Attention-deficit/hyperactivity disorder and dopamine receptor D4 (DRD4) exon 3 variable number of tandem repeats (VNTR) 2-repeat allele.

To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.

Reciprocal causation mixture model for robust Mendelian randomization analysis using genome-scale summary data.

Mendelian randomization using GWAS summary statistics has become a popular method to infer causal relationships across complex diseases. However, the widespread pleiotropy observed in GWAS has made the selection of valid instrumental variables problematic, leading to possible violations of Mendelian randomization assumptions and thus potentially invalid inferences concerning causation. Furthermore, current MR methods can examine causation in only one direction, so that two separate analyses are required for bi-directional analysis. In this study, we propose a ststistical framework, MRCI (Mixture model Reciprocal Causation Inference), to estimate reciprocal causation between two phenotypes simultaneously using the genome-scale summary statistics of the two phenotypes and reference linkage disequilibrium information. Simulation studies, including strong correlated pleiotropy, showed that MRCI obtained nearly unbiased estimates of causation in both directions, and correct Type I error rates under the null hypothesis. In applications to real GWAS data, MRCI detected significant bi-directional and uni-directional causal influences between common diseases and putative risk factors.

Effects of Deferasirox in Alzheimer's Disease and Tauopathy Animal Models.

The accumulation of iron may contribute to Alzheimer's disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients. However, desferrioxamine requires injection, which is inconvenient and may hinder compliance. We therefore tested an oral iron chelator, desferasirox (Exjade), in transgenic animal models. Tg2576 mice overexpress the mutant human APP protein and produce the Aß peptide. JNPL3 mice (Tau/Tau) overexpress the mutant human tau protein. Crossing these produced APP/Tau mice, overexpressing both APP and tau. Treating the three models with 1.6 mg deferasirox thrice weekly from age 8 to 14 months did not affect memory as measured by contextual fear conditioning or motor function as measured by rotarod, but tended to decrease hyperphosphorylated tau as measured by AT8 immunohistochemistry and immunoblotting. Deferasirox might act by decreasing iron, which aggregates tau, or directly binding tau to inhibit aggregation.

Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value. METHODS: We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity. RESULTS: In the primary analysis, nine variants reached genome-wide significance (p < 5e-08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA-B*15:02-negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA-B*15:02 status or zygosity. HLA-B*15:02-positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p < .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p < 5e-6) identified through the primary and subanalyses (stratified by HLA-B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology-related genes. The genes implicated were specific either to the primary analysis (CD9), HLA-B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA-E), or phenytoin exposure (CD24). SIGNIFICANCE: We identified variants that could explain why some carriers of HLA-B*15:02 tolerate treatment, and why some noncarriers develop ASM-induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA-B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM-induced SJS/TEN is complex, likely involving multiple risk variants.

Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia.

Background: Schizophrenia (SCZ) is a heterogeneous psychiatric disorder, with significant contribution from genetic factors particularly for chronic cases with negative symptoms and cognitive deficits. To date, Genome Wide Association Studies (GWAS) and exome sequencing have associated SCZ with a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), but there is still missing heritability. Medium-sized structural variants (SVs) are difficult to detect using SNP arrays or second generation sequencing, and may account for part of the missing heritability of SCZ. Aims and objectives: To identify SVs associated with severe chronic SCZ across the whole genome. Study design: 10 multiplex families with probands suffering from chronic SCZ with negative symptoms and cognitive deficits were recruited, with all their affected members demonstrating uni-lineal inheritance. Control subjects comprised one affected member from the affected lineage, and unaffected members from each paternal and maternal lineage. Methods: Third generation sequencing was applied to peripheral blood samples from 10 probands and 5 unaffected controls. Bioinformatic tools were used to identify SVs from the long sequencing reads, with confirmation of findings in probands by short-read Illumina sequencing, Sanger sequencing and visual manual validation with Integrated Genome Browser. Results: In the 10 probands, we identified and validated 88 SVs (mostly in introns and medium-sized), within 79 genes, which were absent in the 5 unaffected control subjects. These 79 genes were enriched in 20 biological pathways which were related to brain development, neuronal migration, neurogenesis, neuronal/synaptic function, learning/memory, and hearing. These identified SVs also showed evidence for enrichment of genes that are highly expressed in the adolescent striatum. Conclusion: A substantial part of the missing heritability in SCZ may be explained by medium-sized SVs detectable only by third generation sequencing. We have identified a number of such SVs potentially conferring risk for SCZ, which implicate multiple brain-related genes and pathways. In addition to previously-identified pathways involved in SCZ such as neurodevelopment and neuronal/synaptic functioning, we also found novel evidence for enrichment in hearing-related pathways and genes expressed in the adolescent striatum.

Preservation of Retinal Function Through Synaptic Stabilization in Alzheimer's Disease Model Mouse Retina by Lycium Barbarum Extracts.

In Alzheimer's disease (AD), amyloid ß deposition-induced hippocampal synaptic dysfunction generally begins prior to neuronal degeneration and memory impairment. Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In this study, we aimed to investigate the effects of LBE on the synapse loss in AD through the avenue of the retina in a triple transgenic mouse model of AD (3xTg-AD). We fed 3xTg-AD mice with low (200 mg/kg) or high (2 g/kg) dose hydrophilic LBE daily for 2 months from the starting age of 4- or 6-month-old. For those started at 6 month age, at 1 month (though not 2 months) after starting treatment, mice given high dose LBE showed a significant increase of a wave and b wave in scotopic ERG. After 2 months of treatment with high dose LBE, calpain-2, calpain-5, and the oxidative RNA marker 8-OHG were downregulated, and presynaptic densities in the inner plexiform layer but not the outer plexiform layer of the retina were significantly increased, suggesting the presynaptic structure of retina was preserved. Our results indicate that LBE feeding may preserve synapse stability in the retina of 3xTg-AD mice, probably by decreasing both oxidative stress and intracellular calcium influx. Thus, LBE might have potential as a neuroprotectant for AD through synapse preservation.

Systemic neuro-dysregulation in depression: Evidence from genome-wide association.

Depression is the world's leading cause of disability. Greater understanding of the neurobiological basis of depression is necessary for developing novel treatments with improved efficacy and acceptance. Recently, major advances have been made in the search for genetic variants associated with depression which may help to elucidate etiological mechanisms. The present review has two major objectives. First, we offer a brief review of two major biological systems with strong evidence for involvement in depression pathology: neurotransmitter systems and the stress response. Secondly, we provide a synthesis of the functions of the 269 genes implicated by the most recent genome-wide meta-analysis, supporting the importance of these systems in depression and providing insights into other possible mechanisms involving neurodevelopment, neurogenesis, and neurodegeneration. Our goal is to undertake a broad, preliminary stock-taking of the most recent hypothesis-free findings and examine the weight of the evidence supporting these existing theories and highlighting novel directions. This qualitative review and accompanying gene function table provides a valuable resource and guide for basic and translational researchers, with suggestions for future mechanistic research, leveraging genetics to prioritize studies on the neurobiological processes involved in depression etiology and treatment.

Immune dysregulation in depression: Evidence from genome-wide association.

A strong body of evidence supports a role for immune dysregulation across many psychiatric disorders including depression, the leading cause of global disability. Recent progress in the search for genetic variants associated with depression provides the opportunity to strengthen our current understanding of etiological factors contributing to depression and generate novel hypotheses. Here, we provide an overview of the literature demonstrating a role for immune dysregulation in depression, followed by a detailed discussion of the immune-related genes identified by the most recent genome-wide meta-analysis of depression. These genes represent strong evidence-based targets for future basic and translational research which aims to understand the role of the immune system in depression pathology and identify novel points for therapeutic intervention.

Rationale for the development of an Alzheimer's disease vaccine.

Vaccination traditionally has targeted infectious agents and thus has not heretofore been used to prevent neurodegenerative illness. However, amyloid ß (Aß) or tau, which can act like infectious proteins, or prions, might induce Alzheimer's disease (AD). Furthermore, evidence suggests that traditional infectious agents, including certain viruses and bacteria, may trigger AD. It is therefore worth exploring whether removing such targets could prevent AD. Although failing to treat AD patients who already display cognitive impairment, Aß monoclonal antibodies are being tested in pre-symptomatic, at-risk individuals to prevent dementia. These antibodies might become the first AD therapeutics. However, their high cost will keep them out of the arms of the vast majority of patients, who increasingly live in developing countries. Because vaccines produce antibodies internally at much lower cost, vaccination might be the most promising approach to reducing the global burden of dementia.

The potential role of human multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 2 (MRP2) in the transport of Huperzine A in vitro.

1. More than 30% of epilepsy patients suffer pharmacoresistance. Transport of antileptic drugs by P-glycoprotein (P-gp) and MRP2 plays an important role in drug-resistant epilepsy. Huperzine A (Hup-A) is a natural compound, which might have potential in treating neurological disorders including epilepsy and Alzheimer's disease. In this study, we investigated whether human P-gp and MRP2 transport Hup-A.2. LLC-PK1 and MDCKII cells transfected with human P-gp or MRP2 were used to establish concentration equilibrium transport assays (CETAs) and determine the transport profile of Hup-A. The expression of P-gp and MRP2 was detected by qPCR and western blotting. The transport function of P-gp and MRP2 was measured by Rho123 and CDFDA cell uptake assay.3. In CETAs, Hup-A at concentrations of 10 ng/mL or 2 µg/mL was transported by MDR1 and MRP2 from basolateral to apical sides of the cell monolayers. P-gp and MRP2 inhibitors completely blocked the efflux of Hup-A. There was no efflux of Hup-A in LLC-PK1 or MDCKII wild-type (WT) cells.4. We demonstrate that Hup-A is a substrate of P-gp and MRP2. These results imply the efflux of Hup-A across the blood-brain barrier (BBB) in vivo, suggesting potential drug resistance of Hup-A.

More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration.

Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer's disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aß). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.

Hong Kong's role in global health: Public opinion of official development assistance.

Governments in high income countries allocate funding for Official Development Assistance (ODA), and population-based surveys tend to show support for the concept of affluent nations assisting the development of poorer regions. A public opinion survey was conducted in Hong Kong to: (1) assess public support for foreign aid for social development and Hong Kong's current Disaster Relief Fund (DRF); and (2) assess how much respondents thought should be contributed to foreign aid for social development and/or DRF. Interviewers conducted a random telephone survey of Cantonese-speaking Hong Kong citizens aged 18 or above during 2017. Of the 1004 individuals surveyed, 55% (552) agreed that a portion of the government budget should be allocated to the DRF and 37% (372) disagreed. The mean and the median amount of the government budget suggested to be allocated were 5.1% and 2.4% respectively. However only 16% (164) supported the government giving foreign aid for social development, with 79% (793) not supporting, and 5% (47) undecided. The suggested portions of government budget that should be allocated for this purpose were 1.5% (mean) and 0.0% (median). The degree of support for DRF and foreign aid for social development was associated with both age (DRF P < 0.0005; foreign aid for social development P < 0.0005) and education (DRF P = 0.010; foreign aid for social development: P < 0.0005). There was little support for foreign aid for social development amongst the Hong Kong public, in contrast to similar surveys in other countries, but this could be related to the lack of a local tradition of providing ODA to foreign countries. Most respondents supported the current DRF and would like to see a greater proportion of government budget allocated.

Effects of Resveratrol and Morin on Insoluble Tau in Tau Transgenic Mice.

Tauopathies are neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: We investigated the role of rare genetic variants and of de novo variants in the pathogenesis of mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). METHODS: Whole-exome sequencing (WES) was performed in patients with MTLE-HS and their unaffected parents (trios). Genes or gene sets that were enriched with predicted damaging rare variants in the patients as compared to population controls were identified. Patients and their parents were compared to identify whether the variants were de novo or inherited. RESULTS: After quality control, WES data from 47 patients (26 female), including 23 complete trios, were available for analysis. Compared with population controls, significant enrichment of rare variants was observed in SEC24B. Integration of gene set data describing neuronal functions and psychiatric disorders showed enrichment signal on fragile X mental retardation protein (FMRP) targets. Twenty-one de novo variants were identified, with many known to cause neuropsychiatric disorders. The FMRP-targeted genes also carried more de novo variants. Inherited compound heterozygous and homozygous variants were identified. CONCLUSIONS: The genetic architecture underlying MTHE-HS is complex. Multiple genes carrying de novo variants and rare variants among FMRP targets were identified, suggesting a pathogenic role. MTLE-HS and other neuropsychiatric disorders may have shared biology.

Association Between the Apolipoprotein E Gene Polymorphism and Atherosclerotic Middle Cerebral Artery Stenosis.

OBJECTIVES: Stenosis of the intracranial large arteries, especially the middle cerebral artery (MCA), is common in the Chinese population. We conducted a case-control study to investigate clinical and apolipoprotein E (ApoE) gene polymorphism of MCA atherosclerosis in the Chinese population. MATERIALS AND METHODS: Polymerase chain reaction-based protocols were used to identify the genotypes of polymorphisms in ApoE genes. Clinical parameters and the genotypes of polymorphisms in the ApoE genes were compared in patients with and without MCA stenosis. The ApoE exon ε4 genotypes with risk factors were compared in the patients with and without MCA stenosis. RESULTS: In total, 337 ischemic stroke patients were recruited, 156 cases with and 181 without MCA stenosis. Univariate analysis showed that the levels of systolic blood pressure and pulse pressure were higher in the MCA-stenosis group. There were no significant differences in the genotype and allele frequencies of the ApoE polymorphism observed between patients with and without MCA stenosis. However, there was a trend that the MCA-stenosis group tended to have more of genotype ε4/ε4 (3.8% vs. 0.6%, P=0.052) than the non-MCA-stenosis group. There was no effect of ApoE genotype and genotype-by-environment interactions on ischemic stroke susceptibility. CONCLUSIONS: This present study indicated that the hypertension (ie, systolic blood pressure and pulse pressure) and the ApoEε4/ε4 genotype may be associated with the occurrence of MCA stenosis in the ischemic stroke Chinese patients.

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Genetic overlap between epilepsy and schizophrenia: Evidence from cross phenotype analysis in Hong Kong Chinese population.

Epilepsy and schizophrenia are common and typical neurological or mental illness respectively, and sometimes they comorbid in the same patients, however the underlying genetic relationship between the two brain diseases is still not fully understood. To investigate the possible genetic contribution to their comorbidity, we performed polygenic risk score (PRS) analyses and genetic correlation estimation so as to identify the overall genetic overlap between the two diseases. The global schizophrenia PRS is strongly associated with schizophrenia phenotype in Hong Kong population (odds ratio = 1.7, p = 2.26E-16), and focal epilepsy PRS is moderately associated with epilepsy phenotype in Hong Kong population (odds ratio = 1.14, p = 0.013). However the disease-specific PRS can only predict its own well-matched phenotype but not the other ones (p > 0.05). This pattern is further supported by non-significant pairwise genetic correlation and insufficient statistical power for PRS association from the cross-phenotype analyses. Our study reveals there's limited shared genetic aetiology between schizophrenia and epilepsy, and thus supports a model of shared environmental factors to explain the comorbidity between the two phenotypes.

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation.

AIMS: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. METHODS AND RESULTS: We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. CONCLUSIONS: Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.

Outcomes of Phacoemulsification Using Different Size of Clear Corneal Incision in Eyes with Previous Radial Keratotomy.

OBJECTIVE: To evaluate visual outcomes and complications after phacoemulsification in eyes with cataract and previous radial keratotomy (RK) cuts using different sizes of clear corneal incisions. METHODS: The study was a retrospective study. Thirty eyes with cataract and previous RK underwent phacoemulsification and intraocular lens (IOL) implantation. Among them 7 eyes had 8 RK cuts, 13 eyes had 12 RK cuts, and 10 eyes had 16 RK cuts. Phacoemulsification and IOL implantation were performed through a 2.0-3.2 mm clear corneal incision by a single surgeon. In the 8 RK cuts group, 3.2 mm clear corneal incisions were used in 4 eyes, and 3.0 mm clear corneal incisions were used in 3 eyes. In the 12 RK cuts group, 3.2 mm clear corneal incisions were used in 6 eyes, and 2.2 mm clear corneal incisions were used in 7 eyes. In the 16 RK cuts group, 3.2 mm clear corneal incisions were used in 5 eyes, and 2.0 mm clear corneal incisions were used in 5 eyes. Patients were followed up 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, and 3 years postoperatively and were examined for the dehiscence of RK cuts during or after the surgery, post-operative best-corrected visual acuity (BCVA), corneal astigmatism, corneal endothelial cell density and complications. RESULTS: Successful phacoemulsification with IOL implantation was performed in all eyes. No wound dehiscence was noted in any eyes with 8 or 12 RK cuts. Wound dehiscence was noted in 2 eyes with 16 RK cuts. The dehiscence of RK cuts was closed successfully by injecting an air bubble with or without viscoelastic agent into the anterior chamber at the end of surgery. During the follow-up, the cuts were well apposed in all eyes, and no new dehiscence of RK cuts was noted. At the last follow-up, mean BCVA (0.2 ± 0.18 logMAR) was better than preoperative BCVA(0.45±0.19 logMAR) (P < 0.001). There was no significant difference between the long-term preoperative and postoperative mean corneal astigmatism (P = 0.3). However, there was a significant reduction in postoperative corneal endothelial cell density (1866.5±773.9 / mm2 vs 2421.7±655.7 / mm2) (P < 0.001). CONCLUSIONS: Phacoemulsification and IOL implantation with clear corneal incisions in eyes with previous RK were associated with good surgical outcomes. Wound dehiscence was not specificaly related to the size of clear corneal incision during phacoemulsification in these eyes.

Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis.

Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case-control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case-control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10(-5), and TT vs. CC, p = 2 × 10(-5)) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10(-6)). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10(-4), and p = 4 × 10(-3), respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.