Fon Jou Hsieh

HEPATITIS B IMMUNE GLOBULIN (HBIG) EFFICACY IN THE INTERRUPTION OF PERINATAL TRANSMISSION OF HEPATITIS B VIRUS CARRIER STATE: Initial Report of a Randomised Double-Blind Placebo-Controlled Trial

Abstract A randomised double-blind placebo-controlled efficacy trial of hepatitis B immune globulin (HBIG) for prevention of the vertically transmitted HBsAg carrier state was conducted in Taiwan where the carrier rate in the general population is 15-20%. HBIG was given immediately after birth to infants of e antigen positive HBsAg carrier mothers and all infants were followed for 15 months or more. Among 35 placebo-treated infants the carrier rate was 91%. This compares with the carrier rate of only 23% among 40 infants who received 0·5 ml HBIG at birth, three months, and six months and the 45% carrier rate among 42 infants receiving a single 10 ml dose of HBIG at birth only. Efficacy was 75% and 45% respectively for the two treatment schedules. Significantly, the most common response of HBIG-treated infants was passive-active immunisation.

Decreased maternal serum placenta growth factor in early second trimester and preeclampsia.

Objective To compare early second-trimester maternal serum placenta growth factor concentrations in patients with subsequent development of preeclampsia and those with normal pregnancies. Methods We conducted a case-control analysis of stored maternal serum of 27 women who subsequently developed preeclampsia and 227 randomly selected normal controls during the gestational period of 14–19 weeks. Using such a sample size, there was a greater than 95% power to test a difference in the primary study interest. A quantitative sandwich enzyme immunoassay was used to measure the maternal serum placenta growth factor concentration. For statistical analysis, Mann–Whitney U tests, multiple linear regression analysis, multivariable logistic regression model, and receiver-operating characteristic (ROC) curve were used. P < .05 was considered statistically significant. Results Maternal serum placenta growth factor concentration was associated with the occurrence of subsequent preeclampsia (P < .001) and gestational age (P < .001). The median (interquartile range) of multiples (MoM) of the gestational age stratified median for placenta growth factor in preeclampsia was 0.55 (0.33, 0.85). The ROC curve revealed that the specificity was 70% when the diagnostic sensitivity was 70%, and the optimal cutoff value of placenta growth factor MoM was 0.76. The risk of developing preeclampsia subsequently was increased 2.5-fold for maternal serum placenta growth factor concentration decrements of 0.1 MoM. Conclusion A decreased maternal serum placenta growth factor concentration in the early second trimester is highly associated with the subsequent development of preeclampsia, but a large prospective study is needed to explore its use as an early predictor for the condition.

Prediction of adverse perinatal outcome by maternal serum screening for down syndrome in an asian population

Objective To investigate the association between adverse perinatal outcomes and abnormal elevations of serum marker levels (alpha-fetoprotein [AFT] and free β-hCG) or a falso-positive screen for Down syndrome. Mehtods Pregnancy outcome information was available for 5885 Taiwanese women under 35 years of age who had second-trimester maternal serum screening for Down syndrome, using AFP and free β-hCG, and delivered a chromosomally normal fetus. Those with AFT at least 2.0 multiples of the median (MoM), free β-hCG at least 2.5 MoM, or a false-positive screen (risk ratio at least 1:270) were identified, and the risk for adverse perinatal outcome was assessed. Results A serum AFP level at least 2.0 MoM (n = 176, 3.0%) was sognificantly associated with the occurrence of preterm delivery, low Apgar scores, small-for-gestationa-age infants, low birth weight or very low birth weight, fetal death, premature rupture of membranes, oligohydramnios, and a higher incidence of perinatal mortality. a serum free β-hCG level at least 2.5 Mom (n = 416, 7.1%) was significantly associated with low birth weight, an abnormally adherent placementa, and the occurrence of meconium-stained amniotic fluid. A higher incidence of fetal structural anomalies other than neural tube or abdominal wall defects, large-for-gestational-age infants, and postpartum hemorrhage was observed for a calculated risk of at least 1:270 (n = 311, 5.3%) independent of the other biochemical markers. Conclusion Asian women with unexplained elevations of serum AFP or free β-hCG, of a false-positive screen for Down syndrome are at increased risk for various adverse perinatal outcomes. Careful fetal ultrasound examination and thoughtful stragtegy for perinatal management are warranted for these patients.

Angiogenesis of endometrial carcinomas assessed by measurement of intratumoral blood flow, microvessel density, and vascular endothelial growth factor levels

OBJECTIVE To evaluate the relationship between blood flow in the tumor assessed by color Doppler ultrasound, microvessel density, and vascular endothelial growth factor levels in endometrial carcinoma. METHODS Forty-nine patients undergoing surgery for endometrial carcinoma were enrolled. Transvaginal color Doppler ultrasound was performed preoperatively and the lowest resistance index (RI) in the tumor was recorded for analysis. Vascular endothelial growth factor in the tumor was quantified by enzyme immunoassay. The microvessel density of the excised tumor was assessed immunohistochemically. The relationships between the corresponding RI, microvessel density, and vascular endothelial growth factor level of the tumor tissues and clinical and pathologic parameters were analyzed. RESULTS Significantly lower RIs were noted in tumors of stage II or greater (0.37 compared with 0.50, P <.001), of high histologic grade (grade 3) (0.34 compared with 0.49, P =.004), with deep myometrial invasion (one-half depth or greater) (0.39 compared with 0.49, P =.002), with lymphovascular emboli (0.38 compared with 0.49, P <.001), or with lymph node metastasis (0.30 compared with 0.49, P <.001) compared with stage I tumors and tumors of histologic grade 1 or 2, with superficial myometrial invasion, without lymphovascular emboli, or with no lymph node metastasis. Increased vascular endothelial growth factor levels and microvessel density (x200 field) also were detected in tumors of stage II or greater (975 compared with 129 pg/mg, P =.014; and 88 compared with 61, P =.018, respectively), with lymphovascular emboli (1138 compared with 120 pg/mg, P =.002; and 86 compared with 63, P =.023), or with lymph node metastasis (1011 compared with 95 pg/mg, P <.001; and 98 compared with 61, P =. 019). Resistance index, microvessel density, and vascular endothelial growth factor levels in the tumor showed linear correlations (RI compared with microvessel density: r = -.32, P =. 03; RI compared with vascular endothelial growth factor levels: r = -.40, P =.004; microvessel density compared with vascular endothelial growth factor levels: r =.36, P =.011). CONCLUSION Blood flow assessed by color Doppler ultrasound has histologic and biologic correlations with angiogenesis and vascular endothelial growth factor levels and might play an important role in predicting tumor progression and metastasis in endometrial carcinoma.

In search of the Golden Fleece: Unraveling principles of morphogenesis by studying the integrative biology of skin appendages

The mythological story of the Golden Fleece symbolizes the magical regenerative power of skin appendages. Similar to the adventurous pursuit of the Golden Fleece by the multi-talented Argonauts, today we also need an integrated multi-disciplined approach to understand the cellular and molecular processes during development, regeneration and evolution of skin appendages. To this end, we have explored several aspects of skin appendage biology that contribute to the Turing activator/inhibitor model in feather pattern formation, the topo-biological arrangement of stem cells in organ shape determination, the macro-environmental regulation of stem cells in regenerative hair waves, and potential novel molecular pathways in the morphological evolution of feathers. Here we show our current integrative biology efforts to unravel the complex cellular behavior in patterning stem cells and the control of regional specificity in skin appendages. We use feather/scale tissue recombination to demonstrate the timing control of competence and inducibility. Feathers from different body regions are used to study skin regional specificity. Bioinformatic analyses of transcriptome microarrays show the potential involvement of candidate molecular pathways. We further show Hox genes exhibit some region specific expression patterns. To visualize real time events, we applied time-lapse movies, confocal microscopy and multiphoton microscopy to analyze the morphogenesis of cultured embryonic chicken skin explants. These modern imaging technologies reveal unexpectedly complex cellular flow and organization of extracellular matrix molecules in three dimensions. While these approaches are in preliminary stages, this perspective highlights the challenges we face and new integrative tools we will use. Future work will follow these leads to develop a systems biology view and understanding in the morphogenetic principles that govern the development and regeneration of ectodermal organs.

Alpha-thalassemia in the four major aboriginal groups in Taiwan

A total of 1309 unrelated blood samples from four major Taiwan aboriginal groups, including 522 of the Ami, 246 of the Bunun, 227 of the Atayal, and 214 of the Paiwan groups, were collected. Subjects with a mean corpuscular volume below 85 fl and Hb A2 values below 3.5% were further studied with Southern hybridization to determine the status of α-globin genes. In the Ami, 43 (4.1%) chromosomes had α-thalassemia 1 and 43 (4.1%) had α-thalassemia 2. Of the 43 α-thalassemia 1 chromosomes, 33 were of the Thailand, one of the Philippine, and nine of the Southeast Asian deletion. Of the 43 α-thalassemia 2 chromosomes, 42 were of the type I rightward deletion and one was of leftward deletion. In the Bunun group, one chromosome (0.2%) was of the Thailand deletion and two (0.4%) were of type I rightward deletion. In the Atayal group, only one chromosome (0.2%) was of the Philippine deletion. In the Paiwan group, four chromosomes (0.9%) were of the Southeast Asian deletion and three (0.7%) were of the Thailand deletion. Among the four groups, the Ami had the highest prevalence of α-thalassemia, which was also higher than that of the Chinese living in Taiwan.

Prenatal diagnosis of monosomy 10q25 associated with single umbilical artery and sex reversal: report of a case

The association of rare chromosomal rearrangements involving a specific 10q breakpoint with a single umbilical artery (SUA) and sex reversal has never been reported. This report describes the case of a fetus with prenatal ultrasound features of severe intrauterine growth retardation (IUGR), congenital heart disease, and SUA. Fetal blood study revealed de novo deletion of 10q25 and a 46,XY karyotype, while ultrasound demonstrated female genitalia. Based on these findings, sex reversal was diagnosed. Polymerase chain reaction (PCR) amplification revealed the presence of the sex‐determining region of the Y (SRY) gene. The pregnancy was terminated at 36 weeks and the newborn weighed 1908 g with marked facial dysmorphism and abnormal genitalia. Because the parents refused autopsy for this case, histopathological examination of gonads was not performed. Breakpoint of the long arm of chromosome 10 may be responsible for sex reversal in the present case and it could thus confirm the concept of autosomal sex reversal proposed in previous reports.

Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer

Although evidence suggests an importance of genetic factors in the development of breast cancer in Taiwanese (ethnic Chinese) women, including a high incidence of early-onset and secondary contralateral breast cancer, a major breast cancer predisposition gene, BRCA1, has not been well studied in this population. In fact, the carcinogenic impacts of many genetic variants of BRCA1 are unknown and classified as variants of uncertain significance (VUS). It is therefore important to establish a method to characterize the BRCA1 VUSs and understand their role in Taiwanese breast cancer patients. Accordingly, we developed a multimodel assessment strategy consisting of a prescreening portion and a validated functional assay to study breast cancer patients with early-onset, bilateral or familial breast cancer. We found germ-line BRCA1 mutations in 11.1% of our cohort and identified one novel missense mutation, c.5191C>A. Two genetic variants were initially classified as VUSs (c.1155C>T and c.5191C>A). c.1155C>T is not predicted to be deleterious in the prescreening portion of our assessment strategy. c.5191C>A, on the other hand, causes p.T1691K, which is predicted to have high deleterious probability because of significant structural alteration, a high deleterious score in the predictive programs and, clinically, triple negative characteristics in breast tumors. This mutant is confirmed by transcription activation and yeast growth-inhibition assays. In conclusion, we show as high a prevalence of germ-line BRCA1 mutation in high-risk Taiwanese patients as in Caucasians and demonstrate a useful strategy for studying BRCA1 VUSs.

Angiopoietin-like protein 1 decreases blood brain barrier damage and edema following focal cerebral ischemia in mice

Angiopoietin-like protein (Angptl) 1, a member of the angiopoietin-related protein family, modulates angiogenesis but little else is known of its physiological role. We found that angptl1 was upregulated at the 7th day after focal cerebral ischemia in normal mice. In order to understand the role of angptl1 in cerebral infarction, we induced focal cerebral ischemia in normal and glial fibrillary acidic protein promoter-angptl1 transgenic mice. In the transgenic mice without ischemia, overexpression of angptl1 in the whole brain led to a decrease in cortical microvascular density. Following focal cerebral ischemia, edema, but not infarct size, was less in transgenic mice relative to wild type littermates. This effect might be due to a reduction in the blood brain barrier breakdown, as confirmed by a decrease in Evans Blue leakage in the early post-ischemic phase. We conclude that angptl1 may have a beneficial role in the preservation of vascular integrity following focal cerebral ischemia.

Cost‐effectiveness analysis of triple test in second‐trimester maternal serum screening for Down's syndrome: an experience from Taiwan with decreasing birth rate but increasing population of old pregnant women

OBJECTIVES We intended to assess the cost-effectiveness of adding unconjugated oestriol (uE3) in maternal serum screening for Downs syndrome in Taiwan, where there is a decreasing birth rate but an increasing trend of old women having pregnancies. METHODS We used logistic regressions to estimate the risk of Downs syndrome with maternal age and different combinations of biomarkers. Cost-effectiveness analysis was presented in terms of the average and incremental cost-effectiveness ratios. Sensitivity analyses with different parameters were performed. RESULTS Given a cut-off point of 1:270 for the confirmation of Downs syndrome with amniocentesis, the average cost per case averted for maternal age above 35 years only, double test [alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG)] and triple test (AFP, hCG and uE3) were estimated as