Correlations of IL-6 and IL-10 gene polymorphisms with childhood acute lymphoblastic leukemia.

OBJECTIVE: The aim of this study was to investigate the correlations between interleukin-6 (IL-6) and IL-10 gene polymorphisms with childhood acute lymphoblastic leukemia. PATIENTS AND METHODS: Specimens were collected from 200 children with acute lymphoblastic leukemia (disease group) and 200 normal children (control group) in our hospital. DNA was extracted from peripheral blood nucleated cells in both groups to detect the gene polymorphisms rs2069830 and rs2069836 of IL-6, as well as rs3024489 and rs3024493 of IL-10. Then, the content of serum IL-6 and IL-10 was determined via enzyme-linked immunosorbent assay (ELISA). RESULTS: It was found that there were differences in the distribution of alleles of IL-6 gene polymorphism rs2069830 (p=0.000) and IL-10 gene polymorphism rs3024493 (p=0.007) between the disease group and control group. The frequency of T allele of IL-6 gene polymorphism rs2069830 was higher, while that of IL-10 gene polymorphism rs3024493 was lower in the disease group. Besides, the differences in the distribution of genotypes of IL-6 gene polymorphism rs2069830 (p=0.000) and IL-10 gene polymorphism rs3024493 (p=0.000) were also observed between the disease group and control group. Moreover, the disease group had higher frequencies of TT genotype of IL-6 gene polymorphism rs2069830 and TA genotype of IL-10 gene polymorphism rs3024493. The frequencies of dominant model of IL-6 gene polymorphism rs2069830 (p=0.048) and recessive model of IL-10 gene polymorphism rs3024493 (p=0.000) in the disease group were different from those in the control group. In addition, the frequency of CC + CT dominant model of IL-6 gene polymorphism rs2069830 was lower, and the frequency of TA + AA recessive model of IL-10 gene polymorphism rs3024493 was higher in the disease group. There were differences in haplotypes CG (p=0.001), CT (p=0.007), and TG (p=0.000) of IL-6 gene, as well as haplotypes AA (p=0.002) and AT (p=0.005) of IL-10 gene between disease group and control group. Furthermore, the content of IL-6 in the serum was associated with the genotypes of IL-6 gene polymorphism rs2069830 (p<0.05), whereas the children with acute lymphoblastic leukemia carrying CT genotype had remarkably higher content of serum IL-6. The genotypes of IL-6 gene polymorphism rs2069830 was notably related to white blood cell (WBC) (p=0.002), and the WBC level was higher in children with CT genotype. The genotypes of IL-10 gene polymorphism rs3024489 had prominent correlations with platelet (PLT) (p=0.043), and the children with AA genotype had a higher PLT level. In addition, the genotypes of IL-10 gene polymorphism rs3024493 were evidently correlated with hemoglobin, which was significantly higher in children carrying TA genotype. CONCLUSIONS: The gene polymorphisms of IL-6 and IL-10 are significantly correlated with the susceptibility to and pathogenesis of childhood acute lymphoblastic leukemia.

[Clinical study on the relations of obstructive sleep apnea hypopneasyndrome and the degree and prognosis of coronary lesions].

Objective:The aim of this study is to discuss the relations between obstructive sleep apnea hypopnea syndrome (OSAHS) and severity and prognosis of coronary artery disease. Method:The OSAHS patients were divided into mild, moderate and severe groups according to Results of sleep monitoring. The severity of coronary artery lesion in each group was compared by counting the numbers of the lesion extension of coronary artery, calculating the Gensin score and evaluating the Thromblysis in myocardial infarction. The patients were followed up within 2 years, the incidence of major clinical cardiac adverse events was compared between each groups. Result:Three groups confirmed the numbers of the lesion extension of coronary artery and Gensin score increased, the Thromblysis in myocardial infarction reduced with the seriousness of OSAHS by coronary angiography (P<0.05). There was no statistical significance in compliance for oral use of three groups (P>0.05). Incidence of the main adverse cardiac events during two years in three groups were16.28%, 29.36% and 44.26%. Incidence of the main adverse cardiac events increased with the seriousness of OSAHS (P<0.05). Conclusion:The coronary artery pathologic change severity aggravated with the seriousness of OSAHS，and the incidence of the main adverse cardiac events increased with the seriousness of OSAHS.

Prevalence of haematuria positively associated with urine albumin excretion in Type 2 diabetes.

AIMS: Some guidelines or studies consider haematuria an indication for renal biopsy or a potential cause of albuminuria that precludes accurate assessment of urinary albumin excretion. This study examined the justification of excluding haematuria in interpreting urinary albumin excretion in patients with Type 2 diabetes and its associations with other diabetes-related variables. METHODS: Between May and November 2008, patients with Type 2 diabetes at a single centre with data on urinary albumin excretion and urinalysis in the same urine sample were recruited. Urinary albumin excretion was determined by urine albumin/creatinine ratio in spot urine. Diagnosis of haematuria was made by positive urine occult blood from 1+ to 4+ and/or presence of more than nine red blood cells/ml in urinalysis. Demographic, anthropometric, clinical and laboratory variables and diabetes-associated complications were analysed. RESULTS: In total, 743 patients were enrolled. Prevalence of haematuria among patients with normoalbuminuria, microalbuminuria, or macroalbuminuria was 8.7% (n = 13), 16.1% (n = 67) and 35.8% (n = 64), respectively. Urine albumin/creatinine ratio was significantly higher, while macroalbuminuria was more common in patients with haematuria (n = 144) than in those without (n = 599). Multiple regression analysis identified urine albumin/creatinine ratio (odds ratio 1.33, P = 0.01) and macroalbuminuria (odds ratio 2.66, P = 0.01) as the only independent predictors of haematuria. Moreover, urine albumin/creatinine ratio was an independent predictor of haematuria in the macroalbuminuria subgroup (odds ratio 1.30, P = 0.04). CONCLUSIONS: Increased urine albumin/creatinine ratio and macroalbuminuria were the only independent predictors of haematuria in patients with Type 2 diabetes, raising questions on the justifications of excluding haematuria in interpreting urinary albumin excretion in patients with Type 2 diabetes and including haematuria as an indication for renal biopsy in those with macroalbuminuria.

The prediction of late rectal complications following the treatment of uterine cervical cancer by high-dose-rate brachytherapy.

PURPOSE: This study aimed to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients with uterine cervical cancer treated with external beam radiation therapy (EBRT) and high dose rate intracavitary brachytherapy (HDRICB). METHODS AND MATERIALS: From September 1992 to December 1995, a total of 128 patients with uterine cervical cancer, who were treated and survived more than 12 months, were evaluated. After EBRT with 40-44 Gy/20-22 Fr/4-5 weeks to the whole pelvis, the dose was boosted up to 54-58 Gy with central shielding for patients with bilateral parametria of Stage IIb or greater. HDRICB consisted of three to four insertions at doses of 5-7.2 Gy (to Point A) at intervals of 1 week. Patient and treatment factors were analyzed using logistic regression analysis and the cumulative rectal biologic equivalent dose (CRBED) was calculated. RESULTS: After 30-75 months of follow-up (median, 43 months), 38 patients (29.7%) had late rectal sequelae. Patients who had Stage IIb-IVa disease, cumulative rectal dose (external RT + total ICRU rectal dose) greeater than 65 Gy, or age greater than 70 years had a high risk of developing late rectal sequelae. When 110 Gy was used as the cut-off value, 19.6% (10 of 51) of patients whose CRBED was less than 110 Gy had rectal complications, while 36.4% (28/77) of patients whose CRBED was greater than 110 Gy developed rectal complications. CONCLUSION: Risk factors of late rectal complications were advanced stage, age greater than 70 years, and cumulative rectal dose of greater than 65 Gy.

Levothyroxine suppression of thyroglobulin in patients with differentiated thyroid carcinoma.

For patients with differentiated thyroid carcinoma, the appropriate degree of TSH suppression by levothyroxine (L-T4) is still unknown. To find the target level of TSH suppression, we analyzed the relationship between the degree of TSH suppression determined by third generation assay and thyroglobulin (Tg) response during the titration of the dosage of L-T4. Ninety-two patients with differentiated thyroid carcinoma (19 males and 73 females; age, 40.5+/-13.5, mean +/- SD) were included. All of the recruited patients had near-total thyroidectomy, 30-150 mCi 131I thyroid ablation, and negative Tg autoantibodies. They were classified into 3 groups. Group A was composed of 25 patients with local or distant relapse. Group B was composed of 12 patients without clinically detectable relapse, but Tg levels either above 2 ng/mL under L-T4 suppression or above 3 ng/mL off L-T4 therapy. Group C included 55 patients who had no active disease and Tg levels below 2 and 3 ng/mL during and off L-T4 suppression, respectively. Serum TSH and Tg were measured simultaneously at the end of 8-12 weeks of a certain dose of L-T4 therapy during dosage titration and also after withdrawal of L-T4 for 4-6 weeks for the total body scan. Wilcoxon signed ranks test was used to compare paired samples of Tg, and Spearman rank correlation was used to determine the correlation of relative changes in TSH to changes in Tg calculated by individual. The results showed that 1) Tg levels were significantly higher during the period off L-T4 therapy than on L-T4, therapy in all 3 groups (P < 0.01); 2) during L-T4, therapy, within the same treatment course, mean Tg levels were higher when TSH levels were normal than when TSH levels were suppressed, statistically significant in group A (P = 0.001), nonsignificant in group B (P = 0.09), and nonsignificant in group C (P = 0.30); and 3) when TSH was suppressed below normal, there was no correlation between the relative changes in TSH and Tg by individual in all 3 groups (P > 0.05). The data suggest a stratified postoperative thyroid hormone management of patients with differentiated thyroid carcinoma. TSH should be lowered to below normal in patients with active disease. If patients are clinically disease free with Tg levels below 2 ng/mL, TSH can be kept within the normal range. For the most controversial group B patients, it is recommended that the TSH be suppressed and be closely followed up.

Ectopic parathyroid adenoma with severe hungry bone syndrome: a case report.

The presentation rate of ectopic mediastinal parathyroid adenoma is about 5 approximately 22%. Ectopic parathyroid adenoma is a common etiology of failed parathyroid surgery as well as a diagnostic challenge to clinicians. We reported a case of ectopic mediastinal parathyroid adenoma. A 20-year-old girl presented with arthralgia for 2 years before hyperparathyroidism was diagnosed. Parathyroid ultrasonography failed to find the lesion, but a vivid uptake in the superior mediastinum was discovered by thallium-201 (Tl-201) and technetium-99m-sestamibi (Tc-99m-MIBI) images. Removal of the ectopic adenoma resulted in severe Hungry bone syndrome, which required a large amount of calcium and phosphorous supply. Later, the patient suffered from bilateral femoral neck fracture due to marked osteoporosis. Bone mineral density study revealed marked increase of fracture risk. Although bone disorder is rare in cases of hyperparathyroidism nowadays, it still should be considered in patients with arthritis of unknown etiology like our case. Early diagnosis and treatment can reduce the morbidity.

An artificial thyroid hormone receptor mutant without DNA binding can have dominant negative effect.

The syndrome of resistance to thyroid hormone (RTH) encompasses a heterogeneous group of conditions which are caused by mutations of thyroid hormone receptor beta 1 (TR beta 1). Mutations usually cluster in two regions of the ligand-binding domain. The mutant receptors can inhibit normal receptor activity in a dominant negative manner, consistent with the dominant mode of inheritance of RTH. Recent evidence suggested that this dominant negative effect (DNE) of the RTH mutants involves competition for DNA binding and emphasized the essential role of intact DNA binding activity for mutants in order to exert DNE. However, we found that a Cys73Ser substitution in the DNA-binding domain (DBD) of wild-type produces a TR which can inhibit the transcriptional activation by TR alpha 1, either in the presence or absence of T3, on three different TRE-containing reporter genes, in transient co-transfection studies. Co-expression of TRv alpha 2, a TR alpha splicing variant, can enhance this DNE. However, DNE was not observed on the negatively-regulated TSH alpha Luc reporter gene when wild-type and DBD mutant were co-transfected at equimolar ratios. The DNE of DBD mutant is not reversed by co-transfection with excess retinoid X receptor alpha. DBD mutant alone can also inhibit the transactivation from a TK-luciferase reporter gene either linked with rat malic enzyme thyroid response element, or not. These observations parallel those we previously observed using TRv alpha 2. Our results indicate that a DBD mutant can have DNE, possibly through a mechanism similar to that of TRv alpha 2, which may involve interference with basal transcription factors. The clinical significance of these DBD mutants is currently unclear, but it is logical to expect such mutants do occur in nature.

The dominant negative effect of thyroid hormone receptor splicing variant alpha 2 does not require binding to a thyroid response element.

The functionally inactive thyroid hormone receptor splicing variant-alpha 2 (TRv alpha 2) can inhibit transcriptional activation by TR alpha 1 or beta 1, demonstrating a dominant negative effect (DNE). We examine here the three commonly proposed mechanisms, namely, competition for binding to thyroid hormone response elements (TREs), formation of inactive heterodimers, and squelching. A mutation introduced into the DNA-binding domain (DBD) of the TRv alpha 2 was designed to prevent its binding to TREs. In transient cotransfection studies, the DBD mutant has nearly the same DNE as does TRv alpha 2 on three different TRE-containing reporter genes. The DNE of TRv alpha 2 is also not reversed by cotransfection with excess retinoid X receptor-alpha. Extracts of COS cells cotransfected with TR alpha 1 and either TRv alpha 2 or DBD mutant at different ratios were analyzed by gel shift assays. Neither TRv alpha 2 or the mutant altered binding of TR alpha 1 to four radiolabeled TREs. TRv alpha 2 itself can inhibit constitutive transactivation by a thymidine kinase promoter-driven reporter construct. Our results suggest that TRv alpha 2 can function in a dominant negative manner without binding to a TRE, at least for certain TREs. It is concluded that the DNE of TRv alpha 2 may occur through another unrecognized mechanism, perhaps by binding to basal transcription factors.

Ectopic ACTH syndrome with nocardiosis--a case report.

A 25-year-old man was admitted with chief complaints of multiple ecchymoses over face and both arms after a trivial trauma since one month before entry. Physically, he was thin without moon face, buffalo hump, or purple striae, while extensive fungus infection was present. Mild hyperglycemia, hypokalemic alkalosis were also found. Chest x-ray revealed multiple cavitary nodular lesions over bilateral lung fields. Needle biopsy from a rib lesion showed small cell carcinoma with strongly positive ACTH stain. The patient's basal cortisol level was greater than 62 micrograms/dl and failed to be suppressed by both low and high dose dexamethasone. The 24 hours urine free cortisol, 17 KS, and 17 OHCS were 8454 micrograms/24h, 49.8 mg/24h, and 50.8 mg/24h respectively. His plasma ACTH level was 725 pg/ml and remained high (1210 pg/ml) after high dose dexamethasone suppression. On the 10th day after admission, the patient's general condition got worse rapidly. Fever, dyspnea developed with progression of the lung lesions. Nocardia infection was proved. He expired three days later in spite of antibiotics and ketoconazole treatment.

Serum thyroglobulin in the follow-up of patients with treated differentiated thyroid cancer.

To determine the significance of serum thyroglobulin (Tg) level in terms of presence or absence of thyroid cancer, we evaluated available serum Tg data on and off T4 therapy in 180 patients with differentiated thyroid cancer who have now been followed up to 18 yr. The presence of cancer was established by radioiodine scans, x-rays, and clinical examination. Thirty-two patients with detectable serum Tg autoantibodies were excluded from this analysis. Tg was measured by RIA with a sensitivity of 1 ng/mL. Patients who had all stages of cancer, but who had no evidence of active disease after treatment, were grouped according to operative and 131I ablative therapy. In patients with a partial thyroidectomy with or without ablation, the presence of Tg did not indicate the presence of cancer since levels were often above either a 5 ng/mL or a 10 ng/mL cutoff. The presence of residual normal thyroid tissue decreases the diagnostic value of serum Tg assay. In patients who underwent near total (NTT) or total thyroidectomy (TT) and 131I ablation, 3 of 55 (5.5%) patients had Tg greater than 5 ng/mL and 1 of 55 (1.8%) patients had Tg greater than 10 ng/mL during therapy, whereas off therapy 13 of 57 (22.8%) patients had Tg greater than 5 ng/mL and 6 of 57 (10.5%) patients had Tg levels greater than 10 ng/mL. In this group of patients, a Tg level less than 10 ng/mL during suppressive therapy indicated the absence of apparent tumor in 54 of 55 (98.2%) of patients. Whereas sensitivity of the assay was increased by withdrawal of hormone, "false positives" increased especially at lower (3-6 ng/mL) cut-off levels. No cut-off value properly categorized all patients. These data suggest, that even in patients who underwent 131I ablation and total thyroidectomy and were thought to be cured, small foci of thyroid tissue which are undetectable by standard 2 mCi 131I scans may exist and produce some Tg. However, these residual cells do not appear to cause an adverse prognosis in most patients. In patients with recurrent or continued disease, during T4 treatment, Tg levels ranged between 2-21,000 ng/mL and 5 of 11 patients had a Tg less than 5 ng/mL. Off treatment, Tg levels ranged between 6-10,700 ng/mL and 3 of 13 patients had a Tg less than 10 ng/mL. In 4 patients Tg levels were less than 10 ng/mL on treatment but greater than 10 ng/mL off therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Tc-99m pertechnetate trapping and thyroid function in Hashimoto's thyroiditis.

Tc-99m pertechnetate thyroid imaging was studied in 52 patients with Hashimoto's thyroiditis, with special reference to the thyroid functional state and Tc-99m trapping by the gland. The most common finding was diffusely increased trapping of radioactivity, a pattern similar to Graves' disease. On the other hand, the increased trapping in Hashimoto's thyroiditis was usually associated with hypothyroidism. The degree of Tc-99m trapping did not correlate with the degree of the endogenous TSH elevation. However, increased Tc-99m trapping could predict the reversibility of hypothyroidism in just 3 months.

Serum steroid hormonal profiles by reversed-phase liquid chromatography in patients with 17-hydroxylase deficiency and in an affected family.

We used an optimized isocratic reversed-phase high-performance liquid-chromatographic procedure to separate and measure 12 steroid hormones, and studied the steroid hormone profiles in sera from three patients with 17-hydroxylase deficiency (17-OHD). Two of the patients were sisters, one of whom (II-3), expressing normotension and primary amenorrhea, was diagnosed on the basis of chromatographic data and followed up for seven years. The untreated patients had obvious abnormalities on chromatograms of serum extracts, characterized by markedly increased corticosterone (B) and decreased or undetectable cortisol (F) and cortisone (E). The concentration of 11-deoxycorticosterone was much greater in the patient with classical symptoms than in the normotensive patient. In all three patients, concentrations of aldosterone were within the normal range, but concentrations of progesterone were much lower than in the patients with 21-hydroxylase deficiency. We evaluated the responses to corticotropin and dexamethasone. HPLC evaluation of the serum steroid profiles before and after corticotropin stimulation in the affected family showed that in the parents and one other sibling, concentrations of F before and after stimulation were within the normal ranges. The sums of the ratio of B to F before and the ratio of B to F after corticotropin stimulation (sigma B/F) in the parents and the other sibling were 0.292, 0.496, and 0.614, respectively, all much higher than the normal value (mean +/- SD: 0.164 +/- 0.038). Thus the sigma B/F value may be a hormonal marker of heterozygotes carrying this defect.

Outcome following radioactive iodine therapy in Graves' disease.

One hundred and fifty three patients with Graves' hyperthyroidism treated with I-131 from March 1984 to September 1988 were analyzed. The dose of I-131 was given according to the formula: 100 microCi/gm x estimated thyroid size (gm) x 100/24 hr I-131 uptake (%) The mean dose was 5.41 mCi and the maximum dose was 7 mCi. After one year of follow up, 45 patients (29.4%) were euthyroid, 35 patients (22.9%) became hypothyroid, and 73 patients (47.7%) were persistently hyperthyroid. Discriminant analysis of pretreatment variables suggested that those patients who were still hyperthyroid at the end of the first year had significantly larger goiter size, and higher serum T4 and T3 levels. Men had greater incidence of relapse. Besides, those who had received antithyroid drug before I-131 therapy had a significantly higher incidence of failure. As compared with previous studies, our report had a significantly higher incidence (22.9%) of hypothyroidism one year after I-131 therapy, which may be due to recognition of subclinical hypothyroidism through TSH assay.

Insulin autoimmune syndrome as a cause of hypoglycemia--report of four cases.

Insulin autoimmune syndrome is a syndrome consisting of fasting hypoglycemia, hyperinsulinemia and detectable insulin-binding antibodies in patients who have never been exposed to exogenous insulin. Four cases who developed symptoms of hypoglycemic attack with self-limited duration and spontaneous remission were collected in our hospital from 1984 to 1988. The elevated serum total and free insulin and C-peptide levels, as well as the titer of insulin autoantibodies, decreased gradually; but insulin autoantibodies were still present in the serum for more than six months after the initial episodes of hypoglycemia. Three of four patients had Graves' disease and developed the syndrome after methimazole treatment. The fourth one had a history of hemorrhagic cystitis and denied history of specific drug exposure. The cause or stimulus for insulin autoantibody formation is still unknown, but drugs containing a sulfhydryl group like methimazole may play a role in the development of the syndrome. Extremely high insulin antibodies in patients with fasting hypoglycemia along with elevated serum levels of insulin and C-peptide suggest a diagnosis of insulin autoimmune syndrome and usually exclude the possibility of insulinoma or factitious hypoglycemia.