Combined phacoemulsification and microinvasive glaucoma surgery in comparison to phacoemulsification alone for open angle glaucoma.

IMPORTANCE: Microinvasive glaucoma surgery (MIGS) combined with phacoemulsification is increasingly utilised in glaucoma management. OBJECTIVE: To describe the postoperative outcomes of phacoemulsification alone compared to combined phacoemulsification and iStent (Glaukos, San Clemente, CA) or Hydrus (Ivantis, Irvine, CA) for open angle glaucoma. METHODS: Retrospective single surgeon comparative case series in a private practice setting. A total of 297 eyes in 190 patients (M:F = 85:105) were included consecutively from March 2011 to June 2017 with the data analysed using linear mixed models. Main outcome measures were intraocular pressure (IOP) and number of medications. RESULTS: By 6 months, all groups showed a reduction in IOP, with the combined iStent group by 4.2 mm Hg and the combined Hydrus group by 4.5 mm Hg, and this trend was sustained with follow-up to two years. All groups also showed a reduction in number of medications, with the phacoemulsification alone cases by 0.3, the combined iStent group by 0.7 and the combined Hydrus group by 1.1 medications. Both the combined surgeries had sustained reduction of number of medications with follow-up to 2 years. Postoperative complications from MIGS device insertion were uncommon and all resolved by one month. CONCLUSIONS AND RELEVANCE: The combination of phacoemulsification and a MIGS device in open angle glaucoma patients reduced the intraocular pressure and the number of medications by the first postoperative month and had longer-term effects at 2 years follow-up. If the device is inserted without intraoperative complication, the rate of significant short-term risks are low.

Driver's side curtain air bag-related globe rupture.

A 35-year-old man presented after a high-speed motor vehicle accident and the driver's side curtain air bag causing blunt force trauma rupturing his right globe. The tangential force of the air bag resulted in an unusual arcuate horseshoe-shaped rupture through the lateral rectus insertion, causing avulsion of the muscle and tearing the sclera, with the apices of the tear extending anteriorly towards the limbus. Repair of the globe rupture was undertaken, and secondary vitrectomy revealed that the scleral tear had not involved the retina abutting the ora serrata. Silicone oil tamponade was used to fill the globe and the postoperative best corrected vision was 6/9. This is the first reported case of a ruptured globe caused by a side curtain air bag, resulting in a uniquely shaped arcuate scleral wound combined with lateral rectus avulsion, not associated with rhegmatogenous retinal damage, and is the first air bag-related globe rupture with scleral involvement to report a final best-corrected visual acuity better than 6/60.

Infectious crystalline keratopathy.

Infectious crystalline keratopathy was first reported by Gorovoy and colleagues in 1983 when they identified bacteria colonizing a cornea after a penetrating keratoplasty. Subsequent cases have elaborated on the organisms responsible and the management outcomes. Patients present with a white or gray branching opacity originating from an epithelial defect, commonly after a penetrating keratoplasty. Local immunosuppression contributes to the quiescent nature and the limited inflammatory response associated with infectious crystalline keratopathy. Diagnosis of the infective pathogens may be difficult, with a corneal scraping often being too superficial to obtain an adequate specimen. A biofilm is present that advantages microorganism survival, reduces antibiotic bioavailability, and inhibits diagnostic microbial detection. Treatment begins with topical antimicrobials, initially broad spectrum and then targeted to microorganism sensitivity. Adjunctive therapies to enhance the efficacy of treatment include disruption of the microorganism biofilm by laser, intrastromal antibiotics, and keratectomy. In recalcitrant cases, or where corneal scarring ensues, corneal transplantation is required.

Infectious crystalline keratopathy after Descemet’s stripping endothelial keratoplasty.

A 68-year-old woman presented with infectious crystalline keratopathy 4 months after she underwent a combined phacoemulsification and Descemet's stripping endothelial keratoplasty for Fuch's endothelial dystrophy in her left eye. After 5 months of topical moxifloxacin 1%, the infiltrate responded well but had not completely resolved, with the resulting endothelial failure requiring a penetrating keratoplasty 9 months after the initial operation. Microbiology identified Enterococcus faecalis with the histopathology demonstrating bacterial colonies within the graft interface. Postoperatively she developed endophthalmitis, needing vitrectomy and intravitreal antibiotics. The infection settled with no recurrence, with topical and oral antibiotics continued for 2 months. A sutured toric piggyback intraocular lens was performed 18 months postvitrectomy for graft astigmatism, achieving a best-corrected vision of 6/15.Infectious crystalline keratopathy can occur following Descemet's stripping endothelial keratoplasty, requiring long-term topical therapy and potentially leading to graft failure with the necessity for further keratoplasty.

Perseveration by NK1R-/- ('knockout') mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test.

The underlying cause(s) of abnormalities expressed by patients with attention deficit hyperactivity disorder (ADHD) have yet to be delineated. One factor that has been associated with increased vulnerability to ADHD is polymorphism(s) of TACR1, which is the human equivalent of the rodent NK1 (substance P-preferring) receptor gene (Nk1r). We have reported previously that genetically altered mice, lacking functional NK1R (NK1R-/-), express locomotor hyperactivity, which was blunted by the first-line treatment for ADHD, methylphenidate. Here, we compared the effects of this psychostimulant (3, 10 and 30 mg/kg, intraperitoneally) on the behaviour of NK1R-/- mice and their wild types in the 5-Choice Continuous Performance Test, which emulates procedures used to study attention and response control in ADHD patients. Methylphenidate increased total trials (a measure of 'productivity') completed by wild types, but not by NK1R-/- mice. Conversely, this drug reduced perseveration by NK1R-/- mice, but not by wild types. Other drug-induced changes in key behaviours were not genotype dependent, especially at the highest dose: for example, % omissions (an index of inattentiveness) was increased, whereas % false alarms and % premature responses (measures of impulsivity) declined in both genotypes, indicating reduced overall response. These findings are discussed in the context of the efficacy of methylphenidate in the treatment of ADHD. Moreover, they lead to several testable proposals. First, methylphenidate does not improve attention in a subgroup of ADHD patients with a functional deficit of TACR1. Second, these patients do not express excessive false alarms when compared with other groups of subjects, but they do express excessive perseveration, which would be ameliorated by methylphenidate.

Differences in the performance of NK1R-/- ('knockout') and wildtype mice in the 5­Choice Continuous Performance Test.

Mice lacking functional NK1 (substance P-preferring) receptors typically display excessive inattentiveness (omission errors) and impulsivity (premature responses) when compared with wildtypes in the 5-Choice Serial Reaction-Time Test (5-CSRTT). These abnormal behaviours are analogous to those seen in humans suffering from Attention Deficit Hyperactivity Disorder (ADHD). Here we used the 5-Choice Continuous­Performance Test (5C-CPT) to ascertain whether NK1R-/- mice also display excessive false alarms (an inappropriate response to a 'no-go' signal), which is another form of impulsive behaviour. NK1R-/- mice completed more trials than wildtypes, confirming their ability to learn and carry out the task. At the start of Stage 1 of training, but not subsequently, they also scored more premature responses than wildtypes. When the mice were tested for the first time, neither false alarms nor premature responses was higher in NK1R-/- mice than wildtypes but, as in the 5-CSRTT, the latter behaviour was strongly dependent on time of day. NK1R-/- mice expressed excessive perseveration during all stages of the 5C-CPT. This behaviour is thought to reflect compulsive checking, which is common in ADHD patients. These findings point to differences in the 5-CSRTT and 5C-CPT protocols that could be important for distinguishing why the cognitive performance and response control of NK1R-/- mice differs from their wildtypes. The results further lead to the prediction that ADHD patients with polymorphism of the TACR1 gene (the human equivalent of Nk1r) would express more perseveration, but not false alarms, in Continuous Performance Tests when compared with other groups of subjects.

The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene 'knockout' mice: sex differences and implications for the treatment of attention deficit hyperactivity disorder.

Mice lacking functional neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling attention deficit hyperactivity disorder (ADHD): locomotor hyperactivity, impulsivity and inattentiveness. The preferred ligand for NK1R, substance P, is metabolised by angiotensin converting enzyme (ACE), which forms part of the brain renin angiotensin system (BRAS). In view of evidence that the BRAS modulates locomotor activity and cognitive performance, we tested the effects of drugs that target the BRAS on these behaviours in NK1R-/- and wildtype mice. We first tested the effects of the ACE inhibitor, captopril, on locomotor activity. Because there are well-established sex differences in both ADHD and ACE activity, we compared the effects of captopril in both male and female mice. Locomotor hyperactivity was evident in male NK1R-/- mice, only, and this was abolished by treatment with captopril. By contrast, male wildtypes and females of both genotypes were unaffected by ACE inhibition. We then investigated the effects of angiotensin AT1 (losartan) and AT2 (PD 123319) receptor antagonists on the locomotor activity of male NK1R-/- and wildtype mice. Both antagonists increased the locomotor activity of NK1R-/- mice, but neither affected the wildtypes. Finally, we tested the effects of captopril on the performance of male NK1R-/- and wildtype mice in the 5-choice serial reaction-time task (5-CSRTT) and found that ACE inhibition prevented the impulsivity of NK1R-/- mice. These results indicate that certain behaviours, disrupted in ADHD, are influenced by an interaction between the BRAS and NK1R, and suggest that ACE inhibitors could provide a novel treatment for this disorder.

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice.

BACKGROUND: Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). METHODS: Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10mg/kg; LDEB: 1, 3 or 10mg/kg). RESULTS: Atomoxetine reduced the hyperactivity displayed by NK1R(-/-) mice in the LDEB at a dose (3mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10mg/kg) also reduced impulsivity in NK1R(-/-) mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. CONCLUSIONS: This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R(-/-) mice consolidates the validity of using NK1R(-/-) mice in research of the aetiology and treatment of ADHD.

The behavioural response of mice lacking NK1 receptors to guanfacine resembles its clinical profile in treatment of ADHD.

BACKGROUND AND PURPOSE: Mice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R-/- mice) display behavioural abnormalities resembling those in attention deficit hyperactivity disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviated the hyperactivity and impulsivity/inattention displayed by NK1R-/- mice in the light/dark exploration box (LDEB) and 5-choice serial reaction-time task (5-CSRTT), respectively. Following reports of co-morbid anxiety in ADHD, we also investigated effects of guanfacine on anxiety-like behaviour displayed by NK1R-/- and wild-type (WT) mice in the elevated plus maze (EPM). EXPERIMENTAL APPROACH: Mice were treated with guanfacine (0.1, 0.3 or 1.0 mg·kg(-1), i.p.), vehicle or no injection and tested in the 5-CSRTT or the LDEB. Only the lowest dose of guanfacine was used in the EPM assays. KEY RESULTS: In the 5-CSRTT, a low dose of guanfacine (0.1 mg·kg(-1)) increased attention in NK1R-/- mice, but not in WT mice. This dose did not affect the total number of trials completed, latencies to respond or locomotor activity in the LDEB. Impulsivity was decreased by the high dose (1.0 mg·kg(-1)) of guanfacine, but this was evident in both genotypes and is likely to be secondary to a generalized blunting of behaviour. Although the NK1R-/- mice displayed marked anxiety-like behaviour, guanfacine did not affect the behaviour of either genotype in the EPM. CONCLUSIONS AND IMPLICATIONS: This evidence that guanfacine improves attention at a dose that did not affect arousal or emotionality supports our proposal that NK1R-/- mice express an attention deficit resembling that of ADHD patients.