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Biomedical subjects

Vivian Chan

Publications and source records attributed to Vivian Chan.

At least 19 recordsLinked to original sources
PubMed2006

Identification of two sex-specific quantitative trait loci in chromosome 11q for hip bone mineral density in Chinese.

BACKGROUND: Chromosome 11q has not only been found to contain mutations responsible for the several Mendelian disorders of the skeleton, but it has also been linked to bone mineral density (BMD) variation in several genome-wide linkage studies. Furthermore, quantitative trait loci (QTL) affecting BMD in inbred mice and baboons have been mapped to a region syntenic to human chromosome 11q. The aim of the present study is to determine whether there is a QTL for BMD variation on chromosome 11q in the Chinese population. METHODS: Nineteen microsatellite markers were genotyped for a 75 cM region on 11q13-25 in 306 Chinese families with 1,459 subjects. BMD (g/cm(2)) was measured by DXA. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software. RESULTS: For women, a maximum LOD score of 1.62 was achieved at 90.8 cM on 11q21 near the marker D11S4175 for femoral neck BMD; LOD scores greater than 1.0 were observed on 11q13 for trochanter BMD. For men, a maximum LOD score of 1.57 was achieved at 135.8 cM on 11q24 near the marker D11S4126 for total hip BMD. CONCLUSION: We have not only replicated the previous linkage finding on chromosome 11q but also identified two sex-specific QTL that contribute to BMD variation in Chinese women and men.

Bone Density↗
PubMed2006

Confirmation of linkage to chromosome 1q for spine bone mineral density in southern Chinese.

Chromosome 1q has previously been linked to bone mineral density (BMD) variation in the general population in several genome-wide linkage studies in both humans and mouse model. The aim of present study is to replicate and fine map the QTL influencing BMD in chromosome 1q in southern Chinese. Twelve microsatellite markers were genotyped for a 57 cMu region in the chromosome 1q in 306 southern Chinese families with 1,459 subjects. Each of these families was ascertained through a proband with BMD Z-scores less than -1.3 at the hip or spine. BMD (g/cm2) at the L1-4 lumbar spine, femoral neck (FN), trochanter and total hip was measured by dual-energy X-ray absortiometry. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software. Four markers (D1S2878, D1S196, D1S452, and D1S218) achieved a LOD score greater than 1.0 with spine BMD, with the maximum multipoint LOD score of 2.36 at the marker D1S196. We did not detect a LOD score greater than 1.0 for BMD at the FN, trochanter, or total hip in multipoint linkage analyses. Our results present the first evidence for the presence of an osteoporosis susceptibility gene on chromosome 1q in non-Caucasian subjects. Further analyses of candidate genes are warranted to identify QTL genes and variants underlying the variations of BMD in this region.

Adult↗
PubMed2006

T-1213C polymorphism of estrogen receptor beta is associated with low bone mineral density and osteoporotic fractures.

Osteoporosis is a complex disease with a strong genetic component, but the genes involved are poorly defined. To determine whether estrogen receptor beta (ESR2) gene is an osteoporosis risk gene, we examined its association with bone mineral density (BMD) and fracture risk. Using a gene-based approach, a set of 12 polymorphisms of ESR2 was studied in 752 case-control pairs of southern Chinese in ethnicity. Among all polymorphisms, the most significant relation with BMD and fracture risk was observed with T-1213C. Subjects with low BMD had a higher frequency of the variant C allele of T-1213C (cases 11.4%, control 8.4%, P = 0.02). The C allele was associated with 4% reduction in BMD at both the spine and hip in women, and 11% reduction in spine BMD and 9% reduction in hip BMD in men. Similar results were seen with SNP haplotype analysis. Subjects with the C allele of T-1213C were associated with higher risks of osteoporosis and BMD T scores < or = -2.5 (odds ratios: 2.2 at spine and 3.5 at femoral neck for women; 3.5 at lumbar spine for men). Postmenopausal women carrying this C allele were associated with 2.22-fold increased risk of osteoporotic fractures (95% confidence interval 1.26-4.25) even after adjusting for BMD. In conclusion, ESR2 is involved in BMD determination in both sexes. The T-1213C polymorphism influences the risk of fracture in postmenopausal women independent of BMD.

Adult↗
PubMed2006

Full karyotyping, rapid aneuploidy diagnosis or both when invasive prenatal testing is performed for diagnosis of thalassaemia?

A retrospective study was performed to compare the detection rate of chromosomal abnormalities by different approaches of full karyotyping, rapid aneuploidy diagnosis (RAD) or both when invasive prenatal testing is performed for diagnosis of thalassaemia. The karyotype results of 1120 prenatal samples obtained from thalassaemia couples from January 1985 to December 2002 in a referral centre for prenatal diagnosis were studied. The detection rate of chromosomal abnormalities by four different approaches were compared: (i) karyotyping for all samples; (ii) RAD (21,18,13,X,Y) for all samples; (iii) RAD for all samples + karyotyping for cases with ultrasound abnormalities; and (iv) RAD (21,18,13) for all + RAD (X,Y) for cases with ultrasound abnormalities consistent with Turner syndrome + karyotyping for cases with ultrasound abnormalities. Normal karyotypes were found in 1103 samples (98.5%). There were 17 cases (1.5%) of chromosomal abnormalities: four cases (0.36%) were clinically significant, eight cases (0.7%) were of borderline clinical significance and five cases (0.44%) were not confirmed by subsequent prenatal or postnatal tests. The incidences of autosomal (7/1120 = 0.63%) and sex chromosomal (5/1120 = 0.45%) abnormalities were not higher than those (0.41 and 0.22%, respectively) from newborn surveys (Hook and Hamerton, 1977) (P = 0.398 and 0.216, respectively). Approach 1 would detect all 17 chromosomal abnormalities. Approach 2 would detect three of four clinically significant chromosomal abnormalities but not detect six of eight chromosomal abnormalities of borderline clinical significance and three of five chromosomal abnormalities not confirmed by subsequent prenatal or postnatal tests. Approach 3, in addition, would be able to detect all four clinically significant chromosomal abnormalities. Approach 4 would detect all four clinically significant chromosomal abnormalities but would not detect seven of eight chromosomal abnormalities of borderline clinical significance and four of five chromosomal abnormalities not confirmed by subsequent prenatal or postnatal tests. RAD (21,18,13) for all + RAD (X,Y) for cases with ultrasound abnormalities consistent with Turner syndrome + karyotyping for cases with ultrasound abnormalities seemed to be the best approach for the detection of chromosomal abnormalities when invasive prenatal testing is performed for diagnosis of thalassaemia.

Adolescent↗
PubMed2006

Experience in preimplantation genetic diagnosis for exclusion of homozygous alpha degrees thalassemia.

OBJECTIVE: To report our experience in preimplantation genetic diagnosis (PGD) for the exclusion of homozygous alpha degrees thalassemia. PATIENTS AND METHODS: PGD was performed on nine couples with alpha degrees thalassemia genotype undergoing assisted reproduction. Oocytes were aspirated after ovarian stimulation and fertilized by intracytoplasmic sperm injection. One or two blastomeres were biopsied from the six- to eight-cell embryo. Single cell multiplex PCR of the normal and alpha degrees thalassemia alleles was performed for first round, followed by semi-nested PCR of the respective alleles using 5'-end labelled fluorescent primers. Only those embryos with a blastomere diagnosed as having at least one normal allele were selected for transfer. RESULTS: One hundred and twenty-six blastomeres from 82 embryos were analyzed. The rates of allele dropout was 10.2% and PCR failure 12.7%. Fifty-eight embryos (70.7%) had at least one normal allele, of which 31 were transferred to 13 prepared cycles and one triplet pregnancy achieved. The triplets showed no ultrasound features of homozygous alpha degrees thalassemia at 18 weeks and were delivered in healthy condition by caesarean section at 34 weeks. Their genotypes were confirmed by cord blood analysis. CONCLUSIONS: PGD for alpha degrees thalassemia is possible by single cell PCR. The transfer and successful implantation of unaffected embryos ensure birth of disease-free babies.

Alleles↗
PubMed2006

Assessment of linkage and association of 13 genetic loci with bone mineral density.

Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERalpha] and beta [ERbeta], calcium-sensing receptor, vitamin D receptor, collagen type 1alpha1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor beta1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of -1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERalpha and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERbeta and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERbeta and BMD at spine and hip; between D14S1026 of ERbeta and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERalpha was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERalpha, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERalpha, ERbeta and LRP5 are important candidate genes determining BMD variation, especially in females.

Adult↗
PubMed2006

The prevalence and molecular basis of hemoglobinopathies in Cambodia.

Blood counts, hemoglobin (Hb) high performance liquid chromatography (HPLC), and DNA analyses were performed on 260 children, aged 5 months to 16 years, at Siem Reap to assess the prevalence of thalassemia and other hemoglobinopathies in regional Cambodia. Hemoglobinopathies were present in 134 children (51.5%) with 20 abnormal genotypes identified. alpha-Thalassemia (thal) (35.4%) was the most prevalent disorder and the -alpha3.7 gene deletion was the most common alpha-globin gene abnormality. The - -SEA deletion and nondeletional forms of alpha-thal, Hb Constant Spring [Hb CS, alpha142, Term-->Gln, TAA-->CAA (alpha2)], Hb Paksé [alpha142, Term-->Tyr, TAA-->TAT (alpha2)] and triplicated alpha genes, were also present but at low frequencies. Hb E [beta26(B8)Glu-->Lys, GAG-->AAG] (28.8%) was the most common beta-globin gene abnormality, whilst beta-thal was only detected in two children (0.8% of cases). Although hemoglobinopathies were common, the majority of abnormalities detected (heterozygous -alpha3.7 and Hb E) were not clinically significant. On the basis of these findings, and with the majority of abnormalities being mild, it seems improbable that thalassemia represents a major health burden in this region of Cambodia.

Adolescent↗
PubMed2006

Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease.

Seventeen non-transfusion-dependent Chinese haemoglobin H (Hb H) disease patients (age 29-76 years) with serum ferritin >900 microg/l were treated with deferiprone for up to 18 months. One patient withdrew and data from 16 patients were analysed. Sixteen other Hb H patients with ferritin <900 microg/l, matched for age and genotype, acted as controls. Treatment was well tolerated except for mild arthralgia. Serum ferritin fell with treatment, reaching significance at 6 and 18 months (from 1492.3 +/- 901.4 to 519.4 +/- 405.4 microg/l at 18 months, P = 0.0008). Nine of 16 patients had levels below 397 microg/l before 18 months. Serum ferritin remained stable 6 months after stopping treatment. In contrast, there was no change in ferritin levels in the control group. Magnetic resonance imaging was used for measurement of liver iron content. Spin echo T(1)-signal intensity ratio (T(1)-SIR) and gradient echo T(2)-signal intensity ratio (T(2)-SIR) increased with treatment. T(2)-SIR rose from 0.17 +/- 0.08 pretreatment to 0.58 +/- 0.50 at 2 years (P = 0.0055). Improvement occurred in 12 of 16 patients, reaching normal in three patients. Using echocardiography, peak early diastolic : late diastolic blood flow (E/A) remained unchanged with treatment, but isovolumic relaxation time (IVRT) was prolonged at 2 years indicating mild impairment of diastolic function. All systolic function parameters were normal. A longer treatment period is desirable to demonstrate improvement in cardiac function.

Administration, Oral↗
PubMed2006

Thyrotoxic periodic paralysis and polymorphisms of sodium-potassium ATPase genes.

OBJECTIVE: Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism association with recurrent, reversible episodes of muscle weakness. Increased sodium-potassium ATPase (Na/K-ATPase) pump activity is postulated to contribute to the hypokalaemic paralytic attacks in TPP. The aim of this study was to determine the genetic predisposition to TPP in relation to Na/K-ATPase genes. DESIGN: A case-control association study. PATIENTS: Ninety-nine male Chinese TPP patients were compared to 84 male Graves' disease (GD) patients without TPP and 100 normal male controls. MEASUREMENT: A total of 1500 base pairs upstream of the transcriptional start site of the five Na/K-ATPase genes that are expressed in the skeletal muscles, namely ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4, were sequenced in all subjects for mutations or polymorphisms. The single nucleotide polymorphisms (SNPs) of the coding regions of the five genes were also studied for association with TPP. RESULTS: No mutations were detected in the 5' regions of the five genes in any of the patients studied. There was no difference in the distribution of SNPs and SNP haplotypes in the upstream and coding region of these genes between the three groups of subjects. CONCLUSION: No association between the polymorphisms of ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4 genes and TPP could be detected.

Adenosine Triphosphatases↗
PubMed2005

The cell cycle checkpoint gene Rad9 is a novel oncogene activated by 11q13 amplification and DNA methylation in breast cancer.

Human Rad9 (hRad9), a structural homologue of yeast Schizosaccharomyces pombe rad9, is involved in cell cycle checkpoints and apoptosis. hRad9 can serve as a corepressor of androgen receptor in prostate cancer cells, but little is known about its role in the development of breast or other cancers. In the present study, semiquantitative reverse transcription-PCR showed that Rad9 mRNA levels were up-regulated in 52.1% (25 of 48) of breast tumors, and this up-regulation correlated with tumor size (P = 0.037) and local recurrence (P = 0.033). Overexpression of Rad9 mRNA was partly due to an increase in Rad9 gene number as measured by quantitative PCR. In other breast tumors with Rad9 mRNA overexpression but without increase in gene number, there was differential methylation of two putative Sp1/3 binding sites within the first and second introns of the Rad9 gene, which was similarly found in MCF-7 breast cancer cell line with increased Rad9 mRNA. Silencing Rad9 expression by RNA interference in MCF-7 cell line inhibited its proliferation in vitro. Promoter assays indicated that the Sp1/3 site in intron 2 may act as a silencer. In vivo binding of Sp3 to intron 2 was shown by chromatin immunoprecipitation assays. Treatment of MCF-7 cell line with 5'-aza-2'-deoxycytidine reduced Rad9 mRNA expression and also increased binding of Sp3 to the demethylated intron 2 region. Collectively, these findings suggest that Rad9 is a novel oncogene candidate activated by 11q13 amplification and DNA hypermethylation in breast cancer and may play a role in tumor proliferation and local invasion.

Azacitidine↗
PubMed2005

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients.

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.

Adult↗
PubMed2005

Visualization of Helicobacter species within the murine cecal mucosa using specific fluorescence in situ hybridization.

BACKGROUND: Members of the genus Helicobacter have been associated with colitis development in a number of immunodeficient animal models. While it is known that these organisms can initiate colitis development, the location and spatial distribution of these bacteria within the intestinal tract is currently unknown. In this study, we developed and optimized fluorescence in situ hybridization (FISH) probes specifically for Helicobacter species. MATERIALS AND METHODS: Based on 16S-RNA gene alignments, two probes specific for the entire family Helicobacteraceae and two probes specific for Helicobacter ganmani and Helicobacter hepaticus were designed. Evaluation of these probes was determined using ATCC reference strains and cecum samples from ten IL-10 knockout mice. The presence of Helicobacter species was determined using FISH and verified using PCR-DGGE and microscopic examination of silver stained sections. RESULTS: Analysis of the ATCC reference strains revealed that the probes HEL274/HEL717 were specific for the family Helicobacteraceae, while HEP642 was specific for H. hepaticus and GAN1237 for H. ganmani. Using these probes, a pattern of spatial localization of the two different Helicobacter species was observed in the cecum tissues of IL-10 knockout mice. This consistently showed that H. ganmani was localized to the lower regions and H. hepaticus to the mid-upper regions of the crypts. CONCLUSION: We have developed FISH probes specific for the family Helicobacteraceae as well as two individual Helicobacter species. This study will allow the future use of the FISH to better understand host-pathogen interactions in vitro.

Animals↗
PubMed2005

Natural colonization with Helicobacter species and the development of inflammatory bowel disease in interleukin-10-deficient mice.

BACKGROUND: The interleukin-10-deficient (IL-10-/-) mice maintained in specific-pathogen-free (SPF) conditions develop typhlocolitis when experimentally infected with Helicobacter species. However, there is limited information regarding the role of Helicobacter species that naturally colonize IL-10-/- mice in typhlocolitis development. The aim of this study was to examine in SPF IL-10-/- mice the association between natural colonization specific Helicobacter species and typhlocolitis development. MATERIAL AND METHODS: Cecum and proximal colon from 72 C57BL/6 x 129/Ola IL-10-/- mice (8-20 weeks old) were removed for DNA extraction and histologic evaluation. Genus-specific polymerase chain reaction- denaturing gradient gel electrophoresis (PCR-DGGE) and species-specific PCR were used to detect Helicobacter species. Mice were grouped by age, sex, and Helicobacter colonization status, and their histologic scores were compared. The development of clinical typhlocolitis was observed in a further 12 mice. RESULTS: Species-specific PCR showed that mice were colonized with Helicobacter ganmani and/or Helicobacter hepaticus. The PCR-DGGE detected H. ganmani, H. hepaticus and an H. ganmani-like organism. The histologic scores in mice colonized with H. hepaticus were significantly higher than that in mice colonized with H. ganmani. Male mice showed significantly higher histologic scores than female mice. Four of the 12 mice developed clinical typhlocolitis in 38 weeks. CONCLUSION: Natural colonization with different Helicobacter species was found in IL-10-/- mice within the same breeding colony. The severity of typhlocolitis differed according to the colonizing Helicobacter species. Furthermore, the rate of typhlocolitis development in IL-10-/- mice naturally colonized with Helicobacter species was significantly slower than that reported in experimentally infected mice.

Animals↗
PubMed2005

Detection of known haemophilia B mutations and carrier testing by microarray.

The molecular basis of haemophilia B is heterogeneous and many mutations of the Factor IX (FIX) gene have been characterised. Using the allele-specific arrayed primer extension (AS-APEX) technology, we have designed a FIX array to simultaneously analyse 69 mutations found in British, Thai and Chinese patients. This technology overcomes the problem of multiple reverse dot-blot analysis and has a 100% accuracy in the detection of both affected subjects and carriers in families with known mutations. In seven unknown mutations from Thailand, the array could detect the specific mutation in five and in the remainders the normal primer at specific spots failed to extend due to a mutation a few nucleotides upstream, thus allowing their identification. Hence this FIX array can detect 53% of the 2891 mutation entries in the FIX database. Each of the microarray slide can be used for three different test samples and would be useful for carrier testing for common mutations and prenatal diagnosis. It is simpler and more cost effective than genome sequencing and would be particularly useful in laboratories with limited technical capabilities.

Base Sequence↗
PubMed2004

Cost-effectiveness of prenatal screening for thalassaemia in Hong Kong.

OBJECTIVES: To determine the cost effectiveness of a universal prenatal screening program for alpha- and beta-thalassaemia. METHODS: We retrospectively reviewed our program from 1998 to 2002, and calculated the direct and indirect costs of various components. RESULTS: 18,936 women were screened at our prenatal clinic and 153 couples were subsequently referred to our Prenatal Diagnostic Centre for counselling and further investigations. In addition, there were 238 tertiary referrals and 157 self-referrals. After investigations, 84 fetuses were at risk of beta-thalassaemia major/beta-E thalassaemia, 19 of them were affected and 18 were aborted. The total expenditure on our program (HK 10.0 million dollars) would be less than the postnatal service costs (HK 40.4 million dollars) for 18beta-thalassaemia major fetuses if they were born. Of 361 women at risk of carrying a homozygous alpha0-thalassaemia fetus, 311 (86.2%) opted for the indirect approach (using serial ultrasound examinations to exclude Hb Bart's disease), and 76 (24.5%) subsequently underwent an invasive test for a definitive diagnosis. The sensitivity and false positive rate of this indirect approach was 100.0% and 2.9% respectively. CONCLUSION: It is cost effective to run a universal prenatal screening program in an area where both beta-thalassaemia and alpha-thalassaemia are prevalent. The indirect approach can effectively avoid an invasive test in unaffected pregnancies.

Cost-Benefit Analysis↗
PubMed2004

Carrier incidence for spinal muscular atrophy in southern Chinese.

A real time quantitative PCR (QPCR) method using TaqMan technology was used to assess the copy number of the two survival motor neuron genes (SMN1 and SMN2) on chromosome 5q13. This allows the accurate determination of carriers for spinal muscular atrophy (SMA), with one copy of SMN1. Analysis of 569 normal southern Chinese individuals revealed a carrier incidence of 1.6%, similar to that found in the western society. Study of 42 obligatory carriers showed a (2 + 0) genotype in two (4.8 %). In 27 SMA patients with homozygous deletion of the SMN1 gene, the number of SMN2 gene correlated with disease phenotype, with 68% of type II and III patients carrying three or more SMN2 genes, whilst the incidence of three or more SMN2 genes in the normal population was 1.57%.

Asian People↗
PubMed2004

A thalassaemia array for Southeast Asia.

The alpha and beta thalassaemias are the commonest genetic disorders worldwide. The homozygous state is associated with high morbidity and mortality, thus screening of at-risk pregnancies and prenatal testing are strongly advocated. A thalassaemia (thal) array has been designed using allele-specific arrayed primer extension (AS-APEX) for the simultaneous analysis of 15 non-deletion alpha-gene defects and 23 beta-gene mutations commonly found in southeast Asian countries, where thalassaemias are highly prevalent. This overcomes the problem of using multiple reverse dot blot analysis. The array showed 100% sensitivity and specificity in the detection of 120 beta-thal mutants and 35 non-deletion alpha-thal mutants. It is robust enough to be produced in a single place and shipped to other laboratories for use. The production cost of the array is low, each slide can be used for three different test samples and is therefore amenable to large scale antenatal screening in southeast Asian countries.

Asia, Southeastern↗