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.
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.
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.
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.
To compare the safety and efficacy of different doses of intravitreal triamcinolone (ivTA) in treating clinically significant diabetic macular oedema (CSMO).
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.
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).
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.
Although the harms of smoking are well established, it is unclear how they extend into old age in the Chinese.
To examine the relationship of smoking with all‐cause and major cause‐specific mortality in elderly Chinese men and women, respectively, in Hong Kong.
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.
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.
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.
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.
Wildervanck’s syndrome; Mirror movements; Duane syndrome; Klippel–Feil syndrome; Axonal disorder
To determine the genetic cause of Duane’s retraction syndrome (DRS) in two families segregating DRS as an autosomal dominant trait.
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.
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.
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.
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.
Hyperactivating mutations in the CHN1 gene can cause supraduction deficits in the absence of Duane retraction syndrome.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
To examine dose–response associations between depressive symptoms and suicide and modification effects of sex, age and health status in older Chinese.
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).
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.
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.
Depressive symptoms; Geriatric Depression Scale; Suicide
Duane; Duane retraction syndrome; congenital cranial dysinnervation disorder; CHN1; chimaerin
The effects of the built environment on walking in seniors have not been studied in an Asian context. To examine these effects, valid and reliable measures are needed. The aim of this study was to develop and validate a questionnaire of perceived neighborhood characteristics related to walking appropriate for Chinese seniors (Neighborhood Environment Walkability Scale for Chinese Seniors, NEWS-CS). It was based on the Neighborhood Environment Walkability Scale - Abbreviated (NEWS-A), a validated measure of perceived built environment developed in the USA for adults. A secondary study aim was to establish the generalizability of the NEWS-A to an Asian high-density urban context and a different age group.
A multidisciplinary panel of experts adapted the original NEWS-A to reflect the built environment of Hong Kong and needs of seniors. The translated instrument was pre-tested on a sample of 50 Chinese-speaking senior residents (65+ years). The final version of the NEWS-CS was interviewer-administered to 484 seniors residing in four selected Hong Kong districts varying in walkability and socio-economic status. Ninety-two participants completed the questionnaire on two separate occasions, 2-3 weeks apart. Test-rest reliability indices were estimated for each item and subscale of the NEWS-CS. Confirmatory factor analysis was used to develop the measurement model of the NEWS-CS and cross-validate that of the NEWS-A.
The final version of the NEWS-CS consisted of 14 subscales and four single items (76 items). Test-retest reliability was moderate to good (ICC > 50 or % agreement > 60) except for four items measuring distance to destinations. The originally-proposed measurement models of the NEWS-A and NEWS-CS required 2-3 theoretically-justifiable modifications to fit the data well.
The NEWS-CS possesses sufficient levels of reliability and factorial validity to be used for measuring perceived neighborhood environment in Chinese seniors. Further work is needed to assess its construct validity and generalizability to other Asian locations. In general, the measurement model of the original NEWS-A was generalizable to this study context, supporting the feasibility of cross-country and age-group comparisons of the effect of the neighborhood environment on walking using the NEWS-A as a tool to measure the perceived built environment.
The HOXA1-related syndromes result from autosomal recessive truncating mutations in the homeobox transcription factor, HOXA1. Limited horizontal gaze and sensorineural deafness are the most common features; affected individuals can also have facial weakness, mental retardation, autism, motor disabilities, central hypoventilation, carotid artery and/or conotruncal heart defects. Möbius syndrome is also phenotypically heterogeneous, with minimal diagnostic criteria of nonprogressive facial weakness and impaired ocular abduction; mental retardation, autism, motor disabilities, additional eye movements restrictions, hearing loss, hypoventilation, and craniofacial, lingual, and limb abnormalities also occur. We asked, given the phenotypic overlap between these syndromes and the variable expressivity of both disorders, whether individuals with Möbius syndrome might harbor mutations in HOXA1. Our results suggest that HOXA1 mutations are not a common cause of sporadic Möbius syndrome in the general population.
To summarize the clinical, neuroradiologic, and genetic observations in a group of patients with unilateral synergistic divergence (SD).
Five unrelated patients with unilateral SD underwent ophthalmologic and orthoptic examinations; three of them also had magnetic resonance imaging of the brain and orbits. Three patients underwent genetic evaluation of genes known to affect ocular motility (KIF21A, PHOX2A, HOXA1, and ROBO3).
Patients did not meet clinical criteria for CFEOM types 1, 2, or 3. Each patient had severe adduction weakness on the affected side and a large angle exotropia in primary gaze that increased on attempted contralateral gaze because of anomalous abduction. Magnetic resonance imaging revealed a much smaller medial rectus muscle in the involved SD orbit. Oculomotor cranial nerves were present in the one patient imaged appropriately. Genetic sequencing in three patients revealed no mutations in KIF21A, PHOX2A, HOXA1, or ROBO3.
SD should be classified as a distinct congenital ocular motility pattern within congenital cranial dysinnervation disorders. It is possibly caused by denervation of the medial rectus with dysinnervation of the ipsilateral lateral rectus by the oculomotor nerve precipitated by genetic abnormalities (some currently identified) or by local environmental, teratogenic, or epigenetic disturbances.
Hong Kong's rapidly ageing population, characterised by one of the longest life expectancies and the lowest fertility rate in the world, is likely to drive long-term care (LTC) expenditure higher. This study aims to identify key cost drivers and derive quantitative estimates of Hong Kong's LTC expenditure to 2036.
We parameterised a macro actuarial simulation with data from official demographic projections, Thematic Household Survey 2004, Hong Kong's Domestic Health Accounts and other routine data from relevant government departments, Hospital Authority and other LTC service providers. Base case results were tested against a wide range of sensitivity assumptions.
Total projected LTC expenditure as a proportion of GDP reflected secular trends in the elderly dependency ratio, showing a shallow dip between 2004 and 2011, but thereafter yielding a monotonic rise to reach 3.0% by 2036. Demographic changes would have a larger impact than changes in unit costs on overall spending. Different sensitivity scenarios resulted in a wide range of spending estimates from 2.2% to 4.9% of GDP. The availability of informal care and the setting of formal care as well as associated unit costs were important drivers of expenditure.
The "demographic window" between the present and 2011 is critical in developing policies to cope with the anticipated burgeoning LTC burden, in concert with the related issues of health care financing and retirement planning.
Möbius’ syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius’ syndrome.
We examined three related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes 2 mm thick. Subarachnoid cranial nerves were imaged in planes 1 mm thick. Linkage and mutation analysis were performed to determine if the pedigree harbored mutations in four candidate genes.
In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals.
Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius’ syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit, but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius’ syndrome and other congenital cranial dysinnervation disorders (CCDDs). Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the CCDDs defined thus far, rather than a global brainstem insult.
The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.
Moderate alcohol use is generally associated with lower ischaemic heart disease (IHD) mortality but it is difficult to ascertain whether this is due to attributes of moderate alcohol users or the properties of alcohol itself. Evidence from populations with different patterns of alcohol use and IHD can provide crucial evidence. We assessed the association of moderate alcohol use with IHD mortality in older Chinese people from Hong Kong.
We used Cox regression to determine whether moderate alcohol use was associated with IHD mortality in a prospective, population-based cohort study of all 56167 attendees, aged 65 years or over, from July 1998 to December 2000 at all 18 Elderly Health Centers operated by the Department of Health in Hong Kong.
After a median follow-up of 4.2 years, there were 406 (188 in men, 218 in women) deaths from IHD in 54,090 subjects (96.3% successful follow-up). Moderate alcohol use in men was not associated with IHD mortality adjusted only for age [Hazard Ratio, HR 1.01 (95% CI 0.55 to 1.84) compared with never drinkers] or additionally adjusted for socio-economic status and lifestyle. Almost all women were occasional drinkers and their current alcohol use was not significantly associated with IHD mortality [HR 0.88, (95% CI 0.51 to 1.53)].
Moderate alcohol use had no effect on IHD mortality in older Chinese men. Lack of replication of the usual protective effect of moderate alcohol use in a setting with a different pattern of alcohol use and IHD could be due to chance or could suggest that the protective effect of alcohol on IHD does not extend to all populations.
We tested the hypothesis that genetic variants in vasoactive and angiogenic factors regulating the retina vasculature contribute to the development of diabetic retinopathy (DR).
A case-control study was performed to study the genetic association between DR and polymorphic variants of EDN1 (Lys198Asn), LTA (IVS1–80C>A, IVS1–206G>C, IVS1–252A>G), eNOS (Glu298Asp), and ITGA2 (BgI II) in a Chinese population with type 2 diabetes mellitus. A well defined population with type 2 diabetes, consisting of 127 controls and 216 DR patients, was recruited.
A higher frequency of the Asn/Asn genotype of EDN1 was found in individuals with at least 10 years of diabetes and no retinopathy (controls) compared with DR patients with any duration of diabetes (DR: 2.3%; control: 11.0%; p=0.0002). The Asn allele was also more frequent in controls than DR patients (DR: 16.4%; control: 29.5%; p=0.007). Multiple logistic regression analysis showed that the Asn/Asn genotype was the factor most significantly associated with reduced risk of DR (odds ratio=0.19; 95% CI: 0.07-0.53; p=0.002) and with late onset of diabetes (Asn/Asn: 59 years; Lys/Lys + Lys/Asn: 53 years; p=0.02). Moreover, the Lys/Lys genotype was more common among patients with nonproliferative (75.7%) than proliferative DR (56.9%; p=0.008). The distributions of Lys198Asn alleles in hypertension did not differ from normotensive subjects. No associations between DR and polymorphisms of LTA, eNOS, or ITGA2 were detected, and there were no detectable gene-gene or gene-environmental interactions among the polymorphisms.
The Asn/Asn genotype of EDN1 was associated with a reduced risk of DR and with delayed onset of type 2 diabetes.
The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.
Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.
Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.
Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.