Metabolism of triiodothyroacetic acid (TA3) in rat liver. II. Deiodination and conjugation of TA3 by rat hepatocytes and in rats in vivo

The hepatic metabolism of 3,3',5-triiodothyroacetic acid (TA3), a naturally occurring side-chain analog of T3, was studied in vitro and in vivo. Metabolites were quantified by HPLC after Sephadex LH-20 prepurification of samples obtained after incubation of [125I]TA3 or 3,[3'-125I]diiodothyroacetic acid (3,[3'-125I]TA2) with isolated rat hepatocytes under various conditions or after iv administration of [125I]TA3 to normal or 6-propyl-2-thiouracil (PTU)-treated rats. In protein-free incubations with hepatocytes, TA3 glucuronide (TA3G) and I- were normally the main TA3 products, i.e. 44% and 49%, respectively. In the presence of the type I deiodinase inhibitor PTU, the I- production from added TA3 decreased to 3%, and TA3 sulfate (TA3S) increased from 2-14%. Normally, 3,3'-TA2 was converted to I-, but in the presence of PTU 3,3'-TA2S was produced. In SO4(2-)-depleted cultures incubated with TA3 or 3,3'-TA2, production of I- was diminished, and the glucoronides of the substrates and the deiodinated products were generated. If both sulfation and deiodination were inhibited, TA3 and 3,3'-TA2 were cleared completely via glucuronidation. The metabolism of TA3 and especially 3,3'-TA2 was greatly retarded in cultures with 0.1% BSA. PTU treatment of TA3-injected rats reduced plasma I- levels 6-fold, increased plasma sulfates 2.6-fold, but did not affect plasma TA3 clearance. Biliary excretion of radioactivity until 4 h after [125I]TA3 injection amounted to 55% of the dose in controls vs. 85% in PTU-treated rats. In both groups, an unknown metabolite X was detected in serum and its sulfate conjugate XS in bile. The mean percent distribution of TA3G/TA3S/XS in bile amounted to 70:8:13 in control and 57:22:12 in PTU rats. In conclusion, TA3 is effectively metabolized in rat liver by glucuronidation and subsequent biliary excretion of TA3G, which may explain its rapid in vivo clearance relative to T3. Furthermore, a significant proportion of TA3 is deiodinated by the type I deiodinase, either directly or after prior sulfation.     

Telomerase activity and telomere length in acute leukemia: correlations with disease progression,subtypes and overall survival

The progressive shortening of telomeres and the activation of telomerase are considered to be one of the important mechanisms in cellular immortalization and disease progression. Bone marrow samples were collected from 148 patients with acute leukemia (AL). Based on the stage of the disease, patients were divided into the newly diagnosed group, the relapsed group and the complete remission (CR) group. telomerase activity (TA) was examined by PCR-ELISA, and telomere length (TL) was examined by Southern blot analyses. TA and TL were analyzed in relation to AL stage and subtype. Five-year survival was analyzed using Kaplan–Meier survival curve. TA in AL patients was higher than healthy individuals. TA level was the highest in the relapsed group, followed by the newly diagnosed group, and then the CR group. TA had no difference between acute nonlymphocytic leukemia (ANLL) group and acute lymphocytic leukemia (ALL) group. But TA in group of subtype M3 was lower than other subtypes of ANLL. TL in AL group was shorter than the control group. TL was the shortest in the relapsed group, followed by the newly diagnosed group, and finally the CR group. TL exhibited an inverse correlation with TA. The group of patients with high TA had a significantly poorer five-year-survival than that of low TA group. TA is elevated and TL is shortened in AL patients. There is a significant inverse correlation between TL and TA. Patients in late-stage disease had shorter TL and higher TA than those in early stages. The shortened TL and elevated TA correlated with disease progression and relapse, and they may serve as prognostic factors for AL patients with poor outcome. M3 subtype is special with relative lower TA and long-lasting survival than other subtypes.     

Genotyping by"cold single-strand conformation polymorphism" of the UGT1A1 promoter polymorphism in Mexican mestizos

Since no data have previously been reported concerning both the (TA) n polymorphism at the promoter of the UGT1A1 gene in the Mexican population and the use of single-strand conformation polymorphism (SSCP) for the detection of such polymorphism, genotyping by SSCP in 375 G-6-PD normal (Group A) and 81 G-6-PD-deficient (Group B) mestizos belonging to 14 states was carried out. Allele frequencies for (TA)6 and (TA)7 repeats were 0.654 and 0.334, respectively, in Group A and 0.685 and 0.315 in Group B; in the former group, the (TA)5 allele was also observed with a frequency of 0.012. The frequencies of the genotype (TA)7/(TA)7 were 10.1% (Group A) and 8.6% (Group B). The (TA)7/(TA)8 genotype was also observed in a patient with unconjugated hyperbilirubinemia. Due to the importance of its potential medical implications, the observed high frequency (10%) of the (TA)7/(TA)7 genotype is stressed. Genotyping by SSCP of the (TA) n polymorphism is an adequate methodological option.     

Pharmacokinetics of Triamterene

The knowledge about the pharmacokinetics of triamterene (TA) was limited until recently. The metabolic pathway of TA is the formation of p-hydroxytriaraterene (OH-TA), which is subsequently conjugated with active sulfate to form p-hydroxytriamterene sulfuric acid ester (OH-TA-ester). The phase-II-metabolite is surprisingly pharmacologically active. TA and its metabolites were measured by a specific and sensitive tlc-method concomitantly. The i.v. kinetics of TA were determined after application of a newly developed lactic acid solution of the drug. Comparing these data with results after oral application of TA the bioavailabili-ty of TA was 52 % and the extent of absorption 83 %. The bioavail-ability of different dosage forms was correlated with in vitro tests. In liver disease the pharmacokinetics of TA are markedly altered. While in cirrhosis the hydroxylation of TA was decreased, the biliary excretion of this agent was strongly reduced in hepatitis. In renal disease the excretion of TA and OH-TA-ester was reduced according to endogenous creatinine clearance. In older patients the elimination of TA was impaired.     

Co-inherited Gilbert's syndrome: a factor determining hyperbilirubinemia in homozygous beta-thalassemia

BACKGROUND AND OBJECTIVE: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter. DESIGN AND METHODS: We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia. RESULTS: In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype. INTERPRETATION AND CONCLUSIONS: These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co-inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders.     

UGT1A1＊28基因多态性在68例小细胞肺癌中的分布

目的 测定68例小细胞肺癌中UGT1A1＊ 28基因多态性的频率与分布情况.方法 收集中南大学湘雅医院68例中国人小细胞肺癌患者和33名中国正常人外周血标本,抽提基因组DNA,PCR法扩增目的基因片段,荧光标记测序法测定UGT1A1基因启动子区TATA盒胸腺嘧啶-腺嘌呤（TA）序列重复次数,统计中国小细胞肺癌和正常人中UGT1A1＊ 28基因多态性分布情况.结果 68例小细胞肺癌患者中51例（75.00％）为（TA） 6/（TA）6型,17例（25.00％）为（TA） 6/（TA）7型,0例为（TA）7/（TA）7型;33名正常人中25名（75.76％）为（TA） 6/（TA）6型,6名（18.18％）为（TA）6/（TA）7型,2名（6.06％）为（TA）7/（TA）7型.结论 UGT1A1＊ 28基因多态性在中国小细胞肺癌与正常人群中的分布有统计学差异.中国人UGT1A1＊ 28基因多态性发生频率与欧美人群有较大区别.     

Metabolism of triiodothyroacetic acid (TA3) in rat liver. I. Deiodination of TA3 and TA3 sulfate by microsomes

The deiodination of the acetic acid side-chain analogs of T3 as well as 3,3'-diiodothyronine (3,3'-T2) was investigated by incubating 125I-labeled 3,3',5-triiodothyroacetic acid (TA3) and 3,3'-diiodothyroacetic acid (3,3'-TA2) with rat liver microsomes at 37 C and pH 7.2 in the presence of 5 mM dithiothreitol. TA3 sulfate (TA3S) and 3,3'-TA2S were also tested as substrate since sulfation is known to accelerate T3 and 3,3'-T2 conversion. Reaction products were analyzed on Sephadex LH-20 and HPLC. TA3 underwent only inner ring deiodination (IRD), but 3,3'-TA2 was equally converted by IRD and outer ring deiodination (ORD). TA3S was metabolized very rapidly by IRD to 3,3'-TA2S which was only observed transiently due to its rapid deiodination predominantly in the outer ring. Kinetic studies under initial reaction rate conditions yielded apparent Michaelis-Menten (Km) values (micromolar) of 1.8 for TA3, 0.8 for 3,3'-TA2, and 0.004 for TA3S, and 0.02 for 3,3'-TA2S and Vmax values (picomoles per min/mg protein) of 174 for TA3, 49 for 3,3'-TA2, 21 for TA3S, and 63 for 3,3'-TA2S. The Vmax/Km ratios for the IRD of TA3 and TA3S were 16 and 930 times higher, respectively, relative to T3. Deiodinations were sensitive to propylthiouracil inhibition, indicating the involvement of the type I iodothyronine deiodinase. Furthermore, the iodothyroacetic acid derivatives competitively inhibited the ORD of rT3 with apparent inhibition constant (Ki) values (0.45 microM for TA3, 4 nM for TA3S, and 0.04 microM for 3,3'-TA2S) in agreement with corresponding Km values. We conclude that 1) TA3 and 3,3'-TA2 are better substrates than T3 and 3,3'-T2 for the type I deiodinase of rat liver; 2) the IRD of TA3 and ORD of 3,3'-TA2 are markedly enhanced by sulfation similar to the parent iodothyronines; and 3) TA3S in the best known substrate for IRD due to its very high affinity for the type I deiodinase.     

UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians

Gilbert's syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The causative mutation in Caucasians is almost exclusively a TA dinucleotide insertion in the TATA box of the UGT1A1 promoter. Affected individuals are homozygous for the variant promoter and have 7 instead of 6 TA repeats. The aim of the present study was to determine the genotypes of UGT1A1(TA)n promoter polymorphism in the healthy Slovenian population and to investigate the association of genotypes with serum bilirubin levels. 236 healthy subjects were genotyped by single-strand conformation polymorphism analysis, which was validated by sequence analysis. The frequencies of genotypes were as follows: (TA)(6/6) (38.1%), (TA)(6/7) (47.9%), (TA)(7/7) (13.6%). There was a statistically significant association of genotypes with serum bilirubin levels (p<0.001). Subjects with genotype (TA)(7/7) had the highest and subjects with genotype (TA)(6/6) the lowest total serum bilirubin levels. One individual in the group had the rare genotype (TA)(7/8) (0.4%). Analysis of his family showed the following genotypes: (TA)(6/8) in his father and sister and (TA)(7/8) in his two brothers. In conclusion, the frequency of UGT1A1(TA)n promoter polymorphism genotypes was determined for the first time in the Slovenian population and is similar to frequencies observed in other Caucasian populations. The extremely rare (TA)8 allele in Caucasians was found also in Slovenians.     

Inhibition of cholangiocarcinoma growth by tannic acid

Cholangiocarcinoma is an aggressive malignancy of the biliary tract for which effective treatment is lacking. Tannic acid (TA) is a naturally occurring polyphenolic compound with antioxidant and radical scavenging properties as well as anticarcinogenic effects. TA inhibited proliferation of malignant human cholangiocytes in vitro. Furthermore, the growth rate of Mz-ChA-1 cholangiocarcinoma xenografts in balb/c athymic mice was reduced from 10.9 +/- 1.8 mm(3)/d in mice fed with normal water to 5.5 +/- 1.2 mm(3)/d in mice fed with water containing 0.05% TA. Pretreatment with 50 microg/mL TA for 24 hours before xenograft implantation increased tumor latency by 2.5-fold compared with untreated controls, and decreased subsequent growth rates compared with controls in the absence of TA feeding. TA was not cytotoxic to Mz-ChA-1 cells in vitro, but enhanced sensitivity to camptothecin cytotoxicity. TA potently inhibited cell cycle progression, and increased expression of the cyclin-dependent kinase inhibitor p27(KIP1). In addition, TA (0-50 microg/mL) inhibited proteasomal activity in cholangiocyte cell extracts in a concentration-dependent manner. In conclusion, the growth inhibitory effects of TA may result from dysregulation of cell cycle progression due to altered proteasomal degradation of these cell cycle regulatory proteins. TA warrants evaluation as a candidate for the treatment of human cholangiocarcinoma either by itself or in combination with other chemotherapeutic agents.     

Cardiovascular manifestations of Takayasu arteritis and their relationship to the disease activity: analysis of 204 Korean patients at a single center

Takayasu's arteritis (TA) is primary vasculitis. Cardiac involvements in TA is due to the consequences of the vascular lesions as well as the primary pathology of the heart. The disease activity of TA is known to influence the prognosis of TA. We hypothesized that the cardiovascular involvement of TA is related to the disease activity. We evaluated the cardiovascular manifestations of TA, and we assessed their relation to the disease activity of TA. Two hundred four patients were diagnosed with TA from September, 1994 to March, 2009 according to the diagnostic criteria of the 1990 American College of Rheumatology. Their clinical features and the laboratory, angiographic and echocardiographic findings were retrospectively reviewed. The group with active disease activity was defined as satisfying one of the following criteria: i) an elevated ESR or CRP level, ii) thickened arterial wall with mural enhancement on CT or MR angiography, and iii) carotidynia at the time of the initial diagnosis. One hundred thirty nine patients (69.2%) were classified as the active group. The cardiovascular signs and symptoms were not generally different between the active and inactive groups. The active TA patients had more frequent involvement of the ascending aorta and the aortic arch and its main branches than did the inactive group. The active group showed a higher incidence of significant aortic valve regurgitation and pulmonary hypertension, and a higher level of NT-proBNP. These findings suggest that disease activity plays an important role for the cardiovascular manifestations of TA. The TA patients with higher activity have more cardiovascular morbidity compared to the TA patients with low disease activity.     

Dynamic assessment of the tricuspid annulus in a healthy Asian population: A four-dimensional echocardiography study

Background

Tricuspid annulus (TA) geometry and function reference values are limited, especially for Asian populations. We aimed to explore TA using four-dimensional echocardiography (4DE) in a healthy Asian population.

Methods

A total of 355 healthy Asian volunteers (median age 34 years; 52% males) were prospectively enrolled. TA geometry and function were analyzed using 4DE throughout the cardiac cycle.

Results

The TA area, perimeter, and dimensions were smallest at end systole (ES) and largest at late diastole (LD). Normal TA parameters at end diastole (ED) in different sex and age groups were obtained. TA areas, perimeters, and dimensions in males were significantly larger than those in females at ED; BSA-indexed perimeters and BSA-indexed dimensions in males were significantly smaller than those in females at ED. TA parameters correlated well with tricuspid valve (TV) tenting, right ventricle (RV), and right atrium (RA) parameters.

Conclusions

Reference values of TA parameters were obtained by 4DE in an Asian population. Quantitative data on TA geometry and function are essential for TA pathology and therapeutics.     

Comparison of clinical characteristics in patients with Takayasu arteritis with and without concomitant tuberculosis

Because of frequent tuberculosis in patients with Takayasu arteritis (TA), a possible relationship between TA and tuberculosis has been proposed. However, there are no studies to date that have examined clinical manifestations in patients diagnosed with TA with or without tuberculosis. Two hundred sixty-seven patients were diagnosed with TA according to the 1990 American College of Rheumatology criteria between September 1994 and April 2014. Patients with TA were classified into groups with or without tuberculosis. Among the 267 patients with TA studied, 47 patients (17.7 %) who had a history of previous treatment of tuberculosis (34 patients), concurrent diagnosis of tuberculosis with TA (10 patients), or diagnosis of tuberculosis during the follow-up period for TA (3 patients) were included in the group with tuberculosis. The group with tuberculosis comprised of 33 patients (70.2 %) with pulmonary tuberculosis, 12 patients (25.5 %) with tuberculous lymphadenitis, and 2 patients (4.3 %) with tuberculosis of the skin and colon, respectively. Comorbid disease and patients’ signs and symptoms were not significantly different between TA patients with and without tuberculosis. Additionally, the site of disease involvement in angiographic findings and distribution of angiographic type were similar between the two groups. In conclusion, tuberculosis including tuberculous lymphadenitis was frequently observed in patients with TA. Clinical features and angiographic findings in TA were not different according to the presence or absence of concomitant tuberculosis.     

Ames试验对低剂量亚砷酸钠致突变性的研究

目的 体外观察亚砷酸钠诱发鼠伤寒沙门杆菌组氨酸营养缺陷型突变菌株的回复突变(Ames)作用,探讨低剂量亚砷酸钠的致突变性.方法 采用Ames试验中标准平板掺人法,检测不同剂量亚砷酸钠(5000.00、500.00、10.00、1.00、0.10、0.01μg/皿)及阳性、阴性对照在加与不加肝微粒体酶活化系统(+S9、-S9)条件下诱发TA97、TA98、TA100和TA102菌株的致突变作用.结果 +S9或-S9时,500.00、5000.00μg/皿亚砷酸钠作用下,TA97、TA98、TA100、TA102菌株均没有生长;+S9时,0.01、0.10、10.00μg/皿亚砷酸钠诱发TA102产生的回变菌落数与阴性对照相比均达到2倍以上(P<0.05),突变率(MR)分别为2.57、2.10、2.50,其他剂量组无明显增加(P0.05);在-S9条件下,1.00、10.00μg/皿亚砷酸钠诱发TA100菌株产生的回变菌落数与阴性对照相比均达到2倍以上(P<0.05),MR分别为2.18、2.27;0.01、0.10μg/皿亚砷酸钠诱发TA98菌株产生的回变菌落数与阴性对照相比均达到2倍以上(P<0.05),MR分别为3.17、4.22,其他剂量组未见明显增加(P0.05).结论 500.00、5000.00μg/皿亚砷酸钠抑制菌落生长,0.01～10.00μg/皿亚砷酸钠具有致突变性.     

Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai

Background

The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)₆/(TA)₆ and (TA)₆/(TA)₇ genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai.

Methods

One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine–adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)₆/(TA)₆ and (TA)₆/(TA)₇ genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)₆/(TA)₆ and (TA)₆/(TA)₇ genotypes were analyzed statistically.

Results

One hundred and fourteen patients (69.51 %) were identified with the (TA)₆/(TA)₆ genotype, forty-eight patients (29.27 %) with the (TA)₆/(TA)₇ genotype, and two patients (1.22 %) with the (TA)₇/(TA)₇ genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)₆/(TA)₇ genotype group were all higher than those in (TA)₆/(TA)₆ group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)₆/(TA)₆ genotype. In the (TA)₆/(TA)₇ group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)₆/(TA)₆ genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ ² = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)₆/(TA)₇ genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ ² = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)₇/(TA)₇ cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction.

Conclusion

The (TA)₆/(TA)₆ genotype and (TA)₆/(TA)₇ genotype accounted for the most, and (TA)₇/(TA)₇ genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)₆/(TA)₆ genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)₆/(TA)₇ genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)₇/(TA)₇ genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.     

Significance of the intima-media thickness of the thoracic aorta in patients with coronary atherosclerosis

BACKGROUND: The prevalence and clinical significance of atherosclerotic aortic disease have now been documented in a variety of patient populations by use of transesophageal echocardiography (TEE). There are many reports that atherosclerotic aortic plaques detected by TEE are a marker for coronary artery disease (CAD). HYPOTHESIS: The study was undertaken to evaluate the significance of the intima-media thickness (IMT) and formation of atherosclerotic plaques of the thoracic aorta (TA) in patients with CAD, especially in terms of a correlation between the IMT of the TA and the extent of coronary atherosclerosis. METHODS: The IMT of the TA was measured using TEE. The study population comprised 100 patients (68 men, mean age 59 years). The extent of coronary atherosclerosis was divided into four groups (0, 1, 2, 3) according to the number of coronary arteries narrowed > or = 50%. RESULTS: There was no significant difference in the IMT of the ascending TA according to the presence of significant (> 50% narrowed) coronary stenosis, but there was a significant difference in the IMT of the descending TA (1.39 vs. 1.88 mm, p = 0.005). There was a significant correlation between the extent of coronary atherosclerosis and the IMT of the ascending and descending TA (r = 0.24, p < 0.05; r = 0.352, p < 0.001, respectively). The plaques in the TA were seen in 7, 41, 52, and 65% of patients in Groups 0, 1, 2, and 3, respectively. Among atherosclerosis risk factors, hyperlipidemia was the only factor analyzed that affected the IMT of the descending TA (2.11 vs. 1.78 mm, p < 0.05). CONCLUSION: The IMT of the TA correlates significantly with coronary atherosclerosis, and correlation of the descending TA IMT with coronary atherosclerosis is better than that of ascending TA IMT. Age is associated with coronary atherosclerosis, and TA IMT and hyperlipidemia are associated with descending TA IMT. Therefore, although TEE is not recommended for measuring TA IMT or for evaluating aortic plaques in patients with CAD, measurement of TA IMT as well as carotid artery IMT is very helpful for understanding the extent of coronary atherosclerosis.     

UGT1A1 variation and gallstone formation in sickle cell disease

Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease. Subjects were from the Jamaican Sickle Cell Cohort Study (cohort sample, n = 209) and the Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica (clinic sample, n = 357). The UGT1A1 (TA)(n) promoter region was sequenced in 541 SS disease subjects and 111 healthy controls (control sample). Indirect bilirubin levels for (TA)(7)/(TA)(7) and (TA)(7)/(TA)(8) genotypes were elevated compared with (TA)(6)/(TA)(6) (clinic sample, P < 10(-5); cohort sample, P < 10(-3)). The (TA)(7)/(TA)(7) genotype was also associated with symptomatic presentation and gallstones in the clinic sample (odds ratio [OR] = 11.3; P = 7.0 x 10(-4)) but not in the younger cohort sample. These unexpected findings indicate that the temporal evolution of symptomatic gallstones may involve factors other than the bilirubin level. Although further studies of the pathogenesis of gallstones in SS disease are required, the (TA)(7)/(TA)(7) genotype may be a risk factor for symptomatic gallstones in older people with SS disease.     

Triamcinolone acetonide in the treatment of corticosteroid-resistant asthma: risks and benefits

Few therapeutic alternatives to prednisone are available for severe, corticosteroid-resistant asthma. Injectable triamcinolone acetonide (TA) has been used in this type of asthma, although its use is controversial. TA shows considerable efficacy when compared with prednisone according to nearly all studies, although the majority do not provide a high level of evidence. The use of TA has been questioned, with claims put forward that it is equivalent to increasing the corticosteroid dose, thus leading to a higher risk of adverse effects. This would mean that TA would not represent an improvement over prednisone because of the trade-offs between risks and benefits. This interpretation is questionable, however, because the data show that TA causes fewer adverse effects than prednisone, meaning that the balance of risks and benefits does favor TA. Therefore, TA can be considered a useful option for the treatment of patients with severe prednisone-resistant asthma.     

Prednisolone maintenance dose in relation to starting dose in the treatment of polymyalgia rheumatica and temporal arteritis. A prospective two-year study in 273 patients.

OBJECTIVE: To describe the maintenance dose and annual cessation rate of oral corticosteroids in relation to the starting dose in patients with polymyalgia rheumatica (PMR) and temporal arteritis (TA). METHODS: A prospective two-years observational study of 273 patients with PMR and TA followed by rheumatologists. RESULTS: Mean daily maintenance dose of prednisolone during the first and second year was 5.7 mg and 4.3 mg for PMR, 6.6 mg and 4.1 mg for TA, and 8.3 mg and 4.7 mg for PMR with TA. There was a strong association between the initial dose and maintenance dose. The rate of steroid cessation after two years in PMR was 24%, in TA 16%, and in PMR with TA 5%. CONCLUSION: Low initial dose of prednisolone is associated with low maintenance dose. This is important as the majority of patients with PMR and TA will be treated for more than two years.     

Takayasu’s arteritis misdiagnosed as mediastinal malignant lymphoma: a case report and review of the literature

Takayasu’s arteritis (TA) is a rare chronic large-vessel vasculitis. The early diagnosis is difficult, because of lack of characteristic clinical manifestations. In this paper, we reported a TA case of young female was misdiagnosed as mediastinal malignant lymphoma and mediastinoscope biopsy was performed. The biopsy result demonstrated that thickened tissue adjacent to the aortic arch pathological presentations were in accord with TA. Glucocorticoid was administrated and the condition was greatly improved after treatment. Therefore, we reported this case and review of the pertinent literature in order to help clinicians improve the understanding of TA and PET/CT manifestations of TA at early phase to realize the early diagnosis and treatment of TA, finally reducing the hazards.