Betel Nut Chewing Is Associated With Reduced Tacrolimus Concentration in Taiwanese Liver Transplant Recipients.

PURPOSE: Studies have shown that arecoline, the major alkaloid component of betel nuts, alters the activity of enzymes in the cytochrome P450 (CYP-450) family. Tacrolimus, an immunosuppressant that protects against organ rejection in transplant recipients, not only is mainly metabolized by CYP3A enzymes but also has a narrow therapeutic range. We aimed to investigate whether dose-adjusted blood trough levels of tacrolimus differed over time between betel nut-chewing and non-betel nut-chewing liver transplant recipients. METHODS: In this retrospective case-control study, 14 active betel nut-using liver recipients were matched at a 1:2 ratio to 28 non-betel nut-using liver recipients by sex, age, graft source, duration of follow-up after liver transplantation, and estimated glomerular filtration rate. Differences in liver function index, renal function index, and dose-adjusted blood trough levels of tacrolimus over an 18-month period were compared between the 2 groups by using the Generalized Estimating Equation approach. RESULTS: Dose-adjusted blood trough levels of tacrolimus tended to be significantly (P = .04) lower in betel nut chewers (mean = 0.81, medium = 0.7, 95% confidence interval [CI] = 0.73 to 0.90) than in nonchewers (mean = 1.12, medium = 0.88, 95% CI = 1.03 to 1.22) during the 18-month study period. However, there was no significant difference in renal and liver function index between the 2 groups. CONCLUSION: Liver transplant recipients receiving tacrolimus tend to have lower blood trough levels of the drug over time if they chew betel nuts.

Inhibitive effects of mulberry leaf-related extracts on cell adhesion and inflammatory response in human aortic endothelial cells.

Effects of mulberry leaf-related extracts (MLREs) on hydrogen peroxide-induced DNA damage in human lymphocytes and on inflammatory signaling pathways in human aortic endothelial cells (HAECs) were studied. The tested MLREs were rich in flavonols, especially bombyx faces tea (BT) in quercetin and kaempferol. Polyphenols, flavonoids, and anthocyanidin also abounded in BT. The best trolox equivalent antioxidant capacity (TEAC) was generated from the acidic methanolic extracts of BT. Acidic methanolic and water extracts of mulberry leaf tea (MT), mulberry leaf (M), and BT significantly inhibited DNA oxidative damage to lymphocytes based on the comet assay as compared to the H2O2-treated group. TNF- α -induced monocyte-endothelial cell adhesion was significantly suppressed by MLREs. Additionally, nuclear factor kappa B (NF- κ B) expression was significantly reduced by BT and MT. Significant reductions were also observed in both NF- κ B and activator protein (AP)-1 DNA binding by MLREs. Significant increases in peroxisome proliferator-activated receptor (PPAR) α and γ DNA binding by MLREs were also detected in M and MT extracts, but no evidence for PPAR α DNA binding in 50 µ g/mL MT extract was found. Apparently, MLREs can provide distinct cytoprotective mechanisms that may contribute to its putative beneficial effects on suppressing endothelial responses to cytokines during inflammation.

Cardiac iron measurement and iron chelation therapy in patients with ß thalassaemia major: experience from Taiwan.

BACKGROUND: The aims of our study were to evaluate (i) the relationship between cardiac T2* values and cardiac complications in Asian ß-thalassaemia major (TM) patients, and (ii) the association between cardiac T2* values and other parameters currently used to predict cardiac complications as a result of transfusion iron overload. METHODS: We examined the myocardial iron loads of 88 TM patients from Taiwan with cardiac T2* magnetic resonance imaging (MRI) and assessed the correlation between cardiac T2* values and serum ferritin levels, liver iron concentration and left ventricular ejection fraction (LVEF). We also determined the predictive value of these measurements for the development of arrhythmia. RESULTS AND CONCLUSION: In our group of Taiwanese patients, the relative risk for arrhythmia was 10·36 when cardiac T2* values were less than 10 ms (compared with ≥10 ms) and 1·98 when serum ferritin levels increased >2500 ng mL(-1) (compared with ≤2500 ng mL(-1) ). Serum ferritin levels correlated with cardiac T2* values in patients with abnormal myocardial iron loads (T2* < 20 ms, r = -0·48, P = 0·004, n = 34), but LVEF (measured by echocardiography) gave no indication of excess myocardial iron deposition (r = -0·07, P = 0·52) or of the risk of developing arrhythmia.

Improved treatment results for childhood acute myeloid leukemia in Taiwan.

To improve treatment results for children with de novo acute myeloid leukemia (AML), we introduced a novel protocol, Taiwan Pediatric Oncology Group-AML-97A, for AML other than acute promyelocytic leukemia (APL), for which modified conventional protocols were used. From January 1, 1997, to December 31, 2002, 141 children younger than 17 years old with de novo AML were enrolled. In total, 117 patients with non-APL AML were treated with induction therapy of idarubicin and cytarabine (Ara-C), postremission therapy with high-dose Ara-C - containing regimens for four monthly courses, and moderate-dose therapy with idarubicin and Ara-C for four monthly courses. The first 19 patients with APL were treated with all-trans retinoic acid, idarubicin and Ara-C, with the remaining five patients receiving all-trans retinoic acid and idarubicin, followed by maintenance therapy for 2 years. Stem cell transplantation was performed in 29 patients in first remission with a similar outcome as chemotherapy alone. The remission rate in the AML-97A study was 90%, the 5-year survival 51 +/- 5.3% (s.e.) and the 5-year event-free survival 50 +/- 4.8%; for APL, these were 100%, 86 +/- 7.0, and 75 +/- 9.8%. For the whole group, the 5-year survival was 57 +/- 4.7% and the 5-year event-free survival 54 +/- 4.4%. The AML-97A regimen was well tolerated.

Plasma protein regulation by thyroid hormone.

Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, alpha-2-HS-glycoprotein alpha and beta chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, alpha-2-macroglobulin precursor, prothymosin alpha and alpha-fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TRalpha1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T(3)) induced time- and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TRalpha1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.

Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23.

The clinical and biological features of acute myeloid leukemia (AML) with 11q23/MLL translocations are well known, but the characteristics of AML with partial tandem duplication of the MLL gene have not been explored comprehensively. In this study, MLL duplication was analyzed, in 81 AML patients without chromosomal abnormalities at 11q23, using Southern blotting, genomic DNA polymerase chain reaction (PCR), reverse-transcription PCR and complementary DNA sequencing. Nine patients showed partial tandem duplication of the MLL gene, including eight (12%) of the 68 with normal karyotype. Seven patients showed fusion of exon 6/exon 2 (e6/e2), one, combination of differentially spliced transcripts e7/e2 and e6/e2, and the remaining one, combination of e8/e2 and e7/e2. Among the patients with normal karyotype, children aged 1 to 15 showed a trend to higher frequency of MLL duplication than other patients (2/5 or 40% vs 6/62 or 10%, P = 0.102). The patients with tandem duplication of the MLL gene had a significantly higher incidence of CD11b expression on leukemic cells than did those without in the subgroup of patients with normal karyotype (75% vs 28%, P = 0.017). There were no significant differences in the expression of lymphoid antigens or other myeloid antigens between the two groups of patients. In adults, the patients with MLL duplication had a shorter median survival time than those without (4.5 months vs 12 months, P = 0.036). In conclusion, partial tandem duplication of the MLL gene is associated with increased expression of CD11b on leukemic blasts and implicates poor prognosis in adult AML patients. The higher frequency of MLL duplication in children older than 1 year, than in other age groups, needs to be confirmed by further studies.

The characteristics of phosphorus removal in an anaerobic/aerobic sequential batch biofilter reactor.

Previous research has shown that alternated anaerobic/aerobic conditions are effective in removing phosphorus from wastewater using a biofilter system. However, few studies have been conducted on the features of polyphosphate (poly-P) accumulating organisms (PAOs) in biofilm on phosphorus removal. This study investigated the characteristics of the phosphorus removal mechanism in various hydraulic loads and anaerobic/aerobic time ratios using a sequential batch biofilter reactor. The storage and release of intracellular inclusions, especially polyhydroxyalkanoates (PHAs) and poly-P, would be an important factor for phosphorus removal. Under different operating conditions, total phosphorus removal was always determined by accumulation of PHAs and phosphorus release under the anaerobic phase. The PHA accumulation under the anaerobic phase was always in proportion to the biofilm phosphorus content under aerobic conditions. The result shows PAOs activity was closely related to PHA accumulation. However, the PHA accumulation under the anaerobic phase would be dependent on the hydrolysis of the complex carbon source into short chain fatty acids (SCFA). The result would be demonstrated by the simple carbon source effect. The effect of the An/Ox time ratio on TP removal was significant. Shorter anaerobic time would result in insufficient phosphorus release and greater time would result in inactive PAOs. The appropriate An/Ox time ratio was suggested as 1/2. Comparisons of the phosphorus removal characteristics between biofilm and suspended growth under the same growth conditions are discussed in detail.

Abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients.

OBJECTIVE: To study the prevalence of and risk factors for abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients. RESEARCH DESIGN AND METHODS: A total of 89 transfusion-dependent beta-thalassemic patients were interviewed. Diabetes was previously diagnosed in 14 of them. In the remaining 75 patients, 68 participated in an oral glucose tolerance test. Potential risk factors were identified using the independent t test, chi2 test, and Fisher's exact test. Logistic regression analysis was used to select the independent risk factors that best predicted abnormal glucose tolerance A two-tailed P value of <0.05 was considered to be statistically significant. RESULTS: The prevalence of impaired glucose tolerance was 8.5% (7 of 82) and that of diabetes was 19.5% (16 of 82). Presentation with diabetic ketoacidosis was 31.1% (5 of 16). The risk factors for abnormal glucose tolerance found in transfusion-dependent beta-thalassemic patients were serum ferritin concentration and hepatitis C infection. CONCLUSIONS: The interaction of iron overload and hepatitis C infection worsened the prognosis of thalassemic patients. Aggressive iron-chelation therapy as well as prevention and treatment of hepatitis C infection should be mandatory in managing glucose homeostasis in transfusion-dependent beta-thalassemic patients in Taiwan.

The effects of aging on AV nodal recovery properties.

The purpose of this study was to assess the changes of AV nodal recovery properties with aging. Although in children and young adults it was found that there were age dependent changes in their AV nodal recovery properties, in the older population this information was not available. In 92 subjects (aged 16-92 years) without AV nodal disease or dual AV nodal pathway physiology, their AV nodal recovery curves were studied by delivering premature atrial extrastimuli coupled to basic atrial beats during cardiac electrophysiological study. Data were analyzed using linear regression and curve-fitting techniques. Patients were grouped by age, group I < 40 years (n = 33), group II 40-59 years (n = 26), and group III > 60 years (n = 33). The results showed that the AV nodal recovery curve did not change significantly in the aging process except that the AV nodal effective refractory period had a positive correlation with increasing age. The latter was significantly increased in group III when compared to group I or group II. For this parameter, when patients whose AV nodal refractory period was limited by the atrial refractory period were excluded, there was still a statistically significant increase in group III compared to group II (P < 0.05): group I (n = 27): 202+/-42 ms; group II (n = 17): 197+/-26 ms; and group III (n = 17): 224+/-46 ms. The results suggest that the AV nodal recovery curve remains unchanged once it reaches adulthood, with the exception that the nodal effective refractory period becomes slightly longer after age 60.

Dominant negative activity of mutant thyroid hormone alpha1 receptors from patients with hepatocellular carcinoma.

Complementary DNAs for two mutant thyroid hormone alpha1 receptors (TR alpha1) were isolated from hepatocellular carcinomas of two patients. Sequence analyses of the complementary DNAs showed a single Val390Ala and double Pro398Ser/Glu350Lys mutations in mutants H and L, respectively. We characterized their hormone-binding, DNA-binding, and dominant negative activities. Mutants H and L did not bind the hormone T3. Their DNA-binding activities were analyzed using three types of thyroid hormone response elements (TREs) in which the half-site binding motifs are arranged in an everted repeat (Lys), an inverted repeat (Pal), or a direct repeat separated by four nucleotides (DR4). Compared with wild-type TR alpha1 (w-TR alpha1), which bound these TREs with different homodimer/monomer ratios, binding of mutant L to the three TREs as homodimers was reduced by approximately 90%. However, binding of mutant H to these TREs was more complex. Although it bound normally to DR4 as homodimers, its binding to Lys as homodimers was reduced by approximately 80%. Surprisingly, its binding to Pal was markedly enhanced compared with w-TR alpha1. The binding of these two mutants to the three TREs as heterodimers with retinoid X receptors (RXR alpha and -beta) was not significantly affected. Consistent with the lack of T3-binding activity, both mutants had lost their trans-activation capacity. Mutants H and L exhibited dominant negative activity, but differed in their TRE dependency. The dominant negative potency of mutant H was in the rank order of Pal > DR4 > Lys, whereas no TRE dependency was observed for mutant L. The present study indicates that mutations of the TR alpha gene do occur in patients and that these novel TR alpha1 mutants provide a valuable tool to further understand the molecular basis of the dominant negative action of mutant TRs.

Bone marrow transplantation in Taiwan: an overview.

In Taiwan, a country with 21 million people, 388 bone marrow transplants (BMTs), 308 allografts and 80 autografts, were performed in 5 BMT centers from November 1983 to October 1993. The commonest indications were leukemia, aplastic anemia, lymphoma and thalassemia. Campaigns promoting an unrelated marrow donor registry were started in August 1993 and recruited approximately 26,000 volunteers. A peripheral stem cell program is just beginning. The overall results of BMT in Taiwan are comparable to other countries. The complications of BMT are similar to Western series, except that acute GVHD was rarer in one large series; this observation needs further study. A particular indication for allogeneic BMT in Taiwan is thalassemia, accounting for 10% of all patients. Disease-free survival after BMT for thalassemia is 44%; graft rejection is the major cause of treatment failure. Another important issue is the role of hepatitis B virus (HBV) in BMT, since the prevalence of HBV infection in Taiwan is very high (> 90%). Abnormal liver function is currently the most common complication and might be related to HBV. Among nearly 100 allogeneic BMTs with HBV carriers as either donor or recipient, 2 patients (approximately 2%) died of HBV-related hepatic failure. Whether the HBV status of the donor and recipient is an important prognostic factor remains to be defined.

Results of therapy for beta-thalassemia major.

During the last 10 years, 92 transfusion-dependent beta-thalassemia patients have been encountered at the National Taiwan University Hospital and Provincial Taoyuan General Hospital. Seventy-seven of them were followed up regularly. Long-term results of conventional therapy in 63 cases and allogeneic bone marrow transplantation (BMT) in 14 cases are reported. The conventional therapy included regular red cell transfusion and desferrioxamine iron chelation therapy. Preliminary results of conventional therapy showed a mortality of 7/63 (11%). Of those who were alive, the morbidity was 56/56 (100%). There was no disease-free-survival (0/56; 0%). BMT was performed after preparatory regimens of busulfan, cyclophosphamide, and/or total body or lymphoid irradiation. Preliminary results of BMT showed a mortality of 5/14 (36%). For those who were alive, the morbidity was 3/9 (33%), and the disease-free-survival rate was 6/9 (67%) during a follow-up period of three to six years. It is concluded that the only way to cure beta-thalassemia major at present is BMT. However, the risks of BMT and donor non-availability make conventional therapy unavoidable. Further study is needed to decrease the risk of BMT and to improve the efficacy of conventional therapy.

Changes in the nuclear volume of rat hypothalamic neurons in old age.

Nuclear volumes (NV) of neurons in the preoptic are (POA), suprachiasmatic nucleus (SC), paraventricular nucleus (PVN), supraoptic nucleus (SO), anterior hypothalamic area (AHA), arcuate nucleus (ARN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral mammillary nucleus (ML) were measured in 3.5- to 5-month-old female and male rats and in old female and male rats over 22 months of age. Young adult female rats had larger NV than males in the neurons of all measured areas except for the SC during estrus and the ARN. NV of the hypothalamic neurons of female rats decreased in old age in all measured areas except for the VMN of rats exhibiting prolonged vaginal cornification (PVC). Old male rats showed decreased NV only in the neurons of the SC, SO and ML. The extent of NV decrease of the hypothalamic neurons was not similar in different areas. The sexual difference in neuronal NV in most of the areas disappeared in old age. Only the POA of rats with PVC and the ML of old female rats had larger NV than those of old male rats.