Medications for attention deficit hyperactivity disorder associated with increased risk of developing glaucoma.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) therapies including atomoxetine, methylphenidate, and amphetamines are some of the most prescribed medications in North America. Due to their sympathomimetic action, these drugs are contraindicated in patients with a history of angle closure glaucoma (ACG). This study aims to determine the risk of ACG and open angle glaucoma (OAG) among users of these treatments. METHODS: This is a retrospective cohort study with a case control analysis using the PharMetrics Plus Database (IQVIA, USA). We created a cohort of new users of atomoxetine, methylphenidate, and amphetamines and they were followed to the first diagnosis of (1) ACG or OAG; or (2) end of follow up. For each case, four age-matched controls were selected. A conditional logistic regression model was used to adjust for confounders and to calculate adjusted incidence-rate-ratios (aIRRs). RESULTS: A total of 240,257 new users of the ADHD medications were identified. The mean age was 45.0 ± 19.4 years and 55% of the cohort was female. Regular users of atomoxetine and amphetamines had a higher aIRR for developing ACG compared with non-users (aIRR = 2.55 95% CI [1.20-5.43] and 2.27 95% CI [1.42-3.63], respectively); while users of methylphenidate had a higher aIRR for developing OAG (aIRR = 1.23 95% CI [1.05-1.59]). CONCLUSIONS: Use of amphetamines and atomoxetine had a higher risk for ACG, while use of methylphenidate was associated with a higher risk for OAG. Given the prevalence of ADHD medication use (medically and recreationally), our current data on their associated risk of glaucoma have profound public health implications.

Facial Swelling After External Dacryocystorhinostomy.

A 67-year-old woman underwent elective external dacryocystorhinostomy to treat symptomatic nasolacrimal duct obstruction and developed persistent cervicofacial swelling and ecchymoses of the eyelids and cheek. Head computed tomography revealed extensive emphysema throughout the soft tissues of the face and neck. What would you do next?

PreserFlo Microshunt for the management of intraocular pressure elevation in iridocorneal endothelial syndrome.

Purpose: To report on a case of angle-closure glaucoma secondary to iridocorneal endothelial (ICE) syndrome effectively managed with the PreserFlo Microshunt. Observations: We report successful implantation of a PreserFlo Microshunt in a 57-year-old patient with secondary angle-closure glaucoma in the context of ICE syndrome. Following failure of medical therapy to adequately control intraocular pressure (IOP), the patient was consented for surgical intervention and underwent combined cataract surgery and PreserFlo Microshunt implantation. IOP at the last post-operative follow-up (5 months) was 12 mmHg with the patient on brinzolamide/timolol maleate (Azarga®). We report no complications in the post-operative period. Conclusions and importance: The PreserFlo Microshunt may be a promising option for patients with ICE syndrome who fail medical therapy. Implantation of this device was well tolerated in the presented case.

Analysis of deep optic nerve head structures with spectral domain and swept-source optical coherence tomography.

PURPOSE: Histological evidence indicates that the earliest structural changes to the optic nerve head (ONH) in glaucoma occur in the lamina cribrosa (LC) and its interface with the sclera. However, clinical imaging of these structures remains challenging. We compared the visibility of deep ONH structures with newer iterations of spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT). METHODS: Twelve patients with open-angle glaucoma were imaged with SD-OCT with 24 radial B-scans centred on Bruch's membrane opening (BMO) and SS-OCT with a horizontal and vertical raster scan pattern containing five lines each, centred on the ONH. Single best-matched horizontal and vertical scans from the two modalities were selected and exported. Three independent observers masked to modality determined if BMO, posterior choroid surface, anterior scleral canal opening and anterior and posterior LC insertions into the sclera were detectable in the matched B-scan images. We determined the interobserver agreement and concordance in detecting each structure with the two OCT imaging modalities. RESULTS: There was a high interobserver agreement with both SS-OCT and SD-OCT (inter-item correlations: 0.81-0.93 and 0.77-0.82, respectively). There was a consistent tendency for higher overall detection rates with SS-OCT, however, the differences failed to reach statistical significance. With respect to individual structures, only the posterior LC insertion in the nasal quadrant was statistically different, with a detection rate of 13 and 6 (pooled out of a total of 36 across the three observers) with SS-OCT and SD-OCT, respectively (p=0.04). CONCLUSION: Overall, both SS-OCT and SD-OCT showed statistically equivalent visualisation of ONH structures, however, SS-OCT tended to have higher visualisation rates.

Isolated bilateral congenital lacrimal gland agenesis-a case series.

We report 2 pediatric cases of isolated bilateral congenital lacrimal gland agenesis (CLGA). Patient 1 (1 year of age) and patient 2 (2 years of age) presented with symptoms of alacrimia and were diagnosed with bilateral isolated CLGA based on magnetic resonance imaging. Both patients were otherwise healthy, with no systemic associations. Molecular analysis for genetic causes of CLGA were negative. Both have been successfully medically managed.

Epidemiology of invasive ocular surface squamous neoplasia in Canada during 1992-2010.

BACKGROUND: Ocular surface squamous neoplasia (OSSN) is the most common non-pigmented ocular surface malignancy. It is classified as invasive OSNN (IOSSN) when the underlying stroma are infiltrated by dysplastic squamous epithelial cells through the basement membrane. Here, we present the descriptive epidemiology and geographical distribution of IOSSN in Canada. METHODS: We determined the incidence and geographical distribution of IOSSN cases diagnosed between 1992 and 2010 using two independent population-based cancer registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer. RESULTS: The mean annual age-standardised incidence rate (WHO 2000-2025) of IOSSN for 1992-2010 was 0.45 cases per million individuals per year with an average annual percent increase in incidence of 4.5%. IOSSN localisation to the conjunctiva was documented in at least 57% of the reported cases. IOSSN exhibited a male predilection ratio of 3.3:1.0 with a mean age at diagnosis of 69 years. Incidence rates of IOSSN across Canadian provinces and cities showed no significant differences from the crude national average. CONCLUSIONS: Our results, particularly concerning IOSSN patient age and male predilection, corroborate with data reported from the USA. Additional studies are needed to determine whether the observed increase in incidence rate over the study period (1992-2010) is significant.

Incidence trends of conjunctival malignant melanoma in Canada.

BACKGROUND: Melanoma is the most common primary malignancy of the eye in adults. While the epidemiology of uveal melanoma has recently been described in Canada, little is known about the epidemiology and geographic distribution of patients with conjunctival melanoma (CM) in Canada. METHODS: We conducted a population-based study of CM incidence across all Canadian provinces and territories during 1992-2010 using two independent population-based registries. RESULTS: 190 patients were diagnosed with CM in Canada from 1992 to 2010. 55.3 % of these patients were men. The mean annual incidence rate of CM in Canada was 0.32 cases per million individuals (0.35 and 0.29 cases per million individuals for men and women, respectively). The incidence rates for Canadian provinces demonstrated that the eastern provinces of Nova Scotia and New Brunswick had higher age-adjusted incidence rates than the national average, with rates of 0.52 and 0.47 cases per million individuals per year, respectively. CONCLUSIONS: This analysis demonstrates novel variations in CM incidence rates between different Canadian provinces. These results taken together with the data reported from the USA confirm the North-to-South geographic gradient of increasing CM incidence. This research highlights that the epidemiology of CM in North America is comparable to that of cutaneous malignant melanoma in contrast to the trends for uveal melanoma distribution.

Epidemiology of ophthalmic lymphoma in Canada during 1992-2010.

BACKGROUND: Ophthalmic lymphoma (OL) is the most common orbital tumour, particularly in older individuals. Little is known about the epidemiology and geographic distribution of OL in Canada. Descriptive demographic statistics are an important first step in understanding OL burden and are necessary to inform comprehensive national cancer prevention programmes. METHODS: We determined patterns of incidence and geographical distribution of the three major subtypes of OL: extranodal marginal zone B cell lymphoma, follicular lymphoma (FL) and diffuse large B cell lymphoma. Here, we used cases that were diagnosed during 1992-2010 using two independent population-based cancer registries, the Canadian Cancer Registry and Le Registre Québécois du Cancer (LRQC). RESULTS: The OL mean annual age-standardised incidence rate for 1992-2010 was 0.65 cases per million people per year with an average annual increase in the incidence rate of 4.5% per year. The mean age of diagnosis was 65 years. OL incidence rate was the highest in the cities located along the heavily industrialised Strait of Georgia in British Columbia. CONCLUSIONS: Our data on patient age, sex and temporal trends showed similarities with data reported in the USA and Denmark. Additional studies are needed to determine whether the observed increase in OL incidence is genuine or spurious.

Impact of surgical case order on epiretinal membrane peeling surgery.

OBJECTIVE: To determine whether surgical warm-up affects epiretinal membrane (ERM) peeling complication rates and surgical case times. SETTING: Jewish General Hospital, Montreal, QC, Canada. DESIGN: Retrospective case-control study. METHODS: We assessed consecutive patients who underwent pars plana vitrectomy for ERM peel (macular pucker) by one surgeon at the Jewish General Hospital from January 2006 until March 2016. Cases evaluated were sequential ERM peels performed as the first 2 surgeries of the day. The first case of the day was considered the "warm-up" and the second case was the "post-warm-up." Baseline demographics, pre-operative characteristics, perioperative and postoperative best-corrected visual acuity (BCVA) at 2 months and 6 months, as well as postoperative complications are described. Results were analyzed using the χ2 test, t test, and Fischer's exact test. Regression models were used to identify any predictors of postoperative BCVA. RESULTS: The study reviewed 108 patients. The warm-up group was compared with the post-warm-up group, and there was no significant difference between the mean pre-operative BCVA and the post-operative BCVA at 2 and 6 months. ERM peeling surgery complication rates were not statistically different between the warm-up cases and the post-warm-up cases. There was a tendency for performing complex surgeries that needed phaco procedures in post-warm-up cases (13% vs 2%, p = 0.03). Analysis of simple ERM peeling procedures (with no concomitant phaco procedures) showed no statistically significant tendencies for any of the groups to go beyond the 60 minutes allocated for the surgery (25.4% vs 20.0%, p = 0.27). CONCLUSION: Warming-up does not influence the rate of postoperative complications or the postoperative BCVA in patients undergoing ERM peels. The strongest predictor of post-operative BCVA was pre-operative BCVA.

Retinoblastoma Incidence Trends in Canada: A National Comprehensive Population-Based Study.

PURPOSE: To determine the incidence rates and geographic distribution of retinoblastoma in Canada to aid cancer control programs. METHODS: Patients with retinoblastoma whose data were available from the Canadian Cancer Registry (CCR) and Le Registre Québécois du Cancer (LRQC) were studied. Using third edition International Classification of Diseases for Oncology (ICD-O) codes, the authors examined the incidence rates and geographic distribution of patients with retinoblastoma between 1992 and 2010. Patient data including sex, age, and laterality of the retinoblastoma were analyzed. RESULTS: Between 1992 and 2010 in Canada, the average annual incidence rate of retinoblastoma was 11.58 cases per 1 million children younger than 5 years (95% CI [confidence interval]: 10.48 to 12.76). The incidence rate was stable over time, with an average age at diagnosis of 2.30 ± 6.85 years and no gender predilection. The laterality of the reported cases was 81.48% for uni-lateral cases and 18.52% for bilateral cases. Provincially, Nova Scotia had twice the national average and the highest incidence rates of retinoblastoma across the Canadian provinces. CONCLUSIONS: This is the first study to define the disease burden of retinoblastoma and to highlight important longitudinal, geographic, and spatial differences in the distribution of retinoblastoma in Canada between 1992 and 2010. The results of this study indicate continuity of clinical trends between Canada, the United States, and other developed countries. [J Pediatr Ophthalmol Strabismus. 2019;56(2):124-130.].

Uveal melanoma incidence trends in Canada: a national comprehensive population-based study.

BACKGROUND: In the developed countries, uveal melanoma is the most common primary intraocular malignancy in adults. Little is known about the epidemiological and geographical distribution of uveal melanoma in Canada. METHODS: To determine the incidence patterns and geographical distribution of uveal melanoma cases in Canada, we conducted the first comprehensive, population-based national study of this malignancy across all Canadian provinces and territories during 1992-2010 years. We examined two independent population-based registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer using corresponding International Classification of Diseases for Oncology-3rd edition codes for all histological subtypes of uveal melanoma. RESULTS: We report that 2215 patients were diagnosed with uveal melanoma, of which 52.1% were males. The average -annual incidence rate of uveal melanoma in Canada was 3.75 cases per million individuals per year (95% CI 3.60 to 3.91). Overall, we report a steady increase in uveal melanoma incidence with an annual increase of 0.074 cases per million individuals per year. Significant differences in the incidence rates of uveal melanoma between Canadian provinces and territories were noted, where the highest crude incidence was in British Columbia and Saskatchewan with rates of 6.38 and 5.47 cases per million individuals per year, respectively. CONCLUSIONS: This work, for the first time, defines the disease burden of uveal melanoma in Canada and highlights important longitudinal, geographical and spatial differences in the distribution of uveal melanoma in Canada.

Cutaneous malignant melanoma incidence and mortality trends in Canada: A comprehensive population-based study.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is on the rise in many parts of the world. However, there is limited knowledge on the epidemiology of CMM in Canada. OBJECTIVE: To conduct a comprehensive population-based study of CMM in Canada. METHODS: We examined patient clinical and pathologic characteristics as well as the incidence and mortality trends of CMM in Canada using 3 independent population-based registries. RESULTS: In total, 72,565 Canadian patients were given CMM diagnoses during 1992-2010; 47.5% were women. Average age at the time of diagnosis was 56.5 years for women and 60.4 years for men. We report a steady increase in CMM incidence and mortality rates in both sexes. The overall incidence rate of CMM in Canada was 12.29 cases/100,000 person-years. We also report important differences in the incidence and mortality rates between Canadian provinces and territories; the highest incidence of this cancer was documented in Nova Scotia and Prince Edward Island. LIMITATIONS: Data on race, clinical disease stage, and Breslow depth of CMM was not available. CONCLUSION: This study, for the first time, defines the disease burden of CMM in Canada and highlights important longitudinal, geographic, and spatial differences in the distribution of CMM in this country.

KLF13 is a genetic modifier of the Holt-Oram syndrome gene TBX5.

TBX5, a member of the T-box family of transcription factors, is a dosage sensitive regulator of heart development. Mutations in TBX5 are responsible for Holt-Oram Syndrome, an autosomal dominant disease with variable and partially penetrant cardiac defects suggestive of the existence of genetic and environmental modifiers. KLF13, a member of the Krüppel-like family of zinc finger proteins is co-expressed with TBX5 in several cardiac cells including atrial cardiomyocytes and cells of the interatrial septum. We report that KLF13 interacts physically and functionally with TBX5 to synergistically activate transcription of cardiac genes. We show that TBX5 contacts KLF13 via its T-domain and find that several disease-causing mutations therein have decreased KLF13 interaction. Whereas Klf13 heterozygote mice have no detectable cardiac defects, loss of a Klf13 allele in Tbx5 heterozygote mice significantly increases the penetrance of TBX5-dependent cardiac abnormalities including atrial, atrial-ventricular and ventricular septal defects. The results reveal for the first time combinatorial interaction between a T-box protein and a KLF family member and its importance for heart and possibly other organ development. The data also suggest that, in human, KLF13 may be a genetic modifier of the Holt-Oram Syndrome gene TBX5.

Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease-Associated Factors GATA4 and NKX2-5.

AIMS: Transcription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital heart disease (CHD). GATA4 has also been implicated in cardiac regeneration and repair. GATA4 action involves combinatorial interaction with other cofactors such as NKX2-5, another critical cardiac regulator whose mutations also cause CHD. Despite its critical importance to the heart and its evolutionary conservation across species, the structural basis of the GATA4-NKX2-5 interaction remains incompletely understood. METHODS AND RESULTS: A homology model was constructed and used to identify surface amino acids important for the interaction of GATA4 and NKX2-5. These residues were subjected to site-directed mutagenesis, and the mutant proteins were characterized for their ability to bind DNA and to physically and functionally interact with NKX2-5. The studies identify 5 highly conserved amino acids in the second zinc finger (N272, R283, Q274, K299) and its C-terminal extension (R319) that are critical for physical and functional interaction with the third alpha helix of NKX2-5 homeodomain. Integration of the experimental data with computational modeling suggests that the structural arrangement of the zinc finger-homeodomain resembles the architecture of the conserved DNA binding domain of nuclear receptors. CONCLUSIONS: The results provide novel insight into the structural basis for protein-protein interactions between two important classes of transcription factors. The model proposed will help to elucidate the molecular basis for disease causing mutations in GATA4 and NKX2-5 and may be relevant to other members of the GATA and NK classes of transcription factors.

The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipidemia in human astrocytic and hepatic cells.

L-Carnitine is a critical metabolite indispensable for the metabolism of lipids as it facilitates fatty acid transport into the mitochondrion where ß-oxidation occurs. Human astrocytes (CCF-STTG1 cells) and hepatocytes (HepG2 cells) exposed to aluminum (Al) and hydrogen peroxide (H2O2), were characterized with lower levels of L-carnitine, diminished ß-oxidation, and increased lipid accumulation compared to the controls. γ-Butyrobetainealdehyde dehydrogenase (BADH) and butyrobetaine dioxygenase (BBDOX), two key enzymes mediating the biogenesis of L-carnitine, were sharply reduced during Al and H2O2 challenge. Exposure of the Al and H2O2-treated cells to α-ketoglutarate (KG), led to the recovery of L-carnitine production with the concomitant reduction in ROS levels. It appears that the channeling of KG to combat oxidative stress results in decreased L-carnitine synthesis, an event that contributes to the dyslipidemia observed during Al and H2O2 insults in these mammalian cells. Hence, KG may help alleviate pathological conditions induced by oxidative stress.

The monitoring of nucleotide diphosphate kinase activity by blue native polyacrylamide gel electrophoresis.

Nucleoside diphosphate kinase (NDPK) has been shown to play a pivotal role in modulating a plethora of cellular processes. In this study, we report on a blue native (BN) PAGE technique which allows the facile assessment of NDPK activity and expression. The in-gel detection of NDPK relies on the precipitation of formazan at the site of immobilized enzyme activity. This is achieved by coupling the formation of ATP, as a consequence of gamma-phosphate transfer from NTP to ADP, to hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PDH), oxidized nicotinamide adenine dinucleotide phosphate (NADP), phenazine methosulfate (PMS), and iodonitrotetrazolium chloride (INT). 2-D denaturing gel analysis confirmed that the activity bands corresponded to NDPK as indicated by subunit composition. Furthermore, the sensitivity and specificity of this readily accessible procedure was assessed by monitoring the in-gel activity of NDPK using different concentrations of GTP and CTP as well as deoxynucleoside triphosphates. This electrophoretic technique allows the quick and easy detection of NDPK, a housekeeping enzyme crucial to cell survival.