can be produced by exposing the newborn rat to 80% oxygen for the first 7–10 days of life. We have demonstrated that OIR does not develop when oxygen is administered under conditions of moderate hyperbarism (+ 1.8 atm). It is possible that hyperbarism exerts a protective effect on the immature retinal vessels by inducing a vasoconstrictive response which reduces the amount of oxygen transported from the choroid to the inner retina during hypoxia. I recently hypothesized that this vasoconstriction might also affect the ciliary body, thus reducing the quantity of aqueous produced, and we are currently studying the relationship between development of the immature retinal vessels in the rat and production and drainage of the aqueous. The question we are attempting to answer is whether a condition of relatively increased intraocular pressure is capable of promoting the development of OIR.

Effects of hyperbaric, normobaric and hypobaric oxygen supplementation on retinal vessels in newborn rats: a preliminary study

An experimental study was conducted on eight litters of newborn rats to evaluate the effects of supplemental oxygen administration on the retinal vasculature. The animals and their mothers were kept inside a pressure chamber and treated for the first 5 days of life. On the sixth day, they were removed and kept for five more days under room air and normobaric conditions. Three litters received continuous flow oxygen at 80% at a compression pressure of +81 kPa, one litter oxygen at 80% at a pressure of -39.5 kPa atms and three other litters received oxygen at 80% under normobaric conditions. The eighth litter was treated with room air oxygen at a compression pressure of +81 kPa. A severe retinopathy with marked retinal neovascularization was seen only in the newborn animals of the litters that received oxygen supplementation under normobaric or hypobaric conditions. Retinal vessels showed no pathological changes in the litters treated with hyperbaric normoxia or hyperoxia. It is possible to hypothesize that the prolonged period of oxygen supplementation failed to produce harmful effects on the retinal vasculature because the moderate hyperbarism caused mild retinal and choroidal vasoconstriction thus preventing excessive oxygen transport to the inner retina from the choroid during hyperoxia without inducing structural damage to the retinal tissue.

Scleral buckling surgery in stage 4 retinopathy of prematurity

Abstract• Background: Technical advances in neonatal intensive care have significantly increased the number of very low birth-weight babies that survive the perinatal period. Some of these infants develop severe retinopathy of prematurity that may lead to retinal detachment. • Methods: Between November 1988 and January 1994, 28 eyes from 15 preterm babies underwent scleral buckling for stage 4 retinopathy of prematurity at a mean age of 4.2 months. Cryotherapy was performed preoperatively on 12 eyes and intraoperatively in the remaining 16 eyes. The mean follow-up period was 35 months. • Results: Scleral buckling produced retinal reattachment in 13 eyes (46.4%). Severe myopia (−5 D to −15 D) was found in all 13 of these eyes; 12 also presented convergent strabismus. Mean visual acuity, measured in 6 eyes from children over the age of 3 years was 20/40. In 7/28 eyes of the younger children of this group we found a fix and follow the light capability. No light perception was detected in 11/28 eyes; in the remaining 4/28 eyes there was only light perception. Scleral buckling failed to prevent the progression to stage 5 in 15 eyes (53.6%). Additional surgery was excluded for 9 of these eyes based on ultrasonography findings; the other 6 eyes underwent vitrectomy, which led to macular reattachment in 4 cases. • Conclusions: Clinical experience shows that scleral buckling is not always capable of preventing progression of the disease to stage 5. Furthermore, even when the anatomic results of this procedure are good, the functional outcome is often complicated by severe visual impairment.

Refractive Errors and Ocular Motility Disorders in Preterm Babies with and without Retinopathy of Prematurity

Ocular motility, refraction and visual acuity (VA) were evaluated at the age of 4 years in 136 preterm infants with gestational ages (GAs) at birth of less than 32 weeks. Group 1 (non-retinopathy of prematurity, ROP) included 87 children that had never developed ROP. Group 2 contained 19 children whose ROP had regressed spontaneously. Group 3 (cryo-ROP) was composed of 30 patients who had undergone cryotherapy for severe ROP. Strabismus was found in 13.9% of the total population. χ2 analysis revealed that strabismus was significantly (p < 0.01) associated with prematurity (i.e. GA <29 weeks), ROP and cryotherapy. Myopia of more than 3 dpt was significantly (p < 0.001) more common in the cryo-ROP infants than in the regressed-ROP and non-ROP groups. The distribution of hypermetropia was similar in all three groups. VA was measured with the E chart. Of the 272 eyes examined, 251 (92.3%) displayed VA of more than 20/25. The majority of these eyes were from the non-ROP group (65.4%), 15.3% had regressed ROP and 21.1% belonged to the cryo-ROP group. Fifteen eyes (8 non-ROP, 3 regressed ROP and 4 cryo-ROP) presented VAs between 20/25 and 20/60. VA of less then 20/60 was found in 6 eyes (2 non-ROP, 1 regressed ROP, 3 cryo-ROP). Cryotherapy did not appear to preclude the development of good VA.

Intraocular pressure in premature babies in the first month of life

PURPOSE The purpose of this work was to study the values of intraocular pressure (IOP) in premature babies during the first month of life. METHODS Using a hand-held applanation tonometer, IOP was measured in 40 eyes of 20 preterm infants (gestational age ranging from 26 to 32 weeks) shortly after birth and at weekly intervals for the first month of life. RESULTS IOP values in preterm infants ranged from 7.6 to 18.3 mm Hg. The mean IOP decreased during the study period from 13.25+/-2.86 mm Hg to 10.96+/-2.01 mm Hg (P< .001). CONCLUSIONS Although the values of IOP found in this study are by no means within the range that is considered to be pathologic for newborns, the possible lack of the decreasing tendency of IOP observed during the first month of life could have, in a given case, some clinical implications. Because systemic blood pressure in preterm infants is already quite low, even a moderately elevated IOP during the first weeks of life might in some cases result in a significant reduction of the ocular perfusion pressure. The latter might play a contributory role in the development of retinopathy of prematurity by decreasing the blood supply to the peripheral retinal tissues.

Octyl 2-cyanoacrylate in sutureless surgery of extraocular muscles: an experimental study in the rabbit model.

Abstract Background: Sutureless surgery for strabismus eliminates the risk of perforating the ocular bulb in patients with extremely thin sclerae. Thus far, however, the results obtained with tissue adhesives such as the cyanoacrylates instead of sutures have been less than satisfactory. Methods: A new adhesive, octyl 2-cyanoacrylate, was tested in 36 rabbit eyes in which the superior rectus was recessed 5 mm. In 36 other eyes the same operation was performed using 5/0 Vicryl sutures. Animals were killed 1, 3, 5, 15, 30 and 45 days after surgery. One eye from each animal was used for histopathological examination of the reinserted muscle and sclera, while the other was used in a tensiometric test to measure how many grams of weight were needed to detach the muscle from its new insertion site. Results: The tensile strength of the bond achieved with the cyanoacrylate adhesive was 94±12 g 1 day after surgery (vs 238±19 g in the suture group) and 520±24 g after 45 days (vs 576±27 g with sutures). No cases of slippage, muscle detachment, or local tissue reactions were observed in either group. There were no differences in histological findings between the eyes of the two groups.Conclusions: Although further study will be necessary before this technique can be used in humans, our findings indicate that octyl 2-cyanoacrylate is superior to the cyanoacrylate adhesives used in the past in terms of adhesion and holding power; given its favorable toxicity profile, this product may offer interesting applications in the future.

Oxygen-Induced Retinopathy in the Newborn Rat: Morphological and Immunohistological Findings in Animals Treated with Topical Timolol Maleate

Oxygen-induced retinopathy (OIR) similar to that seen in premature infants can be produced in newborn rats by exposure to 80% oxygen for the first 5 days of life, with subsequent recovery for 7 days in a room air environment. Previous studies have shown that the latter phase is associated with degeneration of retinal astrocytes. In the absence of astrocytes, the vascular endothelial growth factor (VEGF) is produced by the neurons of the inner retina. In this study, immunohistochemical methods were used to assess retinal expression of VEGF protein in ratlings exposed to the above protocol, with and without simultaneous treatment with topical timolol maleate. Intraocular pressure (IOP) and arterial pressure were measured. The severity of OIR was also evaluated in retinal flat mounts after India ink perfusion. The mean IOP was 8.25 ± 0.32 mm Hg in untreated ratlings and 5.15 ± 0.24 mm Hg in timolol-treated animals. OIR in retinas from the timolol group was less severe than that seen in untreated ratlings. VEGF protein expression was almost completely absent in the latter group. Retinas from timolol-treated animals expressed VEGF protein, though the level was inferior to that found in controls raised under room air conditions. In conclusion, these data seem to indicate that experimental OIR can be attenuated by a reduction of the IOP during and after oxygen supplementation. It is possible that these effects are due to improved ocular perfusion pressure, which would mitigate the hypoxic insult to the retina during the room air recovery period.

Oxygen-induced retinopathy in the newborn rat: effects of hyperbarism and topical administration of timolol maleate

Abstract• Background: Lesions resembling those of human retinopathy of prematurity can be provoked in newborn Wistar rats by exposure to an FiO2 of 80% for the first 5 days of life followed by 5 days recovery under room-air conditions. • Methods: We evaluated the effects of moderate hyperbarism (+60.75 kPa, i.e. 455 mmHg or 0.6 atm) and topical administration of 0.25% timolol maleate on oxygen-induced retinopathy (OIR) in this experimental model. • Results: OIR (including neovascularization in most cases) was observed in 100% of the retinas of normobaric oxygen-reared ratlings that did not receive timolol. OIR was less frequent in oxygen-reared ratlings treated with hyperbarism (60%) or timolol (65%). Hyperbaric oxygen supplementation combined with timolol treatment during both the hyperoxic and room-air phases reduced the incidence of OIR to 30%. There was no sign of vasoproliferation in any of the retinas from the latter three groups. • Conclusions: The highly significant protective effects of hyperbarism and timolol observed in this study are not fully understood. We speculate that vasoconstriction induced by the hyperbarism reduces the amount of oxygen that reaches the retina from the choroid during O2 supplementation, while an increased ocular perfusion pressure caused by timolol-induced reduction of the intraocular pressure might decrease the stimulus to vasoproliferation that normally occurs with room-air recovery.

Effect of light on oxygen-induced retinopathy in the rat model

The purpose of this study was to establish whether exposure to intense lighting favors the development or aggravates experimental oxygen-induced retinopathy in the new-born rat. Five groups of Wistar rats were studied. The control group was maintained for the first 14 days of life under conditions of cyclical (12L∶12D) lighting at 12 Lx in room air. Two other groups were subjected, for the same amount of time, to semi-darkness (2 Lx; 12L∶12D), one with room air and the other with supplemental 80% oxygen. The final two groups were exposed to the same room air and hyperoxic treatments under intense lighting conditions (600 Lx; 12L∶12D).After the treatment period, four rats were randomly chosen from each group, sacrificed and their retinas examined under electron microscope. Marked structural changes were seen only in the photoreceptor outer segments of those rats exposed to intense light.In eighty-five of the remaining rats retinal vascular morphology was examined in retinal flat mounts after intracardiac injection of India ink. Retinopathy was observed in rats treated with hyperoxia but no significant differences could be attributed to the light conditions under which the retinopathic rats had been maintained.In the rest of the rats, axonal transport along the optical pathways was evaluated after intravitreal injection of (3H) taurine. In the two groups exposed to hyperoxia, axonal transport was altered, but less markedly in those exposed to intense lighting than in those exposed to semi-darnkess. Intense illumination under conditions of normoxia favors axonal transport. Exposure to intense lighting does not seem to aggravate oxygen induced retinopathy in the rat though it does produce structural lesions of the photoreceptors.

Matrix metalloproteinase 9 activity in patients before and after endovascular or surgical repair of abdominal aortic aneurysms

The objective of this prospective study was to assess matrix metalloproteinase 9 (MMP-9) activity in patients undergoing open surgery or endovascular repair of abdominal aortic aneurysms (AAAs), comparing changes in plasma levels in the two groups. We studied 12 patients after conventional open surgery and 9 patients after endovascular aneurysm repair. MMP-9 was assayed in plasma at baseline and 1 week and 1 month thereafter. Preoperative MMP-9 levels were similar in the two groups (41.7 +/- 19.1 vs 44.4 +/- 24.6 ng/mL; p = not significant). Assessment 1 week later showed that MMP levels in both repair groups had increased. In the open surgery group, they increased significantly (59.7 +/- 16.8 ng/mL; p < .05) but not in the endovascular group (49.3 +/- 32.4 ng/mL). One month later, MMP-9 levels decreased in both groups but not significantly (to 32.6 +/- 24.6 ng/mL for open surgery repair and to 34.7 +/- 23.5 ng/mL for endovascular repair). At 1 month after repair, MMP-9 levels decreased significantly only in smokers, whereas in nonsmokers, they did not (from 46.9 +/- 22.1 to 31.7 +/- 21.5 ng/mL in smokers [p < .05] vs from 34.7 +/- 17.4 to 37.1 +/- 28.9 ng/mL in nonsmokers). This study confirms that enzyme secretion changes during the postoperative course. The differing patterns of MMP-9 expression prevent us from reaching definitive conclusions about the use of MMP-9 as a marker during early postprocedural follow-up. An important matter to clarify is the role of MMP-9 in long-term follow-up, especially after endovascular AAA repairs.