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Biomedical subjects

T M Ko

Publications and source records attributed to T M Ko.

At least 19 recordsLinked to original sources
PubMed2001

A predominantly indigenous paternal heritage for the Austronesian-speaking peoples of insular Southeast Asia and Oceania.

Modern humans reached Southeast Asia and Oceania in one of the first dispersals out of Africa. The resulting temporal overlap of modern and archaic humans-and the apparent morphological continuity between them-has led to claims of gene flow between Homo sapiens and H. erectus. Much more recently, an agricultural technology from mainland Asia spread into the region, possibly in association with Austronesian languages. Using detailed genealogical study of Y chromosome variation, we show that the majority of current Austronesian speakers trace their paternal heritage to Pleistocene settlers in the region, as opposed to more-recent agricultural immigrants. A fraction of the paternal heritage, however, appears to be associated with more-recent immigrants from northern populations. We also show that the northern Neolithic component is very unevenly dispersed through the region, with a higher contribution in Southeast Asia and a nearly complete absence in Melanesia. Contrary to claims of gene flow (under regional continuity) between H. erectus and H. sapiens, we found no ancestral Y chromosome lineages in a set of 1,209 samples. The finding excludes the possibility that early hominids contributed significantly to the paternal heritage of the region.

Asia, Southeastern↗
PubMed2001

Maternal serum C-reactive protein level does not change significantly after fetal reduction: it could be used as an indicator of chorioamnionitis.

PURPOSE: This study was aimed at investigating the diagnostic value of maternal serum C-reactive protein (CRP) in the recognition of chorioamnionitis in patients undergoing fetal reduction. METHODS: Seventy-one gravidas with high-order multifetal pregnancies, including 46 with triplets, 18 with quadruplets, and 7 with quintuplets, who underwent transabdominal fetal reduction to twins during the 10th-14th gestational week were recruited. The subjects were followed up clinically and ultrasonographically 1 week and 1 month after fetal reduction for signs of infection, premature uterine contraction, and premature rupture of the membranes CRP levels were measured prior to fetal reduction and at follow-up examinations, and were compared. RESULTS: Among the 71 mothers, 65 (92%) were normal after fetal reduction. The CRP levels were not significantly different prior to the procedure (0.27 +/- 0.26 mg/dL), and 1 week (0.23 +/- 0.24 mg/dL) and 1 month (0.24 +/- 0.20 mg/dL) later. There was no correlation between the number of fetuses reduced and the CRP levels. Six (8%) experienced leakage of amniotic fluid after fetal reduction. Three patients had normal CRP levels at that time and at the following tests. The pregnancies continued smoothly after conservative treatment. The other three patients had elevated CRP levels when leakage of amniotic fluid occurred. Fever and uterine irritability developed subsequently despite parenteral antibiotics and tocolytic therapy. Daily checks showed increasing CRP levels. The pregnancies were aborted, and the histology of the placental membranes revealed chorioamnionitis with infiltration of acute inflammatory cells. CONCLUSIONS: The absorption of inactive gestational tissue after fetal reduction did not affect CRP levels. CRP may be used as a marker of intrauterine infection after fetal reduction.

C-Reactive Protein↗
PubMed2000

Glucose-6-phosphatase gene mutations in Taiwan Chinese patients with glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSD Ia) is caused by a deficiency of glucose-6-phosphatase (G6Pase) activity. Eighteen GSD Ia families were studied for G6Pase gene mutations. Thirty-two mutations were found in 36 GSD Ia chromosomes: 16 were 727 G-->T (44.44%); 13 were R83H (327 G-->T; 36.11%); 1 was 341delG; 1 was 933insAA; and 1 was 793 G-->T. The 727 G-->T and R83H mutations together accounted for 80.56% (29/36) of the GSD Ia chromosomes. These two mutations were easily examined by polymerase chain reaction-based methods, and the prenatal diagnosis of a non-affected fetus was successfully made. The 727 G-->T mutation is the predominant mutation in Japanese GSD Ia patients, but is rarely seen in Western counties. The 727 G-->T mutation is also the most prevalent mutation in Taiwan Chinese, although the incidence is not as high as in Japan.

Asian People↗
PubMed2000

Prenatal diagnosis of Apert syndrome with widely separated cranial sutures.

A 35-year-old Taiwanese woman visited us for prenatal evaluation in the 20th week of pregnancy. Both clinical observation of the mother and analysis of maternal DNA indicated a diagnosis of Apert syndrome. Sonographic examination of the fetus demonstrated findings that were consistent with this diagnosis; however, no prematurely fused cranial sutures were observed. The pregnancy was terminated after genetic counselling and fetal DNA analysis showed the same mutation as found in the mother. Autopsy of the abortus revealed the same findings as were detected by sonography; however, all cranial sutures were widely separated. These findings indicate that, in Apert syndrome, craniosynostosis and syndactyly may develop asynchronously up to 20 weeks of pregnancy.

Abortion, Therapeutic↗
PubMed1999

Molecular genetic study of Pompe disease in Chinese patients in Taiwan.

Pompe disease is caused by mutations in the acid alpha-glucosidase (GAA) gene. Multiple kinds of mutations in the GAA gene have been reported worldwide. In order to elucidate the molecular basis of the disease in Taiwanese patients of Chinese origin, we have recruited 11 unrelated families who had at least one member with Pompe disease for study. We used 16 pairs of oligonucleotide primers to amplify all the coding regions from exon 2 to 20 in the family members. The coding regions were sequenced on both the sense and antisense strands. We identified 7 different mutations in 17 alleles but failed to identify the defects in the other 5 alleles. The most common defect was D645E (Asp645Glu), accounting for 36% (8/22 alleles) of mutations, followed by G615R (Gly615Arg) (3 alleles); 1411del4 (Glu471-shift) (2 alleles); and one allele each of R600H (Arg600His); deltaN675 (deltaAsn675); 2380delC (Arg794-shift) and 2815delGT (Val939-shift). The molecular defects of Pompe disease are highly heterogeneous in Chinese. Characterization of the molecular defects of the disease is useful for a genotype-phenotype correlation and for genetic counseling and prenatal diagnosis.

Alleles↗
PubMed1999

Prevalence study and molecular characterization of alpha-thalassemia in Filipinos.

In order to determine the prevalence and molecular basis of alpha-thalassemia (thal) among Filipinos, a total of 2954 Filipinos in Taiwan were enrolled in this study. A complete blood count was done for every subject. Those with microcytosis (MCV less than 82.5 fl) were studied with hemoglobin (Hb) high-performance liquid chromatography to determine the levels of Hb A2 and Hb F, and with an enzyme immunoassay to determine plasma ferritin levels. Those who had microcytosis and normal or low levels of Hb A2 and Hb F were further studied with molecular methods for alpha-globin gene mutations. We used Southern blot hybridization and/or the polymerase chain reaction to detect Southeast Asian deletion, Filipino deletion, rightward and leftward single alpha-globin gene deletions, and Hb Constant Spring and Hb Quong Sze. Specific amplification and direct DNA sequencing of the alpha2- and alpha1-globin genes were carried out in apparent alpha-thal carriers without any of the above-mentioned mutations. Our results showed that in Filipinos the prevalence of alpha-thal 1 was 5% (147 carriers) and that of alpha-thal 2 was 1.7% (49 carriers); two had Hb H disease. Among the alpha-thal 1 carriers, 89 had the Southeast Asian deletion and 58 had the Filipino deletion. Among the alpha-thal 2 carriers, 48 had a rightward deletion and one had a leftward deletion. None had Hb Constant Spring or Hb Quong Sze. Specific amplification and DNA sequencing in five apparent alpha-thal carriers did not reveal mutations in the 2-kb region spanning the alpha2- and alpha1-globin genes. The molecular defects of alpha-thal in Filipinos were different from those in the neighboring ethnic groups. Elucidation of the alpha-thal mutations in Filipinos is useful in the genetic counseling and prenatal diagnosis of this common disease.

Gene Deletion↗
PubMed1999

Transmission of de novo mutations of the deleted in azoospermia genes from a severely oligozoospermic male to a son via intracytoplasmic sperm injection.

OBJECTIVE: To investigate the transmission of microdeletions in the deleted in azoospermia (DAZ) genes to a male offspring via intracytoplasmic sperm injection (ICSI). DESIGN: Case report. SETTING: Reproductive unit of a university teaching hospital. PATIENT(S): A 29-year-old, severely oligozoospermic male with microdeletions of the DAZ genes in Yq interval 6 and his son, who was conceived via ICSI. INTERVENTION(S): DNA screening for the microdeletions in Yq interval 6 with 24 sequence tagged sites with the use of polymerase chain reaction amplification for the patient, the patient's father, and the patient's son. Paternity identification was performed using nine hypervariable short tandem repeats. MAIN OUTCOME MEASURE(S): Deletion mapping of Yq interval 6 from sequence tagged sites and electropherogram of short tandem repeats for DNA fingerprinting. RESULT(S): The son had the same microdeletions of the DAZ genes as the patient, and the patient's father had normal DAZ genes. The paternity of the patient, the patient's father, and the patient's son was verified. CONCLUSION(S): De novo DAZ microdeletions in an infertile male can be transmitted to a male offspring via ICSI. DNA screening tests for DAZ genes before ICSI may help in the genetic counseling of patients with idiopathic azoospermia or severe oligozoospermia.

Adult↗
PubMed1999

Laminaria and sulprostone in second trimester pregnancy termination for fetal abnormalities.

The efficacy and safety of intracervical placement of laminaria and intravenous prostaglandin E2 (sulprostone) infusion for termination of second-trimester pregnancies with abnormal fetuses was investigated. One hundred and six pregnant women at 13-29 weeks' gestation with fetal anomalies underwent laminaria tent insertion into the cervical canal on admission. The next morning, Sulprostone infusion was started at a rate of 16 microg/h and increased by 16 microg/h every 30 min to induce uterine contractions. Induction-to-abortion time (IAT), success and complete abortion rates, and sulprostone-related side effects were registered. The overall success and complete abortion rates within 24 h were 91.5 and 80.2%, respectively. The mean IAT was 12.1+/-7.6 h. The incidence of nausea and/or vomiting was 17.9%, with 1.7 episodes per case. Diarrhea and fever (9.5%) were not common. Laminaria tent insertion plus sulprostone infusion was an effective and safe regimen for second-trimester termination of pregnancy with live fetuses.

Abortifacient Agents, Nonsteroidal↗
PubMed1998

Molecular characterization and PCR diagnosis of Thailand deletion of alpha-globin gene cluster.

Thailand deletion of alpha-Thalassemia (thal) 1 involves the zeta2-, phi zeta1-, alpha2-, alpha1-, and theta1-globin genes. In Southeast Asians and Taiwanese, this mutation is the second most common long-segment deletion of two alpha-globin genes, after the Southeast Asian deletion. To define the Thailand deletion breakpoints, we used polymerase chain reaction (PCR) to amplify the normal-sequence DNA fragments across the breakpoints. The amplified products were sequenced directly or after cloning into pGem-3Z or pCR2.1 vectors. Comparison of the normal and mutant sequences revealed that the 5' breakpoint lies between nucleotides 1,269 and 1,290 upstream of the initiator codon adenine of the zeta2-globin gene, and the 3' breakpoint lies between nucleotides 29,387 and 29,408 downstream of it. A total of 30,677 nucleotides were deleted. Both breakpoints mentioned above lie within the Alu repetitive sequences and an extensive sequence homology is present around the two breakpoints. These findings suggest that homologous recombination is the mechanism by which the deletion occurs. Based on our data, we used three oligonucleotide primers to amplify the regions across the deletion and its corresponding normal sequence. The feasibility of PCR diagnosis was confirmed in 20 carriers with this deletion.

Base Sequence↗
PubMed1998

Prevalence and molecular characterization of beta-thalassemia in Filipinos.

Beta-thalassemia (thal) is a common single-gene disease worldwide. However, the prevalence of beta-thal and the spectrum of beta-globin gene mutations in Filipinos remain unclear. This study sought to answer these two questions. A total of 2954 apparently healthy Filipinos in Taiwan were recruited for a prevalence study. A complete blood count was done in every subject. Those with microcytosis were studied with hemoglobin (Hb) high-performance liquid chromatography to determine the levels of Hb A2 and Hb F. Twenty-seven subjects had elevated levels of Hb A2 (>4.0%). These 27 suspected beta-thal carriers and another 16 beta-thal major patients who were being treated in the Philippines were studied to determine the spectrum of beta-globin gene mutations. Gap-PCR was used to detect the Filipino deletion of beta-thal, and direct sequencing was used to detect point or small mutations in the beta-globin gene. All of the 27 suspected beta-thal carriers had one mutation in the beta-globin gene, resulting in an overall prevalence of 0.9%. The spectrum of beta-thal mutations was similar in the carrier and patient groups. Analysis of the pooled identified seven different mutations in the study population. The Filipino deletion was the most common mutation, accounting for 45.8% (27/59) of the alleles, followed by codon 67 (-TG) (16 alleles), and Hb E (11 alleles). These three mutations accounted for 92% of the Filipino beta-thal alleles. Elucidation of the beta-thal mutations in Filipinos is useful for the genetic counseling and prenatal diagnosis of this disease.

Alleles↗
PubMed1998

Fluorescence microsatellite analysis to study the parental origin of the supernumerary chromosome in Down's syndrome.

OBJECTIVE: Down's syndrome (DS) is an important cause of mental retardation. This study investigated the parental origin of the extra chromosome 21 in DS patients. METHODS: Fourteen families each with a DS patient were recruited for analysis of nine microsatellite markers on chromosome 21. We collected DNA from both parents and the patient and used polymerase chain reaction to amplify nine segments on chromosome 21: D21S1435, D21S1436, D21S1437, D21S1446, D21S156, D21S258, D21S263, D21S265 and D21S270. One of each pair of DNA primers was labeled with a fluorescence dye. The amplified products were subjected to electrophoresis in a semi-automated DNA sequencer and then analyzed with Genescan software to determine the origin of the extra chromosome 21. RESULTS: The extra chromosome 21 originated from the mother in 13 (93%) patients and from the father in one (7%) patient. CONCLUSIONS: Our findings were compatible with those from Caucasian patients. A great majority of Down's syndrome cases resulted from meiotic errors in the eggs.

Adult↗
PubMed1998

Molecular study and prenatal diagnosis of alpha- and beta-thalassemias in Chinese.

Thalassemia is one of the most common single gene diseases worldwide. Populations in southern China and Taiwan have high prevalence rates of alpha- and beta-thalassemias. This review summarizes the current status of molecular studies, carrier screening, and prenatal diagnosis of thalassemia in Chinese. There are three genotypes of alpha-thalassemia 1 and at least six of alpha-thalassemia 2 in Chinese. For alpha-thalassemia 1, the South-East Asian deletion is the most common, followed by the Thai then Philippino deletions. For alpha-thalassemia 2, the rightward deletion is the most common, followed by the leftward deletion, and the nondeletional defects Hb Constant Spring and Hb Quong Sze. Twenty-eight different beta-thalassemia mutations have been reported. Four mutations, IVS-II-654 (C-->T), codons 41/42 frameshift (-TCTT), and nonsense codons 17 (A-->T) and -28 (A-->G), account for more than 90% of mutant alleles. For detection of alpha-thalassemia, polymerase chain reaction-related techniques are mainly used. Southern blot hybridization is still useful, especially for prenatal diagnosis. For detection of beta-thalassemia mutations, analysis of amplification-created restriction sites and reverse dot blot hybridization have been extensively used. In Taiwan, a national screening program incorporating hematological and molecular biological methods for thalassemia detection in pregnant women has been in progress for 5 years. Prenatal diagnosis has been performed in more than 1,800 pregnancies, including 1,500 cases at risk for homozygous alpha-thalassemia 1 and 300 for beta-thalassemia major, resulting in early prenatal diagnosis and termination of pregnancies affected with homozygous alpha-thalassemia 1 and an approximately 70% decrease in the number of newborns affected with beta-thalassemia major. In mainland China, only one large-scale screening program is in place. Characterization of undefined alleles, a higher awareness of the disease among physicians and the general public, and improvement of the service network will be important for early prenatal diagnosis and prevention of the disease in the future.

China↗
PubMed1998

Congenital adrenal hyperplasia. Molecular characterization.

OBJECTIVE: To study the molecular defects of congenital adrenal hyperplasia (CAH). STUDY DESIGN: Twenty Chinese patients, including 8 with salt-wasting (SW) type CAH, 11 with simple virilizing (SV) type CAH and 1 with nonclassical (NC) type CAH, were recruited. Two rounds of the polymerase chain reaction (PCR) were used to study the 21-hydroxylase gene (CYP21). The primary PCR amplified CYP21-specific DNA fragments, and the secondary PCR used products from the primary PCR for analysis of amplification-created restriction sites (ACRS) and direct DNA sequencing. In all patients, ACRS analysis was done at 12 possible mutation sites, and then direct DNA sequencing was performed to confirm or define the molecular defects. RESULTS: Ten different mutations, including nine point mutations and gross gene deletion or conversion, were found in this study. Of the nine point mutations, eight could be easily detected by ACRS analysis. The three most common mutations were codon (CD)172 t-->a (I172N), IVS-II 656 c/a-->g, and gross gene deletion or conversion, accounting for 27.5% (11/40 alleles), 25% (10/40) and 20% (8/40) of all identified mutations, respectively. All SW patients were compound heterozygotes of IVS-II 656, gross gene deletion or conversion, or other severe defects, including CDs236 (t-->a) (I236N)+ 237 (t-->a) (V237E)+ 239 (t-->a) (M239K), CD306 (+t), CD318 (c-->t) (Q318X) and CD356 (c-->t) (R356W) mutations. All SV patients had one allele with a CD172 (I172N) mutation. One allele of an NC patient had a CD183 (c-->g) (D183E) mutation, and the other allele was not defined. In the whole series, four alleles (10%) had more than one mutation. CONCLUSION: We found 10 different mutations in this study. The correlation between genotypes and phenotypes was compatible with the reported data. Two rounds of PCR and ACRS analysis may provide important information for genetic counseling, prenatal diagnosis and management of families at risk for CAH.

Adrenal Hyperplasia, Congenital↗
PubMed1997

Molecular characterization of beta-thalassemia in Taiwan and the identification of two new mutations.

Polymerase chain reaction-based techniques were used to study the molecular defects of 480 unrelated beta-thalassemia heterozygotes in Taiwan. Analysis of artificially created restriction sites and gap-polymerase chain reaction were performed to detect four common mutations, i.e. IVS-II-654 (C-->T), codons 41/42 (-TCTT), codon 17 (A-->T), -28 (A-->G), and a deletional form of delta beta-thalassemia in the Chinese population. In cases with negative or ambiguous results with the aforementioned methods, direct DNA cycle sequencing using either S35-dATP or a fluorescent dye terminator, was carried out to determine the defects. A total of 14 different mutations have been found in this series. The IVS-II-654 mutation was the most common (39.6%), followed by the codons 41/42 mutation (37.9%). The four common genotypes accounted for 92.3% of defects. Two new mutations were detected: codon 31 (-C) and codons 40/41 (+T). Both defects resulted in a frameshift and a premature terminator, the former at codon 60, the latter at codon 43. Although we have studied our cases extensively, the molecular defects in seven alleles are still unknown.

Adult↗
PubMed1997

Misdiagnosis of homozygous alpha-thalassaemia 1 may occur if polymerase chain reaction alone is used in prenatal diagnosis.

The polymerase chain reaction (PCR) is a quite sensitive diagnostic tool but its specificity may be hampered because of contamination of foreign DNA. In order to determine the diagnostic accuracy of PCR in diseases due to gross gene deletion, a total of 180 fetuses at risk of homozygous South-East Asian deletion (SEA) of alpha-globin genes were included for study. Both PCR and Southern hybridization (SH) were performed. By PCR, three of 43 affected fetuses were misdiagnosed as heterozygotes; four of 50 normal fetuses were misdiagnosed as heterozygotes; and four of 87 heterozygotes were misdiagnosed, two as normal and two as affected. Misdiagnosis in affected and normal fetuses was most likely due to maternal DNA contamination, while misdiagnosis in heterozygotes was probably due to a failed PCR. In the experiments with PCR in which we added DNA from a carrier woman to an affected or a normal fetus, a level of 1/64 and 1/16 contamination resulted in the appearance of normal and SEA breakpoint sequences, respectively. In the SH experiments using artificially contaminated DNA, a level of 1/4 contamination showed the normal and SEA bands, respectively, while a contamination level lower than 1/8 and 1/16 respectively did not reveal contamination bands. The high sensitivity of PCR makes it easier to amplify contaminated DNA. For accurate prenatal diagnosis, PCR should be performed very carefully and SH seems to be a useful back-up.

Diagnostic Errors↗