MIR204 n.37C>T variant as a cause of chorioretinal dystrophy variably associated with iris coloboma,early-onset cataracts and congenital glaucoma

Four members of a three-generation Czech family with early-onset chorioretinal dystrophy were shown to be heterozygous carriers of the n.37C>T in MIR204. The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change in MIR204. Chorioretinal dystrophy was variably associated with iris coloboma, congenital glaucoma, and premature cataracts extending the phenotypic range of the condition. In silico analysis of the n.37C>T variant revealed 713 novel targets. Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants. Haplotype analysis excluded relatedness with the original family reported to harbour the n.37C>T variant in MIR204. Identification of a second independent family confirms the existence of a distinct MIR204-associated clinical entity and suggests that the phenotype may also involve congenital glaucoma.     

Association of total antioxidants level with glaucoma type and severity

Objectives:

To compare the mean total antioxidant status (TAS) among 3 glaucoma types, namely: pseudoexfoliation glaucoma (PEG), primary open angle glaucoma (POAG), and primary angle closure glaucoma (PACG), and study its potential association with various clinical glaucoma-parameters.

Methods:

In this case-control study, plasma samples were obtained between September 2013 and October 2014 from 340 glaucoma patients (PEG [n=54]; POAG [n=147]; PACG [n=139]), and 351 controls of matching age, gender, ethnicity, and 5 different systemic co-morbidities from King Abdulaziz University Hospital, Riyadh, Saudi Arabia. The TAS in all samples was determined by a colorimetric-based assay.

Results:

The mean±standard deviation of TAS was significantly lower among cases: 0.77±0.32 than controls: 1.1±0.22, p<0.0001. Moreover, the TAS levels were significantly different across the 3 types of glaucoma: 0.86±0.24 in PEG, 0.47±0.32 in POAG, and 0.98±0.41 in PACG (all p<0.0001). In addition, there was a significant correlation between TAS and age at onset (Pearson correlation coefficient [R] 0.17, p<0.0001), cup/disc ratio (R: -0.13, p=0.004), and number of anti-glaucoma medications (R: -0.16, p=0.001).

Conclusion:

Our findings provide evidence that plasma TAS levels are decreased in patients with glaucoma, more so in POAG and PEG than PACG, supporting the hypothesis that decreased antioxidative defense and/or increased oxidative stress may have a critical role in the pathogenesis of glaucoma.Glaucoma is a progressive optic neuropathy associated with optic nerve damage, and is one of the most leading cause of blindness worldwide.1 Elevated intraocular pressure (IOP) as a result of reduction in normal aqueous outflow is a major causal risk factor that is well supported by animal studies.2-4 Although IOP is considered a major risk factor for glaucoma,2,3 other concomitant factors affecting the pathophysiology of glaucomatous retinal ganglion cell (RGC) death include retinal ischemia,5 nutritional status,6 and oxidative stress.7 There is evidence of oxidative damage in ocular diseases, such as cataract and age-related macular degeneration.8 In addition, significant oxidative damage has been demonstrated in human trabecular meshwork (TM) cells of patients with glaucoma,7 causing elevated IOP and visual field damage.9 Furthermore, our previous studies have documented mitochondrial abnormalities10-12 (oxidative stress marker), and glutathione-S-transferase (antioxidant) gene (GST) polymorphisms to be associated with various types of glaucoma.13 It is clearly evident from the literature, and our own studies, that oxidative stress mechanisms play a critical role in the pathogenesis of glaucoma. Previous studies had demonstrated reduced total antioxidant capacity in aqueous humor and blood samples from patients with glaucoma.14-17 To evaluate the role of oxidative stress in different types of glaucoma we had previously investigated total antioxidants status (TAS) in the plasma of pseudoexfoliation glaucoma (PEG) patients,18 primary angle closure glaucoma (PACG) patients,19 and in the plasma of primary open angle glaucoma (POAG) patients.20 As an extension to these studies, here, we compare the mean TAS level among these 3 glaucoma types, and study the potential association between the TAS level and various clinical parameters important to each type of glaucoma.18-20     

Increase in the effectiveness of somatodendritic 5-HT-1A receptors in a rat model of tardive dyskinesia

The present study concerns responsiveness of pre- and postsynaptic 5-hydroxytryptamine (5-HT)-1A receptors in a rat model of tardive dyskinesia (TD). Vacuous chewing movements (VCMs) in rats are widely accepted as an animal model of TD. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for 5 weeks elicited VCMs, which increased in a time dependent manner following the drug administration for 3-5 weeks. Tolerance was produced in motor coordination during the potentiation of VCMs. Exploratory activity in an open field and in an activity box decreased in haloperidol treated animals. The effects of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 0.5 mg/kg) were monitored 48-h after withdrawal from repeated administration of haloperidol. 8-OH-DPAT-induced locomotion was greater in haloperidol treated rats. 5-HT synthesis increased in haloperidol treated animals, while 8-OH-DPAT-induced decreases of 5-HT synthesis were greater in repeated haloperidol than repeated saline injected animals. The results suggest that an increase in the effectiveness of somatodendritic 5-HT-1A receptors may decrease the inhibitory influence of 5-HT on the activity of dopaminergic neurons to precipitate VCMs. The 5-HT-1A agonist may help to alleviate neuroleptic-induced TD.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

Population genetic data of 30 insertion–deletion markers in Punjabi population of Pakistan

Insertion–deletion polymorphism (Indels) is valuable diallelic markers for forensic as well as parentage analysis. The Investigator DIPplex Kit (Qiagen) contains thirty autosomal Indels markers along with amelogenin. These thirty markers were tested in the Pakistani Punjabi Population but no significant deviations were observed from Hardy–Weinberg equilibrium rule expectations (Bonferroni corrected) except HLD58, HLD56, HLD99, and HLD40. The mean expected and observed heterozygosity was found 0.4701 and 0.4667 respectively; combined matching probability was computed as 7.31867 × 10−13. However, the use of the 30 Indels markers proved to be a good supplementary tool in forensic casework, particularly when evidence sample is highly degraded. The significant genetic differences were also observed between the Punjabi and other populations of the world.