Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study).

PURPOSE: To determine the efficacy of intravitreal ranibizumab 2.0 mg in patients with recalcitrant neovascular age-related macular degeneration (AMD). METHODS: This single-masked, randomized, prospective, pilot study enrolled patients with subfoveal neovascular AMD. All study eyes had persistent subretinal (SRF) or intraretinal fluid (IRF) on spectral-domain optical coherence tomography (SD-OCT) <30 days following at least 6 monthly intravitreal injections of ranibizumab or bevacizumab. Patients were randomized 2 : 1 to receive either ranibizumab 2.0 or 0.5 mg. Following three-loading treatments 4-weeks apart, both groups were treated using a 'treat and extend' regimen guided by eye-tracked SD-OCT through month 12. The primary end point was the mean change in best-corrected visual acuity (BCVA) at month 6. RESULTS: Nine eyes of 9 patients (mean age ± SD, 82.0 ± 5.8 years) were enrolled. Seven eyes received ranibizumab 2.0 mg and two eyes received 0.5 mg. Owing to the small number of patients enrolled, no statistical comparison could be made between the two dosages. At month 6, the mean improvement in BCVA was +6.1 ± 3.7 (W=0, P<0.001) ETDRS letters and +2.0 ETDRS letters in the 2.0 and 0.5 mg groups, respectively. In the 2.0 mg group, there was a statistically significant decline in central foveal thickness, SRF and maximum pigment epithelial detachment height at 6 months compared with baseline. No adverse events were reported in either group. CONCLUSION: Ranibizumab 2.0 mg has the potential to maintain or improve BCVA in some patients with persistent or recurrent SRF or IRF secondary to neovascular AMD despite prior monthly intravitreal anti-vascular endothelial growth factor therapy with the standard dose.

Intraocular pressure control after Nd:YAG laser posterior capsulotomy in eyes with glaucoma.

BACKGROUND AND OBJECTIVES: To evaluate the long-term intraocular pressure (IOP) control of glaucomatous eyes following Nd:YAG laser capsulotomy. MATERIALS AND METHODS: We performed a retrospective study of 69 glaucoma patients who underwent an Nd:YAG laser posterior capsulotomy over a 3 year period, following cataract extraction or a combined cataract-glaucoma procedure. All patients had a minimum follow-up period of at least 6 months and a median follow-up period of 2 years. We assessed IOP control, number of glaucoma medications required and whether the patient needed additional glaucoma surgery following the capsulotomy. Based on these outcome measures, we strictly defined "disease progression" as one of the following: an IOP rise of at least 5 mm Hg on two consecutive visits, addition of one or more glaucoma medications and additional glaucoma surgery following the capsulotomy. We calculated Kaplan-Meier event rate curves for these eyes with "disease progression". RESULTS: The rate of "disease progression" was 11.6% at 4 months, 20.3% at 6 months, 38.1% at 12 months, 46.1% at 24 months, 52.1% at 36 months and 52.1% at 47 months following the capsulotomy. CONCLUSION: Gradual IOP elevation or a need for more aggressive therapy is common in glaucoma patients following Nd:YAG laser posterior capsulotomy. It is unclear whether this progression is related directly to the Nd:YAG laser procedure or whether it is an independent progression of the patient's glaucoma unrelated to the Nd:YAG laser procedure.

Release of endogenous amino acids, including homocysteic acid and cysteine sulphinic acid, from rat hippocampal slices evoked by electrical stimulation of Schaffer collateral-commissural fibres.

This study examined the release of endogenous amino acids from acute hippocampal slices, upon stimulation of the Schaffer collateral-commissural fibres. One-minute samples of superfusate were collected via a cannula placed over the CA1 stratum radiatum, and were analysed by reversed-phase high performance liquid chromatography. Evoked potentials were recorded to ascertain stimulation efficacy. Four minutes of continuous 50 Hz stimulation produced a tetrodotoxin-sensitive release of aspartate and glycine in the second minute of stimulation, as well as a tetrodotoxin-sensitive release of cysteine sulphinic acid, during stimulation and of homocysteic acid, following stimulation. Such 50 Hz stimulation also produced a tetrodotoxin-insensitive decrease in methionine levels, but no significant changes in any of the other 15 amino acids measured. Four minutes of continuous 1 Hz stimulation produced no changes in the levels of any of the amino acids measured, but four 600-ms trains of 100 Hz stimulation, which, unlike the 1 Hz stimulation, produced long-term potentiation, resulted in significant increases in levels of cysteine sulphinic acid and homocysteic acid, but not of any of the other amino acids measured. These results suggest that aspartate, glycine, homocysteic acid, and cysteine sulphinic acid play a role in synaptic transmission in the Schaffer collateral-commissural fibres, and that cysteine sulphinic acid and homocysteic acid may be released specifically by high-frequency stimulation.

The effects of serotonergic compounds on evoked responses in the dentate gyrus and CA1 region of the hippocampal formation of the rat.

The effects of serotonin (5-HT), the 5-HT1A receptor subtype agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT2 receptor subtype agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on electrophysiological responses in the dentate gyrus and area CA1 were examined in the in vitro hippocampal slice preparation. Superfusion of either serotonin or 8-OH-DPAT in the bath was found to inhibit population responses in a dose-dependent manner in both regions, with a greater effect in the CA1. The effects of 8-OH-DPAT in both regions were attenuated significantly by the serotonergic antagonist methysergide, as were the effects of 5-HT on the population spike in the CA1. The application of DOI did not produce statistically significant effects in either region. These findings support an inhibitory role for the 5-HT1A receptor in both area CA1 and the dentate gyrus.

Modulation of synaptic plasticity in the dentate gyrus of the rat by electrical stimulation of the median raphe nucleus.

The effects of median raphe nucleus (MRN) stimulation on the induction of long-term potentiation (LTP) was investigated in the dentate gyrus (DG) of urethane-anaesthetized rats. LTP of both DG population spike amplitude and population EPSP slope was induced when tetanic electrical stimulation (100 Hz, 1 s) of the perforant path (PP), at an intensity which did not produce significant LTP alone, was presented concurrently with tetanic stimulation of the MRN. Tetanic stimulation of either the PP alone or of the PP and MRN together did not affect the short-term enhancement of population spike amplitude produced by single stimuli to the MRN. These findings suggest that serotonergic afferents from brainstem raphe nuclei may modulate the induction of LTP in the dentate gyrus.

Increased population spike amplitude in the dentate gyrus following systemic administration of 5-hydroxytryptophan or 8-hydroxy-2-(di-n-propylamino)tetralin.

This study investigated the effects of the serotonin (5-HT)precursor 5-hydroxytryptophan (5-HTP) and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on population responses in the dentate gyrus evoked by perforant path stimulation. Intraperitoneal injections of either compound into urethane anesthetized rats produced a substantial increase in the amplitude of the population spike, without affecting the granular layer population EPSP. These data suggest that enhanced serotonergic tone facilitates synaptic transmission between the entorhinal cortex and dentate gyrus in vivo, and that this facilitation may be mediated by a 5-HT1A receptor.