Publications by authors named "Mary Ho"

33 Publications

Clinical features and treatment outcomes of endogenous endophthalmitis: a 12-year review.

Int J Ophthalmol 2020 18;13(12):1933-1940. Epub 2020 Dec 18.

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, New Territories, Hong Kong, China.

Aim: To identify the clinical features and treatment outcomes of endogenous endophthalmitis and investigate prognostic factors of poor visual outcome.

Methods: The clinical records of all patients diagnosed with endogenous endophthalmitis between January 2007 to December 2018 in Prince of Wales Hospital, Hong Kong, China were retrospectively reviewed. Thorough ophthalmological examination findings were recorded in the case note, including visual acuity testing, slit-lamp examination, indirect ophthalmoscopy and B-scan ultrasonography if media opacity precluded fundus viewing.

Results: A total of 18 eyes in 14 patients were identified. Bilateral involvement was noted in 4 patients (28.6%). Hepatobiliary sepsis was the source in 9 patients (64.3%). Culture of intraocular fluid was positive in 5 out of 18 eyes (27.8%). Mortality was noted in 2 patients (14.3%). Mean final visual acuity was 20/1500. Six out of 16 eyes had total loss of sight (37.5%) and 3 eyes required evisceration (18.8%). Multivariate linear regression revealed poor presenting visual acuity (=0.031) and lack of fundus view due to vitritis (=0.02) as prognostic factors of poor visual outcome.

Conclusion: Visual outcome of endogenous endophthalmitis is poor. Poor presenting visual acuity and lack of fundus view predict poor visual outcome. High index of suspicion for endophthalmitis is important in sepsis patients with complaints of ocular symptoms. Ophthalmological screening is recommended in non-communicable patients with sepsis.
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http://dx.doi.org/10.18240/ijo.2020.12.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708374PMC
December 2020

Outcomes and complications in scleral-fixated intraocular lens implantations.

Int Ophthalmol 2020 Nov 1;40(11):2969-2977. Epub 2020 Jul 1.

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Purpose: This study compares outcomes and complications of scleral-fixated intraocular lens implantation between 2 levels of surgeons.

Methods: A retrospective case series of patients undergoing scleral-fixated intraocular lens implantation at Prince of Wales Hospital, Hong Kong, between May 2012 and April 2017 were reviewed. Data collected included age, gender, affected eye, preoperative and postoperative visual acuities, refractive target and outcome, surgeon profile, operative details including method of scleral fixation, intraoperative and postoperative complications and length of follow-up.

Results: Ninety eyes of 90 patients were included for analyses. The mean LogMAR visual acuities were 1.17 ± 0.70 at postoperative week 1, 0.81 ± 0.56 at 1 month, 0.66 ± 0.55 at 3 months, 0.56 ± 0.59 at 6 months, and 0.51 ± 0.60 at 1 year, respectively. After adjusting for age at operation, operative time, axial length, subspecialty of the surgeon and preoperative LogMAR, surgeon seniority was not significantly associated with final visual outcomes. There was no statistically significant difference between the mean improvement in visual acuities between eyes operated by consultants and fellows under direct supervision of a senior surgeon.

Conclusion: Scleral-fixated intraocular lens implantation is safe and effective in improving visual acuity in aphakic adults without capsular support. Under good supervision, fellows were able to produce comparable results compared with experienced specialists.
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http://dx.doi.org/10.1007/s10792-020-01480-8DOI Listing
November 2020

Analysis of choriocapillaris perfusion and choroidal layer changes in patients with chronic central serous chorioretinopathy randomised to micropulse laser or photodynamic therapy.

Br J Ophthalmol 2021 Apr 12;105(4):555-560. Epub 2020 Jun 12.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China

Purpose: The purpose of this study was to investigate the signal changes in choriocapillaris flow deficits and choroidal thickness changes using swept-source optical coherence tomography angiography (OCTA) following different treatments.

Design: A double-blind, randomised controlled trial.

Methods: Patients with unilateral chronic central serous chorioretinopathy (CSC) were randomised to receive subthreshold micropulse laser therapy (MLT) or half-dose photodynamic therapy (PDT). Choroidal thickness and choriocapillaris flow deficit signals were investigated.

Results: Eighteen patients were randomised into the MLT group and 15 patients into the PDT group. Areas with flow deficit signals were identified in all baseline OCTA images of the choriocapillaris, with mean areas of 0.420 and 0.465 mm in the MLT and PDT groups, respectively. These flow deficit signal areas were significantly reduced at 6 months (p=0.011) in the MLT group and at 3 months (p=0.008) in the PDT group. Patients from the PDT group were shown to have smaller flow deficit areas than patients from the MLT group at all time points after treatment (p=0.001, analyses of variance). The mean choroidal volume of the fovea showed a significant reduction at 1 month (p=0.003), 3 months (p=0.199) and 6 months (p=0.006) in the PDT group.

Conclusion: The flow deficit areas identified in the choriocapillaris layer may suggest possible relative choroidal ischaemia. With measurement of choroidal volume reduction and faster rates of flow deficit area change, PDT has a stronger effect than MLT in promoting choriocapillaris recovery.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316076DOI Listing
April 2021

Impairments in face discrimination and emotion recognition are related to aging and cognitive dysfunctions in Parkinson's disease with dementia.

Sci Rep 2020 03 9;10(1):4367. Epub 2020 Mar 9.

College of Medicine, China Medical University, Taichung, Taiwan.

Patients with Parkinson's disease (PD) suffer from motor and non-motor symptoms; 40% would develop dementia (PD-D). Impaired face and emotion processing in PD has been reported; however, the deficits of face processing in PD-D remain unclear. We investigated three essential aspects of face processing capacity in PD-D, and the associations between cognitive, neuropsychiatric assessments and task performances. Twenty-four PD-D patients (mean age: 74.0 ± 5.55) and eighteen age-matched healthy controls (HC) (mean age: 71.0 ± 6.20) received three computerized tasks, morphing-face discrimination, dynamic facial emotion recognition, and expression imitation. Compared to HC, PD-D patients had lower sensitivity (d') and greater neural internal noises in discriminating faces; responded slower and had difficulties with negative emotions; imitated some expressions but with lower strength. Correlation analyses revealed that patients with advancing age, slow mentation, and poor cognition (but not motor symptoms) showed stronger deterioration in face perception. Importantly, these correlations were absent in the age-matched HC. The present study is among the first few examined face processing in patients with PD-D, and found consistent deficits correlated with advancing age and slow mentation. We propose that face discrimination task could be included as a potential test for the early detection of dementia in PD.
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http://dx.doi.org/10.1038/s41598-020-61310-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062803PMC
March 2020

Identification of as a susceptibility gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Br J Ophthalmol 2020 Mar 9. Epub 2020 Mar 9.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Purpose: The endothelial and cell-specific angiopoietin-Tie pathway plays an important regulatory role in angiogenesis. In this study, we investigated the associations of the () gene with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), using haplotype-tagging single-nucleotide polymorphisms (SNPs) analysis.

Methods: This study involved totally 2343 subjects, including a Hong Kong Chinese cohort (214 nAMD patients, 236 PCV patients and 433 control subjects), a Shantou Chinese cohort (189 nAMD patients, 187 PCV patients and 531 control subjects) and an Osaka Japanese cohort (192 nAMD patients, 204 PCV patients and 157 control subjects). Thirty haplotype-tagging SNPs in were genotyped in the Hong Kong cohort using TaqMan technology. Two SNPs (rs625767 and rs2273717) showing association in the Hong Kong cohort were genotyped in the Shantou and Osaka cohorts. The SNP-disease association of individual and pooled cohorts were analysed.

Results: Two SNPs (rs625767 and rs2273717) showed suggestive association with both nAMD and PCV in the Hong Kong cohort. In the meta-analysis involving all the three cohorts, rs625767 showed significant associations with nAMD (p=0.01; OR=0.82, 95% CI 0.70 to 0.96; I=0%), PCV (p=0.02; OR=0.83, 95% CI 0.71 to 0.97; I=27%) and pooled nAMD and PCV (p=0.002; OR=0.82, 95% CI 0.72 to 0.93; I=0%), with low inter-cohort heterogeneities.

Conclusion: This study revealed as a novel susceptibility gene for nAMD and PCV in Japanese and Chinese. Further studies in other populations are warranted to confirm its role.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315746DOI Listing
March 2020

Identification and characterization of a novel promoter variant in placental growth factor for neovascular age-related macular degeneration.

Exp Eye Res 2019 10 1;187:107748. Epub 2019 Aug 1.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China. Electronic address:

Purpose: Intronic variants in the placental growth factor (PGF) gene have been associated with neovascular age-related macular degeneration (AMD). This study is to discover and characterize rare variants in the PGF gene for neovascular AMD.

Methods: The promoter region, coding sequences and splicing regions of the PGF gene were sequenced in a Hong Kong southern Chinese cohort of 235 neovascular AMD patients and 435 controls. A detected 18 base-pair deletion variant in the promoter region of PGF was analyzed in a Shantou southern Chinese cohort of 189 neovascular AMD patients and 846 controls. The transcription activity of this disease-associated promoter variant was determined in human ARPE-19 cells by promoter-luciferase analysis.

Results: A novel 18-base-pair deletion mutation in the promoter region of PGF was identified in 3 (1.28%) patients and 1 (0.23%) control subject (OR = 5.61; 95% CI 0.58-54.26) in the Hong Kong cohort, and in 2 (1.06%) patients and 2 (0.24%) controls (OR = 4.51; 95% CI: 0.63-32.25) in the Shantou cohort. In the combined southern Chinese sample, this deletion had a significant association with neovascular AMD (P = 0.026; OR = 5.08, 95% CI: 1.21-21.36). The 18-base-pair deletion was predicted to alter the transcription factor binding sites in the PGF promoter, and higher luciferase expression was detected in ARPE-19 cells transfected with the deletion variant plasmid than those transfected with wild type plasmid (P = 0.0002).

Conclusions: This study identified a rare, functional promoter variant in the PGF gene that increases PGF transcription activity and confers a 5-fold risk to neovascular AMD.
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http://dx.doi.org/10.1016/j.exer.2019.107748DOI Listing
October 2019

Experience of using adalimumab in treating sight-threatening paediatric or adolescent Behcet's disease-related uveitis.

J Ophthalmic Inflamm Infect 2019 Jul 31;9(1):14. Epub 2019 Jul 31.

Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, Hong Kong SAR.

Purpose: To report the clinical outcomes of adalimumab in treating refractory Behcet's disease (BD)-related uveitis in paediatric or adolescent patients.

Methods: Retrospective review of five paediatric or adolescent patients with BD-related uveitis with a minimum follow-up of 24 months.

Results: Disease quiescence was observed in 9 (90%) of 10 eyes at 12 months. The mean number of relapses per year per patient was 5 (range, 3-7) before initiation of adalimumab treatment. This was reduced to 0.2 relapse per patient per year among the five patients during the first 24 months after starting adalimumab treatment. At baseline, 5 eyes had active retinal vasculitis. Retinal vasculitis resolved in all cases (100%) after starting adalimumab. The mean time to complete resolution of inflammation was 3.4 weeks. The mean ± standard deviation logMAR best-corrected visual acuity was 0.711 ± 0.63 at baseline and improved to 0.172 ± 1.04 at 12 months (P < 0.001). None of the patients developed any adverse events associated with adalimumab treatment.

Conclusion: Adalimumab was effective in preventing irreversible sight-threatening BD-related uveitis in paediatric or adolescent patients. Adalimumab appears to be a promising treatment option for young patients with recalcitrant BD-related uveitis and has a favourable safety profile.
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http://dx.doi.org/10.1186/s12348-019-0181-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669227PMC
July 2019

Presenting Features, Treatment and Clinical Outcomes of Cytomegalovirus Retinitis: Non-HIV Patients Vs HIV Patients.

Ocul Immunol Inflamm 2020 May 5;28(4):651-658. Epub 2019 Jun 5.

Department of Ophthalmology & Visual Sciences, Chinese University of Hong Kong, Prince of Wales Hospital , Shatin, Hong Kong SAR.

Purpose: To compare clinical features, complications, and outcomes of CMV retinitis in non-HIV immunocompromised patients with HIV infected patients.

Methods: A retrospective study of patients diagnosed with CMV retinitis with or without HIV infection was performed. Results: Thirty-five eyes from 27 patients (median follow up 26 months) were included. Six patients had HIV infection, the others were immunocompromised from a range of causes. The baseline visual acuity (VA) was similar in the two groups. Prevalence of different types of retinitis (fulminant/indolent) was similar in the two groups. Presence of vitreous haze ≥1+ ( = .041), presence of arteritis, ( = .016) and widespread vascular occlusion ( = .003) were more common in the non-HIV group.

Conclusion: CMV retinitis can present with different features depending on the cause of immunocompromise. Evidence of intraocular inflammation such as vitritis, retinal arteritis, and vascular occlusions was more common in HIV-negative subjects.
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http://dx.doi.org/10.1080/09273948.2019.1604003DOI Listing
May 2020

Trends in the incidence of retinopathy of prematurity over a 10-year period.

Int Ophthalmol 2019 Apr 16;39(4):903-909. Epub 2018 Jun 16.

Department of Ophthalmology and Visual Sciences, 1/F Eye Centre, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

Aim: To describe and evaluate the trends in the incidence of retinopathy of prematurity over a 10-year period in a tertiary hospital in Hong Kong.

Methods: A retrospective review was performed on all preterm infants screened and/or treated for retinopathy of prematurity from January 2006 to December 2015 at Prince of Wales Hospital, Hong Kong. Preterm infants with incomplete records or transferred-in from other hospitals/region solely for treatment of ROP were excluded. The incidence of any ROP or Type 1 ROP was analysed with gestational age and birth weight over a 10-year period with consecutive 2-year intervals to evaluate the trends.

Results: Of all 754 infants included in the study, 234 (31.0%) patients had any ROP and 34 (4.5%) infants developed Type 1 ROP. The incidence of any ROP demonstrated a statistically significant decreasing trend over the five consecutive 2-year intervals (p = 0.016), but the incidence trend of Type 1 ROP is not statistically significant. No infants weighing more than 1250 g developed Type 1 ROP.

Conclusion: We observed a decreasing trend in the incidence of any ROP across the 10-year period in a tertiary hospital in Hong Kong, while the incidence of Type 1 ROP remained stable at 4.5%. The factors leading to the trend were unclear. Improved prenatal care, changing proportion of cases with different birth weight and gestational age, oxygenation level practice in neonatal unit may all contribute to the decreasing trend. Revision of screening criteria may be made according to local experience to maximise cost-effectiveness.
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http://dx.doi.org/10.1007/s10792-018-0896-0DOI Listing
April 2019

Categorizing Two Taiwanese Major Political Parties From Their Faces: The Influence of Provincial Appearance.

Front Psychol 2018 21;9:271. Epub 2018 Mar 21.

Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan.

People go beyond the inferences afforded by a person's observable features to make guesses about personality traits or even social memberships such as political affiliations. The present study extended Hu et al. (2016) to further investigate the influence of provincial appearance on differentiating KMT (Kuomintang) and DPP (Democratic Progressive Party) candidates by headshot photos with three experiments. In Experiment 1 (Membership categorization task), participants categorized the photos from the pilot study (where the difference between the perceived age of KMT and DPP candidates was reduced) and divided into four blocks by their perceived age. We found that participants were able to distinguish KMT from DPP candidates significantly better than chance, even when the perceived age difference between the two parties was minimized. In Experiment 2 (Trait rating task), we asked young and middle-aged adults to rate six traits on candidate's photos. We found that "provincial appearance" is the core trait differentiating the two parties for both young and older participants, while "facial maturity" is another trait for older participants only. In Experiment 3 (Double categorization task), we asked participants to categorize the photos from the Exp. 1 on their membership (KMT or DPP) and on provincial appearance (mainlander or native Taiwanese) in two separate sessions. Results showed that young adults were likely to use the "provincial appearance" as the main characteristic cue to categorize candidates' political membership. In sum, our study showed that Taiwanese adults could categorize the two parties by their headshot photos when age cue was eliminated. Moreover, provincial appearance was the most critical trait for differentiating between KMT and DPP candidates, which may reflect a piece of significant history during the development of the two parties.
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http://dx.doi.org/10.3389/fpsyg.2018.00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872903PMC
March 2018

Bilateral acute retinal necrosis after bilateral cataract surgery in an immunocompromised patient: a case report.

Int Ophthalmol 2018 Jun 23;38(3):1329-1332. Epub 2017 May 23.

Department of Ophthalmology and Visual Sciences, The Prince of Wales Hospital, 1/F, Eye Centre, 30-32 NganShing Street, Shatin, New Territories, Hong Kong.

Purpose: To report a case of bilateral varicella zoster virus (VZV)-associated acute retinal necrosis (ARN) occurring after both eyes sequential cataract surgery in an elderly immunocompromised patient.

Methods: Medical records and investigation results of the patient were reviewed.

Results: Patient experienced floaters and blurring of vision in both eyes 4 weeks after her second uncomplicated cataract surgery. Clinical signs of granulomatous keratic precipitates, prominent vitritis, retinitis and vascular thrombosis were noted in both eyes. Aqueous samples from both eyes were positive for VZV. Disease was treated with intravitreal foscarnet bilaterally and 10 days of systemic intravenous acyclovir (10 mg/kg) followed by oral valaciclovir 1 g three times daily. Final visual acuity at 4 months after initial presentation was 20/60 in both eyes with no retinal detachment noted.

Conclusions: Cataract surgery may have been the trigger for bilateral VZV-associated ARN. Immunocompromised patients can develop ARN and require close observation after cataract surgery. This is, to our knowledge, the first report of bilateral ARN following routine cataract surgery.
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http://dx.doi.org/10.1007/s10792-017-0555-xDOI Listing
June 2018

Treatment of polypoidal choroidal vasculopathy by photodynamic therapy, aflibercept and dexamethasone triple therapy.

Sci Rep 2016 11 16;6:36870. Epub 2016 Nov 16.

Department of Ophthalmology and Visual Sciences, Prince of Wales hospital, Hong Kong, China.

Polypoidal choroidal vasculopathy is a relatively common type of degenerative macular disease among the Chinese population. This study aims to describe the therapeutic responses to combination therapy with photodynamic therapy, intravitreal aflibercept and intravitreal dexamethasone in patients with polypoidal choroidal vasculopathy. A prospective series of 17 eyes of 13 patients suffering from treatment-naïve polypoidal choroidal vasculoapathy were recruited. All cases received triple therapy with photodynamic therapy, intravitreal aflibercept and intravitreal dexamethasone and one year outcomes were reported. The baseline visual acuity was 0.65logMAR +/- 0.38 (Snellen 20/80 to 20/100). The visual acuity at 1 week, 3 months, 6 months and one year after treatment were significantly improved to 0.522logMAR+/- 0.365 (P < 0.04) (Snellen 20/70), 0.363logMAR+/-0.382 (Snellen 20/50;P < 0.001), 0.377logMAR +/- 0.440 (Snellen 20/50;p = 0.005), and 0.35logMAR +/- 0.407 (Snellen 20/40;P < 0.001), respectively. The baseline central foveal thickness (CFT) on optical coherence tomography (OCT) was 394.7 +/- 70.6 μm. CFT at 6 months and 1 year after treatment were significantly reduced to 259 +/- 54 μm (p = 0.004) and 271 +/- 49.7 μm(p = 0.016), respectively. Triple therapy with photodynamic therapy, intravitreal aflibercept and intravitreal dexamethasone is an effective treatment for polypoidal choroidal vasculopathy. The majority of cases responded well with significant responses observed as early as 1 week after initiation of therapy.
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http://dx.doi.org/10.1038/srep36870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111116PMC
November 2016

SUCCESSFUL TREATMENT OF REFRACTORY PROLIFERATIVE RETINOPATHY OF INCONTINENTIA PIGMENTI BY INTRAVITREAL RANIBIZUMAB AS ADJUNCT THERAPY IN A 4-YEAR-OLD CHILD.

Retin Cases Brief Rep 2017 Fall;11(4):352-355

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

Purpose: To describe a case of incontinentia pigmenti with proliferative retinopathy successfully treated by combination of repeated retinal laser photocoagulation and intravitreal ranibizumab injection.

Methods: Single interventional case report of a 4-year-old girl, known case of incontientia pigmenti, first screened at the age of two, presented with proliferative retinopathy. Sole treatment by panretinal laser photocoagulation failed to control the progression of retinal neovascularization. Intravitreal ranibizumab injections were used as an adjunct therapy.

Results: The proliferative retinopathy was brought under control and halted till this date with repeated intravitreal ranibizumab and panretinal photocoagulation. No systemic side effect was noted.

Conclusion: Intravitreal ranibizumab can be considered as an adjunct therapy in proliferative retinopathy secondary to incontinentia pigmenti when monotherapy with panretinal photocoagulation fails. Intravitreal ranibizumab may quickly inhibit the intraocular vascular endothelial growth factor and may prevent devastating complications like tractional retinal detachment. Extra caution has to be taken in adopting different dosages and injection regimes especially in pediatric cases.
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http://dx.doi.org/10.1097/ICB.0000000000000369DOI Listing
January 2018

RETINAL VEIN OCCLUSIONS, FROM BASICS TO THE LATEST TREATMENT.

Retina 2016 Mar;36(3):432-48

*Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong; †Dennis Lam Eye Center, Central District, Hong Kong; ‡Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Guangzhou, China; and §Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.

Purpose: To review the pathophysiology, diagnosis, and updated treatments of retinal vein occlusions (RVOs).

Methods: A review of the literature was performed, focusing on the epidemiology, pathophysiology, diagnosis, and treatments (including both medical and surgical treatments) of RVO. Based on this review, a comprehensive overview was provided regarding the topic of RVO and focused on recent treatment updates.

Results: Retinal vein occlusions have an age- and sex-standardized prevalence of 5.20 per 1,000 for any RVO, 4.42 per 1,000 for branch RVO, 0.80 per 1,000 for central RVO. Worldwide, an estimated 16.4 million adults are affected by RVOs, with 2.5 million affected by central RVO and 13.9 million affected by branch RVO. Retinal vein occlusion is recognized as an important cause of blindness and the diagnostic approaches and treatment options for RVO are reviewed and reported. The current treatment options including medical treatments (bevacizumab, ranibizumab, aflibercept, triamcinolone, and dexamethasone implants) and surgical alternatives were reviewed and reported with summaries on the corresponding strength of evidence.

Conclusion: Despite the understanding of this disease entity, challenges persist in the long-term treatment of RVO-related complications and visual loss. This review provided a detailed summary on the rationality and efficacy of recently developed treatment regimes and evaluated the potential benefit of combination therapy.
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http://dx.doi.org/10.1097/IAE.0000000000000843DOI Listing
March 2016

Combined conjunctival rotational autograft with 0.02% mitomycin C in primary pterygium surgery: a long-term follow-up study.

Br J Ophthalmol 2015 Oct 2;99(10):1396-400. Epub 2015 Apr 2.

Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital & Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, Shatin, Hong Kong.

Background/aims: To compare the long-term outcomes of primary pterygium surgery with combined conjunctival rotational autograft and mitomycin C (CRA-MMC), mitomycin C alone (MMC) and limbal conjunctival autograft (LCAU).

Methods: The outcomes of primary pterygium excision followed by conjunctival rotational autograft (CRA) combined with intraoperative 0.02% MMC for 5 min (group 1, CRA-MMC, n=61) were compared with historical control groups consisting of, pterygium excision with MMC (group 2, n=47), and, pterygium excision with limbal conjunctival autograft (LCAU) (group 3, n=29). The main outcome measures were recurrence rate and complications.

Results: The mean follow-up period was 101±3 months, 138±2 and 137±2 months in the CRA-MMC, MMC and LCAU groups respectively. Recurrence was noted in one patient (1.6%) in the CRA-MMC, 12 patients with MMC (25.5%) and 2 patients with LCAU (6.9%). The difference in recurrence rate between CRA-MMC and MMC was statistically significant (p<0.001). Early postoperative complications included 3 conjunctival cysts (1 from the CRA-MMC, 2 with MMC alone), 2 symblephara (1 in the MMC group, 1 in the LCAU group), and 1 granuloma in the CRA-MMC group.

Conclusions: Pterygium excision followed by CRA-MMC or LCAU are effective means of preventing recurrence. The use of CRA-MMC in pterygium excision may be considered for cases where conventional autograft harvesting is contraindicated or when large grafts for double-head pterygium are required.
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http://dx.doi.org/10.1136/bjophthalmol-2014-305817DOI Listing
October 2015

GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides.

Elife 2014 Apr 22;3:e02450. Epub 2014 Apr 22.

Waksman Institute, Rutgers University, Piscataway, United States.

Using a combination of genetic, biochemical, and structural approaches, we show that the cyclic-peptide antibiotic GE23077 (GE) binds directly to the bacterial RNA polymerase (RNAP) active-center 'i' and 'i+1' nucleotide binding sites, preventing the binding of initiating nucleotides, and thereby preventing transcription initiation. The target-based resistance spectrum for GE is unusually small, reflecting the fact that the GE binding site on RNAP includes residues of the RNAP active center that cannot be substituted without loss of RNAP activity. The GE binding site on RNAP is different from the rifamycin binding site. Accordingly, GE and rifamycins do not exhibit cross-resistance, and GE and a rifamycin can bind simultaneously to RNAP. The GE binding site on RNAP is immediately adjacent to the rifamycin binding site. Accordingly, covalent linkage of GE to a rifamycin provides a bipartite inhibitor having very high potency and very low susceptibility to target-based resistance. DOI: http://dx.doi.org/10.7554/eLife.02450.001.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994528PMC
http://dx.doi.org/10.7554/eLife.02450DOI Listing
April 2014

Management of Choroidal Neovascularization Secondary to Pathological Myopia: The Era of Changes.

Asia Pac J Ophthalmol (Phila) 2014 Mar-Apr;3(2):94-103

From the *Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China; and †Dennis Lam and Partners Eye Center, Central Building, Central, Hong Kong, People's Republic of China.

Choroidal neovascularization (CNV) secondary to pathological myopia is an important cause of significant visual impairment in young adults. High myopia is particularly prevalent in Asian population. New scientific contributions have been made to the understanding of high myopia and myopic CNV. Treatment for myopic CNV has previously relied on photodynamic therapy, laser photocoagulation, and submacular surgery. The treatment outcomes from these modalities are, however, controversial. The introduction of antiangiogenic agents including bevacizumab and ranibizumab has brought the treatment of myopic CNV into a new era. The purpose of this review was to provide an overview of the natural history of myopic CNV, the prognostic factors, and the various treatment options including laser photocoagulation and photodynamic therapy, with particular attention on antiangiogenic agents.
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http://dx.doi.org/10.1097/APO.0000000000000017DOI Listing
August 2015

Genes in the high-density lipoprotein metabolic pathway in age-related macular degeneration and polypoidal choroidal vasculopathy.

Ophthalmology 2014 Apr 3;121(4):911-6. Epub 2014 Jan 3.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China. Electronic address:

Purpose: To investigate the associations of genetic variants in the high-density lipoprotein (HDL) metabolism pathway with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

Design: Cross-sectional, case-control association study.

Participants: A Chinese case-control group of 200 neovascular AMD patients, 233 PCV patients, and 275 control subjects.

Methods: Eight single nucleotide polymorphisms (SNPs) from 6 genes of the HDL metabolism pathway and 2 known AMD-associated SNPs, rs800292 (from complement factor H [CFH]) and rs11200638 (from HtrA serine peptidase 1 [HTRA1]), were genotyped in all study subjects using the TaqMan genotyping technology (Applied Biosystems, Foster City, CA).

Main Outcome Measures: Allele and genotypic frequencies of selected SNPs.

Results: The SNP rs3764261 in the cholesteryl ester transfer protein (CETP) gene was associated significantly with neovascular AMD (P = 1.82×10(-4); odds ratio [OR], 1.89) and PCV (P = 4.04×10(-4); OR, 1.80). The associations remained significant after adjusting for the CFH SNP rs800292 and the HTRA1 SNP rs11200638. A significant interaction between the CETP SNP rs3764261 and the CFH SNP rs800292 existed in both neovascular AMD and PCV, the rs800292 G allele conferring a significantly increased risk of the diseases only in individuals carrying the risk allele T of rs3764261. A borderline association was detected between the ATP-binding cassette, subfamily G, member 1 (ABCG1) gene SNP rs57137919 and PCV (P = 0.03).

Conclusions: Our results showed that CETP is a susceptibility gene for neovascular AMD and PCV and that ABCG1 a putative gene for PCV. CETP exerts a modifying effect on CFH in the genetic risk. Our data suggest a link of the HDL metabolism pathway with neovascular AMD and PCV.
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http://dx.doi.org/10.1016/j.ophtha.2013.10.042DOI Listing
April 2014

Ten-year results of a randomized controlled trial comparing 0.02% mitomycin C and limbal conjunctival autograft in pterygium surgery.

Ophthalmology 2013 Dec 16;120(12):2390-2395. Epub 2013 Jul 16.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR.

Objective: To compare the long-term outcome of pterygium surgery and the long-term effect on endothelial counts after mitomycin C (MMC) or limbal conjunctival autograft (LCAU) in pterygium surgery.

Design: We performed a 10-year follow-up study of a randomized controlled trial.

Participants: A total of 115 eyes of 114 patients with primary pterygium were treated with intraoperative MMC (n = 63) or LCAU transplants (n = 52). A total of 76 patients completed the current 10-year long-term follow-up (47 in the MMC group, 29 in the LCAU group).

Methods: This is a follow-up study of a randomized controlled trial of a cohort of 114 patients in 2 groups that was performed at the Prince of Wales Hospital 10 years ago: group 1, intraoperative 0.02% MMC for 5 minutes; group 2, LCAU. Consecutive patients enrolled in the original study (recruitment began in February 2001) were invited back for a detailed clinical examination to document the long-term outcome of both surgical groups.

Main Outcome Measures: The main outcome measures included the recurrence rate, residual conjunctival bed status, complications, and corneal endothelial cell density (ECD) differences.

Results: A total of 115 eyes of 114 patients were enrolled and randomized in our previous study. For the current study, 76 of the 114 patients (47 in the MMC group, 29 in the LCAU group) were contacted, whereas 18 patients were lost to follow-up and 20 patients had died. The mean follow-up period was 138 ± 2 months in the MMC group and 137 ± 2 months in the LCAU group. Twelve of 47 patients (25.5%) in the original MMC group and 2 of 29 patients (6.9%) in the LCAU group had recurrent pterygium (P = 0.021). The mean ECD was 2,39 2 ± 342 cells/mm(2) in the MMC group and 2,390 ± 388 cells/mm(2) in the LCAU group (P = 0.978). There was no significant difference in the ECD between the operated eyes and the fellow eyes in both groups (P = 0.926 MMC, P = 0.468 LCAU). No other significant ocular complications were observed in either group at the 10-year postoperative follow-up.

Conclusions: Limbal conjunctival autograft was more effective than intraoperative MMC in minimizing pterygium recurrence at the 10-year follow-up. Treatment with intraoperative MMC was not associated with long-term corneal endothelial cell loss.
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http://dx.doi.org/10.1016/j.ophtha.2013.05.033DOI Listing
December 2013

Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome.

Mol Vis 2013 6;19:986-94. Epub 2013 May 6.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, and Department of Ophthalmology, Prince of Wales Hospital, Hong Kong, China.

Purpose: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family.

Methods: Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects.

Results: Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family.

Conclusions: We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654842PMC
September 2013

Choroidal thickness measurement in myopic eyes by enhanced depth optical coherence tomography.

Ophthalmology 2013 Sep 15;120(9):1909-14. Epub 2013 May 15.

Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong.

Purpose: To measure choroidal thickness (CT) in myopic eyes using enhanced depth imaging (EDI).

Design: A cross-sectional study.

Participants: Fifty-six consecutive patients with spherical equivalent refractive error of at least 6 diopters (D) were evaluated.

Methods: Enhanced depth imaging optical coherence tomography (OCT) images were obtained by positioning the spectral-domain OCT device close enough to the eye to acquire an enhanced signal of the choroidal layer. Choroidal depth was measured as the distance between the outer reflective retinal pigment epithelium (RPE) layer and the inner sclera border. Measurements were made in a horizontal fashion across the fovea at 500-μm intervals of the sections. The CT was measured at the subfoveal region in a horizontal fashion, 3 mm temporal to fovea and 3 mm nasal to fovea.

Main Outcome Measures: Correlations among CT with age, refractive error in diopters, and visual acuity in logarithm of the minimum angle of resolution (logMAR) were analyzed with linear mixed models.

Results: The mean age of the 56 patients was 50.4 years (± 2.03 years standard deviation; interquartile range [IQR], 42-62 years), and the mean refractive error was -8.7 D (IQR, -6.1 to -11 D). The mean subfoveal CT was 118 μm (± 68 μm) and correlated negatively with age (P = 0.032) and refractive error (P = 0.011). Regression analysis suggested that subfoveal CT decreased by 11.9 μm for each decade of life and by 6.205 μm for each diopter of myopia. The subfoveal CT was inversely correlated with the logMAR visual acuity (P = 0.008), and visual acuity improved by 0.02 (logMAR) in a 10-μm increase in CT.

Conclusions: Choroidal thickness decreases with age and severity of myopia. Visual acuity decreases in line with decreasing subfoveal CT. A reduction in CT is related to aging and the severity of myopia, whereas visual acuity depends on subfoveal CT. Our study supports the theory that choroidal abnormality may play a key role in the pathogenesis of myopic degeneration.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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http://dx.doi.org/10.1016/j.ophtha.2013.02.005DOI Listing
September 2013

Randomized trial on silicone intubation in endoscopic mechanical dacryocystorhinostomy (SEND) for primary nasolacrimal duct obstruction.

Ophthalmology 2013 Oct 11;120(10):2139-45. Epub 2013 May 11.

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, HKSAR, China; Department of Ophthalmology and Visual Science, The Chinese University of Hong Kong, HKSAR, China. Electronic address:

Purpose: To study the effect of bicanalicular silicone intubation on endonasal endoscopic mechanical dacryocystorhinostomy (EEM-DCR) for primary acquired nasolacrimal duct obstruction (PANDO).

Design: Randomized clinical trial.

Participants: A total of 120 consecutive adults (103 females) with a presenting age of 64 ± 13.7 years (range, 39-92 years) underwent EEM-DCR for PANDO from November 2005 to May 2009 in a lacrimal referral center.

Methods: The EEM-DCR was performed by 2 lacrimal surgeons using standard techniques. Patients were randomly assigned to receive or not receive bicanalicular silicone intubation for 8 weeks. No antimetabolite was used. All patients received a course of oral antibiotics during nonabsorbable nasal packing for flaps tamponade, which was removed at the first postoperative visit. Patients were assessed at 1, 3, 6, 12, 26, and 52 weeks after the operation.

Main Outcome Measures: Surgical success was defined by symptomatic relief of epiphora, reestablishment of nasolacrimal drainage confirmed by irrigation by 1 masked observer, and positive functional endoscopic dye test by the operative surgeon at 12 months postoperatively. Intraoperative and postoperative complications were recorded.

Results: A total of 118 of the 120 randomized cases completed 12 months of follow-up. Two patients died of unrelated medical illnesses during follow-up. At 12 months postoperatively, there was no statistical difference in the success rate between patients with (96.3%) and without (95.3%) intubation (P=0.79). The odds ratio of failure without silicone intubation was 1.28 (95% confidence interval, 0.21-7.95). There was no difference in the incidence (P=0.97) or the time to develop (P=0.12) granulation tissue between the 2 groups. No significant difference was found between successful and failed cases in terms of age (P=0.21), sex (P=0.37), laterality (P=0.46), mode of anesthesia (P=0.14), surgeon (P=0.26), use of stent (P=0.79), or presence of granulation tissue postoperatively (P=0.39).

Conclusions: The current study design provided 90% statistical power to detect more than 21% difference in surgical outcome, and no such difference was found whether intubation was used or not used in EEM-DCR for PANDO at the 12-month follow-up.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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http://dx.doi.org/10.1016/j.ophtha.2013.02.036DOI Listing
October 2013

Eyelid tumours and pseudotumours in Hong Kong: a ten-year experience.

Hong Kong Med J 2013 Apr;19(2):150-5

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

Objective: To describe the clinicopathological characteristics of patients with eyelid tumours in Hong Kong.

Design: Retrospective case series.

Setting: A tertiary eye centre in Hong Kong.

Patients: A computerised retrieval system was used to identify all patients who underwent eyelid mass excisions with histological reports, encountered in the period 2000 to 2009, in a tertiary eye centre. The demographics (age, gender), clinical features (laterality, tumour topography), and the pathological diagnosis of each patient were documented. Descriptive statistical tabulation and analyses were performed on the data.

Results: In all, 198 patients were identified; all were Chinese. Their mean age was 54 years for benign lesions and 68 years for malignant ones. Women were more commonly affected. Benign tumourous lesions occurred more commonly on the upper (n=91; 54%) than lower eyelid (n=79; 47%), whereas malignant lesions more often affected the lower (n=17, 61%) than upper (n=11, 39%) eyelid. The distribution of left and right eye involvement was similar (103 vs 101, respectively). In six patients, there were bilateral benign lesion. Regarding benign masses, 45 (27%) were intradermal neavi, 38 (22%) were squamous papillomas, 25 (15%) were seborrhoeic keratosis lesions, 14 (8%) were epidermoid cysts, and 7 (4%) were compound naevi. Regarding malignant eyelid tumours, the most common was basal cell carcinomas (n=12, 43%), 5 (18%) were squamous cell carcinomas, 3 (11%) were actinic keratosis lesions, and 2 (7%) each were sebaceous gland carcinomas and melanomas.

Conclusion: Benign lesions constituted the majority of these eyelid tumours. Among the malignant lesions, basal cell carcinoma was the commonest type, with lower lid involvement in majority. Sebaceous gland carcinoma is not rare, which is in contrast to Caucasian populations. The relative frequencies of the most common malignant tumours in Hong Kong differed substantially from those reported in other Asian studies.
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April 2013

Structural basis of transcription initiation.

Science 2012 Nov 18;338(6110):1076-80. Epub 2012 Oct 18.

Howard Hughes Medical Institute, Waksman Institute, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.

During transcription initiation, RNA polymerase (RNAP) binds and unwinds promoter DNA to form an RNAP-promoter open complex. We have determined crystal structures at 2.9 and 3.0 Å resolution of functional transcription initiation complexes comprising Thermus thermophilus RNA polymerase, σ(A), and a promoter DNA fragment corresponding to the transcription bubble and downstream double-stranded DNA of the RNAP-promoter open complex. The structures show that σ recognizes the -10 element and discriminator element through interactions that include the unstacking and insertion into pockets of three DNA bases and that RNAP recognizes the -4/+2 region through interactions that include the unstacking and insertion into a pocket of the +2 base. The structures further show that interactions between σ and template-strand single-stranded DNA (ssDNA) preorganize template-strand ssDNA to engage the RNAP active center.
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http://dx.doi.org/10.1126/science.1227786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593053PMC
November 2012

Effects of a novel mGlu₂/₃ receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid.

Psychopharmacology (Berl) 2012 Feb 17;219(4):959-70. Epub 2011 Aug 17.

Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD 11), National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.

Rationale: Accumulating evidence suggests that the primary symptoms of schizophrenia may be associated with altered central glutamate transmission. LY2140023 monohydrate is the methionine prodrug of the selective mGlu(2/3) receptor agonist LY404039 and is currently being assessed for the treatment of schizophrenia.

Objective: The objective of this study was to evaluate the central pharmacological activity of LY2140023 monohydrate in preclinical and clinical studies.

Methods: Effects on neurotransmitter/metabolite concentrations were assessed in male rats following single oral doses of LY2140023 monohydrate (microdiasylates from the prefrontal cortex), single intraperitoneal injection of LY404039 [cerebrospinal fluid (CSF)], or LY2140023 monohydrate dosed once daily for 7 days (CSF). A clinical study in 16 healthy subjects assessed the effects of LY2140023 monohydrate 40 mg orally twice daily for 14 days in lumbar CSF.

Results: Rat studies: Acute dosing with LY2140023 monohydrate resulted in significant dose-dependent increases in extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not 5-hydroxyindoleacetic acid (5-HIAA), in the prefrontal cortex. LY2140023 monohydrate dosing for 7 days elevated the concentrations of HVA in CSF, while acutely dosed LY404039 increased the concentrations of DOPAC, HVA, and methoxy-hydroxyphenylglycol (MHPG), but not 5-HIAA. Clinical study: Significant increases were seen for DOPAC, HVA, 5-HIAA, and MHPG in the CSF of subjects receiving LY2140023 monohydrate, but not placebo.

Conclusions: LY2140023 monohydrate and/or LY404039 dosing potently affected dopamine turnover and also significantly affected serotonin turnover in the human and rat central nervous systems. The measurement of biogenic amine metabolites such as DOPAC and HVA may serve as useful biomarkers of LY2140023 monohydrate and/or LY404039 central pharmacodynamic activity.
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http://dx.doi.org/10.1007/s00213-011-2427-9DOI Listing
February 2012

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants.

Br J Clin Pharmacol 2012 Jan;73(1):93-105

Lilly-NUS Centre for Clinical Pharmacology, Singapore.

Aims: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.

Methods: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].

Results: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).

Conclusions: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.
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http://dx.doi.org/10.1111/j.1365-2125.2011.04049.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248259PMC
January 2012

Structures of RNA polymerase-antibiotic complexes.

Curr Opin Struct Biol 2009 Dec 18;19(6):715-23. Epub 2009 Nov 18.

Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA.

Inhibition of bacterial RNA polymerase (RNAP) is an established strategy for antituberculosis therapy and broad-spectrum antibacterial therapy. Crystal structures of RNAP-inhibitor complexes are available for four classes of antibiotics: rifamycins, sorangicin, streptolydigin, and myxopyronin. The structures define three different targets, and three different mechanisms, for inhibition of bacterial RNAP: (1) rifamycins and sorangicin bind near the RNAP active center and block extension of RNA products; (2) streptolydigin interacts with a target that overlaps the RNAP active center and inhibits conformational cycling of the RNAP active center; and (3) myxopyronin interacts with a target remote from the RNAP active center and functions by interfering with opening of the RNAP active-center cleft to permit entry and unwinding of DNA and/or by interfering with interactions between RNAP and the DNA template strand. The structures enable construction of homology models of pathogen RNAP-antibiotic complexes, enable in silico screening for new antibacterial agents, and enable rational design of improved antibacterial agents.
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http://dx.doi.org/10.1016/j.sbi.2009.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950656PMC
December 2009

Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes.

Sci Signal 2009 Apr 14;2(66):pt2. Epub 2009 Apr 14.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, Ras-GRP and SOS (Ras-guanine nucleotide-releasing protein and Son of Sevenless, respectively), catalyze Ras activation in lymphocytes. Binding of active Ras to the allosteric pocket of SOS markedly increases the activity of SOS. Thus, there is a positive feedback loop regulating SOS. Combining in silico and in vitro studies, we demonstrate that "digital" signaling in lymphocytes (cells are "on" or "off") is predicated on this allosteric regulation of SOS. The SOS feedback loop leads to hysteresis in the dose-response curve, which may enable T cells to exhibit "memory" of past encounters with antigen. Ras activation by Ras-GRP alone is "analog" (a graded increase in activation in response to an increase in the amplitude of the stimulus). We describe how the complementary analog (Ras-GRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output and make predictions regarding the importance of digital signaling in lymphocyte function and development.
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http://dx.doi.org/10.1126/scisignal.266pt2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755093PMC
April 2009

Digital signaling and hysteresis characterize ras activation in lymphoid cells.

Cell 2009 Jan;136(2):337-51

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, RasGRP and SOS, catalyze Ras activation in lymphocytes. Binding of active Ras to SOS' allosteric pocket markedly increases SOS' activity establishing a positive feedback loop for SOS-mediated Ras activation. Integrating in silico and in vitro studies, we demonstrate that digital signaling in lymphocytes (cells are "on" or "off") is predicated upon feedback regulation of SOS. SOS' feedback loop leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen. Ras activation via RasGRP alone is analog (graded increase in amplitude with stimulus). We describe how complementary analog (RasGRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output. Numerous predictions regarding the impact of our findings on lymphocyte function and development are noted.
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http://dx.doi.org/10.1016/j.cell.2008.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662698PMC
January 2009

Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes.

Mol Cell Biol 2007 Apr 5;27(7):2732-45. Epub 2007 Feb 5.

Department of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0795, USA.

Ras activation is crucial for lymphocyte development and effector function. Both T and B lymphocytes contain two types of Ras activators: ubiquitously expressed SOS and specifically expressed Ras guanyl nucleotide-releasing protein (RasGRP). The need for two activators is enigmatic since both are activated following antigen receptor stimulation. In addition, RasGRP1 appears to be dominant over SOS in an unknown manner. The crystal structure of SOS provides a clue: an unusual allosteric Ras-GTP binding pocket. Here, we demonstrate that RasGRP orchestrates Ras signaling in two ways: (i) by activating Ras directly and (ii) by facilitating priming of SOS with RasGTP that binds the allosteric pocket. Priming enhances SOS' in vivo activity and creates a positive RasGTP-SOS feedback loop that functions as a rheostat for Ras activity. Without RasGRP1, initiation of this loop is impaired because SOS' catalyst is its own product (RasGTP)-hence the dominance of RasGRP1. Introduction of an active Ras-like molecule (RasV12C40) in T- and B-cell lines can substitute for RasGRP function and enhance SOS' activity via its allosteric pocket. The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. We hypothesize that this mechanism enables lymphocytes to maximally respond to physiologically low levels of stimulation.
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http://dx.doi.org/10.1128/MCB.01882-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1899892PMC
April 2007