Sherif El-Defrawy

Differential Effects of Scopolamine on Working and Reference Memory of Rats in the Radial Maze

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.

Effects of scopolamine and unilateral lesions of the basal forebrain on T-maze spatial discrimination and alternation in rats

Cholinergic systems are thought to play a role in memory. It has been suggested that cholinergic neurons, possibly the cortically projecting cells of the nucleus basalis magnocellularis, are differentially involved in working and reference memory. To evaluate this hypothesis the effects on memory of scopolamine (0, 0.3, 0.6 mg/kg) or unilateral kainic acid (4.7 nmoles in 1 microliter) lesions of the basal forebrain of rats were tested. Working memory, the recall of recent events of transient importance that is vulnerable to interference, was tested using a T-maze alternation task; reference memory, information stored over the long term that is relatively resistant to interference, was evaluated using a spatial discrimination task in the T-maze. The differential sensitivity of the two tasks to interference effects was confirmed by the finding that the insertion of a 30-sec delay between trials significantly reduced performance in the alternation but not the spatial discrimination task. Furthermore, scopolamine or the lesions significantly impaired alternation but not spatial discrimination performance. Biochemical assays of the kainate-injected brains confirmed that the cortical cholinergic marker, choline acetyltransferase, was significantly reduced. These results support the hypothesis that working and reference memory may be differentially controlled by cholinergic systems.

Effect of prophylactic nonsteroidal antiinflammatory drugs on cystoid macular edema assessed using optical coherence tomography quantification of total macular volume after cataract surgery

PURPOSE: To evaluate the efficacy of prophylactic administration of the topical nonsteroidal antiinflammatory drug (NSAID) ketorolac tromethamine 0.5% on acute (within 4 weeks of surgery) cystoid macular edema (CME) and total macular volume (TMV) in patients having phacoemulsification cataract surgery. SETTING: Department of Ophthalmology, Queens University, Hotel Dieu Hospital, Kingston, Ontario, Canada. METHODS: This open‐label nonmasked randomized (random number assignment) study comprised 106 eyes of 98 patients. Exclusion criteria included hypersensitivity to the NSAID drug class, aspirin/NSAID‐induced asthma, and pregnancy in the third trimester. Ketorolac tromethamine 0.5% was administered starting 2 days before surgery and for 29 days after surgery for a total of 31 days. The outcome measure was macular swelling, which was quantified by the optical coherence tomography. RESULTS: At 1 month, there was a statistically significant difference in TMV between the control group (0.4420 mm3) and the ketorolac group (0.2392 mm3), with the ketorolac group having 45.8% less macular swelling (P = .009). Multiple linear regression with backward selection indicated a 44.3% (P = .013) and 46.1% (P = .030) reduction in macular swelling in the ketorolac group at 1 week and 1 month, respectively. CONCLUSION: Used prophylactically after cataract surgery, ketorolac 0.5% was efficacious in decreasing postoperative macular edema.

Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical 3H-acetylcholine (3H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of 3H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of 3H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. The results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimers type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm.(ABSTRACT TRUNCATED AT 250 WORDS)

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and 3H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by co-injecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimers disease.

Lack of recovery of cortical cholinergic function following quinolinic or ibotenic acid injections into the nucleus basalis magnocellularis in rats

Abstract Cortical cholinergic markers fail to recover following injection of quinolinic or ibotenic acid into the rat nucleus basalis magnocellularis.

Prophylactic nepafenac and ketorolac versus placebo in preventing postoperative macular edema after uneventful phacoemulsification

Purpose To evaluate the efficacy of prophylactic ketorolac 0.5% versus nepafenac 0.1% versus placebo on macular volume 1 month after uneventful phacoemulsification and evaluate the health‐related quality‐of‐life (HRQOL) of topical nonsteroidal antiinflammatory drugs (NSAIDs) in the context of cataract surgery. Setting Hotel Dieu Hospital, Kingston, Ontario, Canada. Design Prospective placebo‐controlled parallel‐assignment double‐masked randomized clinical trial. Methods In this study, patients 18 years or older scheduled for routine phacoemulsification were randomized to a placebo, ketorolac 0.5%, or nepafenac 0.1% and dosed 4 times a day starting 1 day before surgery and continuing for 4 weeks. Spectral‐domain macular cube ocular coherence tomography scans measuring central subfield thickness, macular cube volume, and average macular cube thickness were performed at baseline and 1 month postoperatively. The HRQOL metrics were determined with the Comparison of Ophthalmic Medications for Tolerability (COMTOL) questionnaire. Results Each study group comprised 54 patients. One month postoperatively, although a trend toward significance occurred for nepafenac and ketorolac, analysis of the means of differences showed no statistically significant differences between the 3 study groups (P=.2901). The COMTOL analysis found no difference in tolerability, compliance, side‐effect frequency and bother, and effects on HRQOL between ketorolac and nepafenac compared with the placebo. Conclusions One month after uneventful phacoemulsification, there was no difference in macular volume between the placebo, ketorolac, and nepafenac. Ketorolac and nepafenac were well tolerated with minimal side‐effect profiles. Thus, for patients without risk factors having routine surgery, prophylactic topical NSAIDs are not recommended. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Subspecialization in Glaucoma Surgery

PURPOSE To evaluate trends in glaucoma surgery subspecialization. DESIGN Population-based analysis of incisional glaucoma surgery and laser trabeculoplasty practice patterns among all ophthalmologists in Ontario, Canada, from 1995 through 2010. PARTICIPANTS All ophthalmologists in Ontario, Canada, providing universal health care for the provincial population of approximately 12 million. METHODS The province of Ontario provides government-funded universal health care insurance to all citizens through the Ontario Health Insurance Plan (OHIP). Anonymized physician services data were obtained from the OHIP database, which has excellent accuracy for procedure performance. MAIN OUTCOME MEASURES Proportion of ophthalmologists providing incisional glaucoma surgery and laser trabeculoplasty and the distribution of these surgical and laser procedures among ophthalmologists. RESULTS Between 1995 and 2010, the median number of ophthalmologists in Ontario was 427 (35.1 per 1 million population), ranging from 417 to 453 (32.9-40.3 per 1 million population). The percentage of ophthalmologists providing incisional glaucoma surgery dropped from 35% in 1995 to 19% in 2010, a 47% decline. Over the same period, the mean number of incisional glaucoma surgeries performed per surgeon doubled, and the percentage of incisional glaucoma operations provided by high-volume surgeons rose from 23% to 59%. The percentage of ophthalmologists performing laser trabeculoplasty was relatively stable (48% in 1995 to 50% in 2010). CONCLUSIONS Over the past 16 years, the proportion of ophthalmologists providing incisional glaucoma surgery has declined significantly. At the same time, the proportion of incisional glaucoma surgery provided by high-volume glaucoma surgeons has more than doubled. These trends will have important implications for stakeholders from policy makers and hospitals to academic departments and residency education programs.

Kynurenic acid-induced protection of neurochemical and behavioural deficits produced by quinolinic acid injections into the nucleus basalis of rats

Injection of the endogenous tryptophan metabolite, quinolinic acid (120 nmol in 1.0 microliter) unilaterally into the basal forebrain of rats resulted in a significant ipsilateral decrease in cortical choline acetyltransferase activity, suggesting that cholinergic cells of the nucleus basalis magnocellularis (nbm) were damaged. Injected animals also showed a significant deficit in performance on an 8-arm radial maze, compared to sham operated controls, indicating an impairment of memory. Co-injection of another endogenous tryptophan metabolite, kynurenic acid (360 nmol in 1.0 microliter) with quinolinic acid afforded an almost complete protection against the neurotoxic and memory-impairing effects of quinolinic acid alone. These findings support previous reports that kynurenic acid can protect against the neurotoxic effects of quinolinic acid and indicate for the first time that kynurenic acid can also protect against impairments of memory produced by injection of quinolinic acid into the nbm.

Comparison of retinal nerve fibre layer measurements from time domain and spectral domain optical coherence tomography systems

OBJECTIVE To compare retinal nerve fibre layer (RNFL) thickness measurements acquired using spectral domain (SD) and time domain (TD) optical coherence tomography (OCT) systems. STUDY DESIGN Prospective clinical study. PARTICIPANTS Twenty eyes of 20 healthy volunteers. METHODS All patients underwent 3 sets of circular OCT scans around the optic disc using both a TD OCT system, and a new SD OCT system. RNFL thickness measures within each of 4 quadrants, as well as overall mean RNFL thickness, were compared. Bland-Altman plots were also used to assess agreement. RESULTS Using the RTVue-100, RNFL measurements in the superior quadrant were, on average, 20 microm greater than those obtained from the Stratus (151.8 microm vs 131.7 microm, p< 0.0001). RNFL measures within other quadrants and overall mean RNFL thickness were not significantly different between systems. Bland-Altman plots indicated large differences between Stratus and RTVue-100 for all variables, with 95% limits of agreement spanning clinically important ranges of >50 microm for all RNFL variables. CONCLUSIONS Significant differences exist between RNFL measurements obtained from the TD and SD OCT systems used in this study. These related, but distinct, technologies are not interchangeable. Further studies will be required to allow for appropriate clinical use of new SD OCT systems.