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1.  Complex cytogenetic rearrangements at the DURS1 locus in syndromic Duane retraction syndrome 
Clinical case reports  2013;1(1):10.1002/ccr3.11.
doi:10.1002/ccr3.11
PMCID: PMC3885256  PMID: 24416505
Duane retraction syndrome; DURS1; 8q12 microduplication syndrome; cytogenetics; copy number variation
2.  RYR1 mutations cause ophthalmoplegia, facial weakness, and malignant hyperthermia 
JAMA ophthalmology  2013;131(12):10.1001/jamaophthalmol.2013.4392.
Objective
To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis and mild hypotonia segregating in two pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles (CFEOM).
Methods
Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed.
Results
Missense mutations resulting in two homozygous RYR1 amino acid substitutions (E989G and R3772W) and two compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a non-consanguineous pedigree, respectively. Orbital magnetic resonance imaging (MRI) revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsies revealed non-specific myopathic changes. Clinically, the patients’ ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness, and were accompanied by an unrecognized susceptibility to malignant hyperthermia.
Conclusions
Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis.
Clinical relevance
RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated pre-surgically.
doi:10.1001/jamaophthalmol.2013.4392
PMCID: PMC3865174  PMID: 24091937
3.  Factors Associated With Adoption of the Electronic Health Record System Among Primary Care Physicians 
JMIR Medical Informatics  2013;1(1):e1.
Background
A territory-wide Internet-based electronic patient record allows better patient care in different sectors. The engagement of private physicians is one of the major facilitators for implementation, but there is limited information about the current adoption level of electronic medical record (eMR) among private primary care physicians.
Objective
This survey measured the adoption level, enabling factors, and hindering factors of eMR, among private physicians in Hong Kong. It also evaluated the key functions and the popularity of electronic systems and vendors used by these private practitioners.
Methods
A central registry consisting of 4324 private practitioners was set up. Invitations for self-administered surveys and the completed questionnaires were sent and returned via fax, email, postal mail, and on-site clinic visits. Current users and non-users of eMR system were compared according to their demographic and practice characteristics. Student’s t tests and chi-square tests were used for continuous and categorical variables, respectively.
Results
A total of 524 completed surveys (response rate 524/4405 11.90%) were collected. The proportion of using eMR in private clinics was 79.6% (417/524). When compared with non-users, the eMR users were younger (users: 48.4 years SD 10.6 years vs non-users: 61.7 years SD 10.2 years, P<.001); more were female physicians (users: 80/417, 19.2% vs non-users: 14/107, 13.1%, P=.013); possessed less clinical experience (with more than20 years of practice: users: 261/417, 62.6% vs non-user: 93/107, 86.9%, P<.001); fewer worked under a Health Maintenance Organization (users: 347/417, 83.2% vs non-users: 97/107, 90.7%, P<.001) and more worked with practice partners (users: 126/417, 30.2% vs non-users: 4/107, 3.7%, P<.001). Efficiency (379/417, 90.9%) and reduction of medical errors (229/417, 54.9%) were the major enabling factors, while patient-unfriendliness (58/107, 54.2%) and limited consultation time (54/107, 50.5%) were the most commonly reported hindering factors. The key functions of computer software among eMR users consisted of electronic patient registration system (376/417, 90.2%), drug dispensing system (328/417, 78.7%) and electronic drug labels (296/417, 71.0%). SoftLink Clinic Solution was the most popular vendor (160/417, 38.4%).
Conclusions
These findings identified several physician groups who should be targeted for more assistance on eMR installation and its adoption. Future studies should address the barriers of using Internet-based eMR to enhance its adoption.
doi:10.2196/medinform.2766
PMCID: PMC4288082  PMID: 25599989
electronic medical record; physicians; adoption; associated factors; medical informatics
4.  The well-being of community-dwelling near-centenarians and centenarians in Hong Kong a qualitative study 
BMC Geriatrics  2014;14:63.
Background
Hong Kong has one of the highest life expectancy rankings in the world. The number of centenarians and near-centenarians has been increasing locally and internationally. The relative growth of this population is a topic of immense importance for population and health policy makers. Living long and living well are two overlapping but distinct research topics. We previously conducted a quantitative study on 153 near-centenarians and centenarians to explore a wide range of biopsychosocial correlates of health and “living long”. This paper reports a follow-up qualitative study examining the potential correlates of “living well” among near-centenarians and centenarians in Hong Kong.
Methods
Six cognitively, physically, and psychologically sound community-dwelling elders were purposively recruited from a previous quantitative study. Semi-structured interviews were conducted.
Results
Four major themes related to living long and well emerged from the responses of the participants: (a) Positive relations with others, (b) Positive events and happiness, (c) Hope for the future, and (d) Positive life attitude. Specifically, we found that having good interpersonal relationships, possessing a collection of positive life events, and maintaining salutary attitudes towards life are considered as important to psychological well-being by long-lived adults in Hong Kong. Most participants perceived their working life as most important to their life history and retired at very old ages.
Conclusions
These findings also shed light on the relationships between health, work, and old age.
doi:10.1186/1471-2318-14-63
PMCID: PMC4031324  PMID: 24886462
Ageing; Hong Kong SAR; Chinese culture; Community and public health; Health and well-being; Psychology; Psychosocial issues
5.  Pontine malformation, undecussated pyramidal tracts and regional polymicrogyria: a new syndrome 
Pediatric neurology  2013;50(4):384-388.
BACKGROUND
Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, which plays a role in axonal guidance during brain development. HGPPS is characterized by the congenital absence of conjugate lateral eye movements with preserved vertical gaze and progressive scoliosis, as well as dysgenesis of brainstem structures and ipsilateral projection of the pyramidal tract.
PATIENT
A 4-year-11-month-old girl presented with psychomotor retardation and autistic traits. Magnetic resonance imaging revealed hypoplasia and malformation of the ventral portion of the pons and medulla oblongata. Diffusion tensor imaging revealed the absence of decussation of the bilateral pyramidal tracts. These findings were similar to the typical findings for HGPPS. However, restriction of horizontal eye movement was minimal, and bilateral polymicrogyria were also noted in the occipitotemporal cortex in the present patient. These findings have not been previously reported in patients with HGPPS. No mutations in the ROBO3, SLIT1, SLIT2, NTN1, SEMA3A and SEMA3F genes were identified.
CONCLUSION
This patient may have a disorder caused by an unidentified factor, other than a mutation in the genes analyzed, involved in corticogenesis, axonal guidance, and brainstem morphogenesis.
doi:10.1016/j.pediatrneurol.2013.12.013
PMCID: PMC3959267  PMID: 24507697
pontine malformation; brainstem hypoplasia; polymicrogyria; axonal guidance; decussation of the pyramidal tract; horizontal gaze palsy and progressive scoliosis
6.  A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3 
Brain  2013;136(2):522-535.
Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the ‘TUBB3 E410K syndrome’. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype–genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.
doi:10.1093/brain/aws345
PMCID: PMC3572929  PMID: 23378218
Kallmann syndrome; cyclic vomiting; peripheral neuropathy; CFEOM; TUBB3
7.  Walking for Recreation and Perceptions of the Neighborhood Environment in Older Chinese Urban Dwellers 
Engagement in walking for recreation can contribute to healthy aging. Although there is growing evidence that the neighborhood environment can influence walking for recreation, the amount of such evidence in relation to older adults is scarce and limited to Western low-density urban locations. Asian urban environments are typified by distinctive environmental and cultural characteristics that may yield different patterns to those observed in Western countries. Therefore, the main aim of this study was to examine associations of perceived environmental attributes with overall and within-neighborhood walking for recreation in Chinese elders (65+ years) residing in Hong Kong, an ultradense Asian metropolis. A sample of 484 elders was recruited from 32 neighborhoods stratified by socio-economic status and walkability (dwelling and intersection densities). Validated questionnaires measuring perceived neighborhood environment and weekly minutes of overall and within-neighborhood walking for recreation were interviewer administered. Results showed that the level of recreational walking was twice to four times higher than that reported in Western adults and elders. While overall walking for recreation showed a general lack of associations with perceived environmental attributes, within-neighborhood recreational walking was positively related with proximity of recreational facilities, infrastructure for walking, indoor places for walking, and presence of bridge/overpasses connecting to services. Age and educational attainment moderated the associations with several perceived environmental attributes with older and less-educated participants showing stronger associations. Traditional cultural views on the benefits of physical activity and the high accessibility of facilities and pedestrian infrastructure of Hong Kong may explain the high levels of walking. Although specific neighborhood attributes, or their perception, may influence recreational walking within the neighborhood, the compactness and public transport affordability of ultradense metropolises such as Hong Kong may make it easy for elders to compensate for the lack of favorable neighborhood attributes by walking outside the neighborhood.
doi:10.1007/s11524-012-9704-8
PMCID: PMC3579303  PMID: 22678651
Walking for recreation; Older adults; Perceived environment; Moderators
8.  An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation 
Human Molecular Genetics  2012;21(26):5484-5499.
Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors in axon guidance. All identified mutations in TUBB2B result in polymicrogyria, but it remains unclear whether TUBB2B mutations can cause axon dysinnervation as a primary phenotype. We have identified a novel inherited heterozygous missense mutation in TUBB2B that results in an E421K amino acid substitution in a family who segregates congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor imaging of brains of affected family members reveals aberrations in the trajectories of commissural projection neurons, implying a paucity of homotopic connections. These observations led us to ask whether axon dysinnervation is a primary phenotype, and why the E421K, but not other, TUBB2B substitutions cause CFEOM. Expression of exogenous Tubb2b-E421K in developing callosal projection neurons is sufficient to perturb homotopic connectivity, without affecting neuronal production or migration. Using in vitro biochemical assays and yeast genetics, we find that TUBB2B-E421K αβ-heterodimers are incorporated into the microtubule network where they alter microtubule dynamics and can reduce kinesin localization. These data provide evidence that TUBB2B mutations can cause primary axon dysinnervation. Interestingly, by incorporating into microtubules and altering their dynamic properties, the E421K substitution behaves differently than previously identified TUBB2B substitutions, providing mechanistic insight into the divergence between resulting phenotypes. Together with previous studies, these findings highlight that β-tubulin isotypes function in both conserved and divergent ways to support proper human nervous system development.
doi:10.1093/hmg/dds393
PMCID: PMC3516133  PMID: 23001566
9.  Complex cytogenetic rearrangements at the DURS1 locus in syndromic Duane retraction syndrome 
Clinical Case Reports  2013;1(1):30-37.
Key Clinical Message
A patient with syndromic Duane retraction syndrome harbors a chromosome 811.1q13.2 inversion and 8p11.1-q12.3 marker chromosome containing subregions with differing mosaicism and allele frequencies. This case highlights the potential requirement for multiple genetic methods to gain insight into genotype–phenotype correlation, and ultimately into molecular mechanisms that underlie human disease.
doi:10.1002/ccr3.11
PMCID: PMC3885256  PMID: 24416505
8q12 microduplication syndrome; copy number variation; cytogenetics; Duane retraction syndrome; DURS1
10.  Narrowband UVB-induced lichen planus pemphigoide 
Dermatology Reports  2011;3(3):e43.
Lichen planus pemphigoides (LPP) is an autoimmune disease characterised by evolution of subepidermal blisters on normal and lichen planus affected skin. We describe a case of LPP in a 54-year-old Chinese woman. The patient presented with psoriasiform plaques and was diagnosed with guttate psoriasis. Narrowband ultraviolet B (NBUVB) therapy was commenced, and she experienced a generalised eruption of violaceous papules, bullae over the lower limbs, and Wickham's striae over the buccal mucosa. Histology from a plaque revealed interface dermatitis, while a specimen from a blister showed subepidermal bulla. Direct immunofluorescence showed linear deposition of IgG and C3 along the basement membrane. A diagnosis of LPP was made on clinicopathological grounds. This is the first case report of NBUVB alone in unmasking LPP. In this case report, we describe the pathological mechanism of NBUVB in the development of LPP and key features distinguishing LPP from bullous lupus erythematosus, bullous lichen planus, bullous pemphigoid, and psoriasis.
doi:10.4081/dr.2011.e43
PMCID: PMC4211512  PMID: 25386295
bullous pemphigoid; lichen planus pemphigoides; lichen planus; narrowband UVB; psoriasis.
11.  Walking for transportation in Hong Kong Chinese urban elders: a cross-sectional study on what destinations matter and when 
Background
Walking for transport can contribute to the accrual of health-enhancing levels of physical activity in elders. Identifying destinations and environmental conditions that facilitate this type of walking has public health significance. However, most findings are limited to Western, low-density locations, while a larger proportion of the global population resides in ultra-dense Asian metropolises. We investigated relationships of within-neighborhood objectively-measured destination categories and environmental attributes with walking for transport in 484 elders from an ultra-dense metropolis (Hong Kong).
Methods
We estimated relationships of diversity (number of different types) and prevalence of within-neighborhood destination categories (environmental audits of 400 m buffers surrounding residential addresses) with transport-related walking (interviewer–administered questionnaire) in 484 Chinese-speaking elders able to walk unassisted and living in 32 neighborhoods stratified by socio-economic status and transport-related walkability. We examined the moderating effects of safety and pedestrian infrastructure-related neighborhood attributes on destination-walking associations.
Results
Participants reported on average 569 and 254 min/week of overall and within-neighborhood walking for transport, respectively. The prevalence of public transit points and diversity of recreational destinations were positively related to overall walking for transport. The presence of a health clinic/service and place of worship, higher diversity in recreational destinations, and greater prevalence of non-food retails and services, food/grocery stores, and restaurants in the neighborhood were predictive of more within-neighborhood walking for transport. Neighborhood safety-related aspects moderated the relationship of overall walking for transport with the prevalence of public transit points, this being positive only in safe locations. Similar moderating effects of safety-related attributes were observed for the relationships of within-neighborhood walking for transport with diversity of recreational and entertainment destinations. Pedestrian-infrastructure attributes acted as moderators of associations of within-neighborhood walking for transport with prevalence of commercial destination categories. Composite destinations indices consisting of destination categories related to the specific measures of walking were positively associated with walking for transport.
Conclusions
The availability of both non-commercial and commercial destinations may promote within-neighborhood walking for transport, while recreational facilities and public transit points may facilitate overall walking for transport. However, destination-rich areas need to also provide adequate levels of personal safety and a physically-unchallenging pedestrian network.
doi:10.1186/1479-5868-10-78
PMCID: PMC3689599  PMID: 23782627
Utilitarian walking; Elders; China; Environmental audit; Neighborhood; Destinations
13.  Wildervanck’s syndrome and mirror movements: a congenital disorder of axon migration? 
Journal of neurology  2011;259(4):761-763.
Cell outgrowth and migration in the developing nervous system result from guidance cues, whose molecular bases and clinical correlates are only partly known. We describe a patient with brain stem malformation, paroxysmal left sided lacrimation when eating (“crocodile tears”) and mirror movements in addition to Wildervanck’s cervico-oculo-acusticus (COA) syndrome, which encompasses Klippel–Feil anomaly, congenital hearing loss and Duane’s syndrome. The unique symptom constellation has not been reported in that combination before and can be discussed in the context of congenital disordered axonal migration based on dysfunction of signalling pathways. However, mutations in some recently discovered genes, associated with single findings also present in our patient, were not found. Therefore, we suppose that the disturbance of an as yet unknown regulatory factor may explain the congenital malformation syndrome of our patient. In general, only a few human disorders have yet been found to result from defects in axon guidance. Nevertheless, disorders of axon guidance can certainly be regarded as a new category of neurodevelopmental disorders.
doi:10.1007/s00415-011-6239-y
PMCID: PMC3517171  PMID: 21947222
Wildervanck’s syndrome; Mirror movements; Duane syndrome; Klippel–Feil syndrome; Axonal disorder
14.  Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of choroidal neovascularisation secondary to pathological myopia: a pilot study 
Background
To assess the efficacy and safety of combined intravitreal triamcinolone (IVTA) and photodynamic therapy (PDT) with verteporfin in the treatment of choroidal neovascularisation (CNV) secondary to pathological myopia.
Methods
22 eyes of 22 patients with subfoveal or juxtafoveal CNV due to pathological myopia were prospectively recruited for combined PDT with IVTA. The treatment outcomes at 1 year were compared with those in a control group of 22 eyes that received PDT monotherapy.
Results
At 1 year, the logMAR best‐corrected visual acuity (BCVA) for the combined PDT with IVTA group changed from 0.62 to 0.61 (p = 0.74), whereas that for the monotherapy group changed from 0.61 to 0.67 (p = 0.33). The mean logMAR BCVA and proportions of patients without losing ⩾3 lines at 1 year were similar between the two groups (p = 0.68 and 0.74, respectively). Subgroup analyses showed that eyes with baseline logMAR BCVA worse than 0.6 (Snellen equivalent 20/80) or CNV with greatest linear dimension ⩾750 μm which received combined therapy had better mean logMAR BCVA at 1 year (p = 0.023 and 0.041, respectively), with a higher proportion of eyes gaining ⩾2 lines of BCVA (p = 0.027 and 0.017, respectively) compared with PDT monotherapy.
Conclusions
Combined PDT with IVTA did not seem to result in significantly better visual outcome compared with PDT monotherapy. However, combined therapy might result in better visual outcome in selected patients with worse initial visual acuity or larger myopic CNV. Further studies are warranted to investigate the role of combined PDT with IVTA in the treatment of myopic CNV, especially in patients with worse prognostic factors.
doi:10.1136/bjo.2006.103606
PMCID: PMC1857631  PMID: 16987898
15.  A prospective randomised trial of different doses of intravitreal triamcinolone for diabetic macular oedema 
Objective
To compare the safety and efficacy of different doses of intravitreal triamcinolone (ivTA) in treating clinically significant diabetic macular oedema (CSMO).
Methods
63 eyes of 63 patients with CSMO and central foveal thickness (CFT) of ⩾250 μm on optical coherence tomography were randomised to receive 4 mg (n = 23), 6 mg (n = 20) or 8 mg (n = 20) ivTA. Patients were followed up for 6 months, and changes in best‐corrected visual acuity (BCVA), optical coherence tomography CFT, standardised change in macular thickness (SCMT), and side effects such as intraocular pressure and cataractogenesis were compared between the three groups.
Results
After ivTA injection, improvements of BCVA and CFT occurred in all groups. The mean BCVA improvement at 6 months was significantly higher for the 8 mg group compared with the 4 mg group, with 9.9 and 3.1 improvement in letters on the Early Treatment of Diabetic Retinopathy Study chart, respectively (p = 0.047). The mean SCMT at 6 months for the 4, 6 and 8 mg groups was 28.7%, 42.3% and 60.5%, respectively (p = 0.06). The proportion of eyes with SCMT ⩾75% at 6 months was higher in the 8 mg group, but the difference failed to reach significance (p = 0.06). Ocular hypertensive responses (>21 mm Hg) occurred in 39%, 30% and 55% of eyes in the 4, 6, and 8 mg groups, respectively (p = 0.27).
Conclusions
Higher doses of ivTA may prolong the duration of visual benefit in diabetic CSMO and seemed to result in more sustained reduction in macular oedema. Further studies are warranted to investigate the optimum dose of ivTA in treating diabetic CSMO.
doi:10.1136/bjo.2006.102848
PMCID: PMC1857621  PMID: 16973659
16.  Smoking, quitting and mortality in an elderly cohort of 56 000 Hong Kong Chinese 
Tobacco Control  2007;16(3):182-189.
Background
Although the harms of smoking are well established, it is unclear how they extend into old age in the Chinese.
Aim
To examine the relationship of smoking with all‐cause and major cause‐specific mortality in elderly Chinese men and women, respectively, in Hong Kong.
Methods
Mortality by smoking status was examined in a prospective cohort study of 56 167 (18 749 men, 37 416 women) Chinese aged ⩾65 years enrolled from 1998 to 2000 at all the 18 elderly health centres of the Hong Kong Government Department of Health.
Results
After a mean follow‐up of 4.1 years, 1848 male and 2035 female deaths occured among 54 214 subjects (96.5% successful follow‐up). At baseline, more men than women were current smokers (20.3% vs 4.0%) and former smokers (40.8% vs 7.9%). The adjusted RRs (95% CI) for all‐cause mortality in former and current smokers, compared with never smokers, were 1.39 (1.23 to 1.56) and 1.75 (1.53 to 2.00) in men and 1.43 (1.25 to 1.64) and 1.38 (1.14 to 1.68) in women, respectively. For current smokers, the RRs (95% CI) for all‐cause mortality were 1.59 (1.39 to 1.82), 1.72 (1.48 to 2.00) and 1.84 (1.43 to 2.35) for daily consumption of 1–9, 10–20 and >21 cigarettes, respectively (p for trend <0.001). RRs (95% CI) were 1.49 (1.30 to 1.72) and 2.20 (1.88 to 2.57) in former and current smokers for all deaths from cancer, and 1.24 (1.04 to 1.47) and 1.57 (1.28 to 1.94) for all cardiovascular deaths, respectively. Quitters had significantly lower risks of death than current smokers from all causes, lung cancer, all cancers, stroke and all cardiovascular diseases.
Conclusions
In old age, smoking continues to be a major cause of death, and quitting is beneficial. Smoking cessation is urgently needed in rapidly ageing populations in the East.
doi:10.1136/tc.2006.019505
PMCID: PMC2598507  PMID: 17565138
17.  Two novel CHN1 mutations in two families with Duane’s retraction syndrome 
Archives of ophthalmology  2011;129(5):649-652.
Objective
To determine the genetic cause of Duane’s retraction syndrome (DRS) in two families segregating DRS as an autosomal dominant trait.
Method
Members of two unrelated pedigrees were enrolled in an ongoing genetic study. Linkage analysis was performed using fluorescent microsatellite markers flanking the CHN1 locus. Probands and family members were screened for CHN1 mutations.
Results
Of the six clinically affected individuals in the two pedigrees, three have bilateral and three have unilateral DRS. Both pedigrees are consistent with linkage to the DURS2 locus, one with complete and one with incomplete penetrance. Sequence analysis revealed the pedigrees segregate novel heterozygous missense CHN1 mutations, c.422C>T and c.754C>T, predicted to result in α2-chimaerin amino acid substitutions P141L and P252S, respectively.
Conclusion
Genetic analysis of two pedigrees segregating nonsyndromic DRS reveals two novel mutations in CHN1, bringing the number of DRS pedigrees know to harbor CHN1 mutations, and the number of unique CHN1 mutations, from seven to nine. Both mutations identified in this study alter residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of α2-chimerin, and thus are predicted to result in its hyper-activation. Moreover, amino acid residue P252 was altered to a different residue in a previously reported DRS pedigree; thus, this is the first report of two CHN1 mutations altering the same residue, further supporting a gain-of-function etiology.
Clinical Relevance
Members of families segregating DRS as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis.
doi:10.1001/archophthalmol.2011.84
PMCID: PMC3517173  PMID: 21555619
18.  The Therapeutic Profile of Rolipram, PDE Target and Mechanism of Action as a Neuroprotectant following Spinal Cord Injury 
PLoS ONE  2012;7(9):e43634.
The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell infiltration, while preventing post-injury reductions in IL-10. This work supports the use of Rolipram as an acute neuroprotectant following SCI and defines an optimal administration protocol and target for its therapeutic application.
doi:10.1371/journal.pone.0043634
PMCID: PMC3446989  PMID: 23028463
19.  Expansion of the CHN1 Strabismus Phenotype 
Hyperactivating mutations in the CHN1 gene can cause supraduction deficits in the absence of Duane retraction syndrome.
Purpose.
Hyperactivating CHN1 mutations have been described in individuals with Duane retraction syndrome with or without vertical gaze abnormalities. This was a study of five family members with distinctive ocular dysmotility patterns that co-segregated with a novel hyperactivating CHN1 mutation.
Methods.
Participating members of a family segregating pleomorphic incomitant strabismus underwent ophthalmic examinations, and several underwent high-resolution magnetic resonance imaging (MRI) of the orbits and brain stem. Participant DNA was extracted and amplified for haplotype analysis encompassing the CHN1 region on chromosome 2q31.1, and mutation analysis of the CHN1 gene, which encodes the Rac-GAP signaling protein α2-chimaerin. In vitro functional studies of the co-inherited mutation were performed, including a Rac-GTP activation assay, quantification of α2-chimaerin translocation, and co-immunoprecipitation.
Results.
All five clinically affected family members exhibited monocular or binocular supraduction deficits, three in the absence of Duane retraction syndrome. MRI in four affected individuals demonstrated small or absent abducens nerves in all four, small oculomotor nerve in one, and small optic nerves in three. Superior oblique muscle volume was also decreased in three of the individuals, supporting trochlear nerve hypoplasia. Strabismus segregated with the CHN1 locus and affected individuals harbored a c.443A>T CHN1 mutation (p.Y148F). In vitro, this novel mutation behaved similarly to previously reported CHN1 mutations underlying familial Duane syndrome, hyperactivating α2-chimaerin by enhancing its dimerization and membrane association and lowering total intracellular Rac-GTP.
Conclusions.
Analysis of the current pedigree expands the phenotypic spectrum of hyperactivating CHN1 mutations to include vertical strabismus and supraduction deficits in the absence of Duane retraction syndrome.
doi:10.1167/iovs.11-7950
PMCID: PMC3175992  PMID: 21715346
20.  HTRA1 Variants in Exudative Age-Related Macular Degeneration and Interactions with Smoking and CFH 
Purpose
Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD.
Methods
The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status.
Results
Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (–625G>A), rs2672598 (–487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 × 10−14, 3.0 × 10− 10, 3.7 × 10−12, and 3.7 × 10−12. Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94–14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 × 10−14). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found.
Conclusions
A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD.
doi:10.1167/iovs.07-1520
PMCID: PMC3215269  PMID: 18316707
21.  Measuring walking within and outside the neighborhood in Chinese elders: reliability and validity 
BMC Public Health  2011;11:851.
Background
Walking is a preferred, prevalent and recommended activity for aging populations and is influenced by the neighborhood built environment. To study this influence it is necessary to differentiate whether walking occurs within or outside of the neighborhood. The Neighborhood Physical Activity Questionnaire (NPAQ) collects information on setting-specific physical activity, including walking, inside and outside one's neighborhood. While the NPAQ has shown to be a reliable measure in adults, its reliability in older adults is unknown. Additionally its validity and the influence of type of neighborhood on reliability and validity have yet to be explored.
Methods
The NPAQ walking component was adapted for Chinese speaking elders (NWQ-CS). Ninety-six Chinese elders, stratified by social economic status and neighborhood walkability, wore an accelerometer and completed a log of walks for 7 days. Following the collection of valid data the NWQ-CS was interviewer-administered. Fourteen to 20 days (average of 17 days) later the NWQ-CS was re-administered. Test-retest reliability and validity of the NWQ-CS were assessed.
Results
Reliability and validity estimates did not differ with type of neighborhood. NWQ-CS measures of walking showed moderate to excellent reliability. Reliability was generally higher for estimates of weekly frequency than minutes of walking. Total weekly minutes of walking were moderately related to all accelerometry measures. Moderate-to-strong associations were found between the NWQ-CS and log-of-walks variables. The NWQ-CS yielded statistically significantly lower mean values of total walking, weekly minutes of walking for transportation and weekly frequency of walking for transportation outside the neighborhood than the log-of-walks.
Conclusions
The NWQ-CS showed measurement invariance across types of neighborhoods. It is a valid measure of walking for recreation and frequency of walking for transport. However, it may systematically underestimate the duration of walking for transport in samples that engage in high levels of this type of walking.
doi:10.1186/1471-2458-11-851
PMCID: PMC3231973  PMID: 22070768
22.  Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance 
Cell  2010;140(1):74-87.
We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-tubulin isotype III, result in a spectrum of human nervous system disorders we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves, and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate normal TUBB3 is required for axon guidance and maintenance in mammals.
doi:10.1016/j.cell.2009.12.011
PMCID: PMC3164117  PMID: 20074521
23.  Institutional risk factors for norovirus outbreaks in Hong Kong elderly homes: a retrospective cohort study 
BMC Public Health  2011;11:297.
Background
Most of the institutional outbreaks of norovirus in Hong Kong occur in elderly homes, the proportion being 69% in 2006. Residents in elderly homes are a special population seriously affected by norovirus infections, it is necessary to investigate the risk factors of the norovirus outbreaks in Hong Kong elderly homes at the facility level.
Methods
A cohort of 748 elderly homes was followed up from January 2005 to December 2007; each elderly home was treated as one observation unit and the outcome event was the norovirus outbreak. Cox regression models were fitted to estimate the rate ratio (RR) and 95% confidence interval (CI) for the potential risk factors.
Results
A total of 276 norovirus outbreaks were confirmed during the study period; the outbreak rate was 12.2 (95% CI: 9.9-14.6) per 100 home-years; elderly homes with a larger capacity (RR = 1.4, 95% CI: 1.3-1.5 (per 30-resident increment)), a higher staff-to-resident ratio (RR = 1.2, 95% CI: 1.1-1.3 (per 1/30 increment) and better wheelchair accessibility (RR = 2.0, 95% CI: 1.3-3.2) were found to have an elevated norovirus outbreak rate in Hong Kong elderly homes; Elderly homes with partitions between beds had a lower rate of norovirus outbreaks (RR = 0.6, 95% CI: 0.4-0.8).
Conclusions
Elderly home capacity, staff-to-resident ratio and wheelchair accessibility were risk factors for norovirus outbreaks in Hong Kong elderly homes. Partitions between beds were a protective factor of norovirus outbreaks. These results should be considered in the infection control in Hong Kong elderly homes.
doi:10.1186/1471-2458-11-297
PMCID: PMC3103461  PMID: 21569308
24.  Depressive symptoms and suicide in 56,000 older Chinese: a Hong Kong cohort study 
Objective
To examine dose–response associations between depressive symptoms and suicide and modification effects of sex, age and health status in older Chinese.
Methods
We used the Chinese version of the 15-item Geriatric Depression Scale (GDS) to measure depressive symptoms (GDS score ≥ 8) and Cox regression to examine association with suicide mortality in a population-based cohort of 55,946 individuals, aged 65 years or above, enrolled from July 1998 to December 2000 at one of 18 Elderly Health Centres of Hong Kong Department of Health. The cohort was followed up for suicide mortality till 31 March 2009 (mean follow-up 8.7 years).
Results
Depressive symptoms were associated with suicide in men [hazard ratio (HR) 2.03, 95% confidence interval (CI) 0.96–4.29] and women (HR = 2.36, 95% CI 1.31–4.24) after adjusting for age, education, monthly expenditure, smoking, alcohol drinking, physical activity, body mass index, health status, and self-rated health. There was no threshold for GDS score and suicide in either sex. Age, sex and health status did not modify the association.
Conclusions
Depressive symptoms predict higher suicide risk in older Chinese in a dose–response pattern. These associations were not attenuated by adjustment for health status, suggesting that depressive symptoms in older people are likely to be an independent causal factor for suicide. The GDS score showed no threshold in predicting suicide risk, suggesting that older people with low GDS scores deserve further attention and those with very high scores need urgent intervention.
doi:10.1007/s00127-011-0362-z
PMCID: PMC3304054  PMID: 21384121
Depressive symptoms; Geriatric Depression Scale; Suicide
25.  CHN1 Mutations are not a Common Cause of Sporadic Duane’s Retraction Syndrome 
doi:10.1002/ajmg.a.33168
PMCID: PMC2801889  PMID: 20034095
Duane; Duane retraction syndrome; congenital cranial dysinnervation disorder; CHN1; chimaerin

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