Prenatal findings in congenital leukemia: a case report.

We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death.

[Mobile-phone e-mail use, social networks, and loneliness among Japanese high school students].

PURPOSE: The purposes of this study were to assess the loneliness of Japanese high school students who own and use a mobile phone, to clarify the relationships between students' loneliness and their social network and frequency of use of e-mail feature, and to demonstrate relationships with a student's social network and recognition of the benefits and drawbacks of mobile phone use. METHOD: The participants were 227 students from two classes in each grade of a high school in the Kanto region of Japan. Participants answered a questionnaire covering the UCLA Loneliness Scale as well as questions pertaining to the circumstances of use of their mobile phones, their social networks (e.g., number of friends), and their perceptions of the benefits and drawbacks of mobile phone use. The questionnaires of students owning a mobile phone were analyzed. Total scores for the UCLA Loneliness Scale were calculated, and factor analysis was performed for the benefits and drawbacks. RESULT: A total of 220 questionnaires were returned, for which 94.1 percent of respondents owned a mobile phone. The percentages of male and female respondents were 58% and 42%. Chronbach's alpha for the UCLA Loneliness Scale (total score) was 0.87, a result similar to previous studies with high school and university students. Factor analysis revealed five factors associated with the benefits and drawbacks of mobile phone use. Multiple-regression analysis showed that 42.9% of the variance in "frequency of e-mail use" was explained by grade level, frequency of mobile phone use, and two of the five factors from the benefits and drawbacks ("difficulty of communication," and "possible sleep loss due to nighttime e-mailing"). Stepwise multiple-regression analysis revealed that 24.4% of the variance in UCLA Loneliness Score was explained by gender, the frequency of e-mail use, the number of friends and the presence/absence of a girlfriend or boyfriend. CONCLUSION: Presence of an active social network and frequent e-mailing by mobile phone reduced students' loneliness. The frequency depended on their recognition of the benefits and drawbacks of mobile phone use and by the frequency of mobile phone use. This study established that students appreciate the usefulness of their mobile phone as an immediate communication tool, and are aware of its limitations. Although they experience frustration and lack of sleep (because of nighttime use), students use mobile phones to deepen their friendships.

Usefulness of the 2nd generation assay for anti-TSH receptor antibodies to differentiate relapse of Graves' thyrotoxicosis from development of painless thyroiditis after antithyroid drug treatment for Graves' disease.

After antithyroid drug (ATD) treatment for Graves' disease, either a relapse of Graves' thyrotoxicosis or painless thyroiditis can develop. It is important to differentiate these two types of thyrotoxicosis because of the difference in required therapy. However, differentiation of thyrotoxicosis is usually difficult without radioactive iodine uptake (RAIU) which is not available in general practice. We investigated the clinical usefulness of the 2nd generation assay for anti-TSH receptor antibodies (TRAb) to differentiate these two types of thyrotoxicosis after ATD treatment for Graves' disease. We recruited 26 patients who developed thyrotoxicosis after ATD treatment for Graves' disease. These patients once became negative for TRAb and seemed to be in remission after ATD treatment. Upon development of thyrotoxicosis after ATD treatment, TSH, free T4, free T3 and TRAb were measured. TRAb were measured by the 2nd generation assay using recombinant human TSH receptors instead of porcine TSH receptors. Fourteen patients relapsed into Graves' thyrotoxicosis and 12 patients developed painless thyroiditis. Twelve (85.7%) of 14 patients with relapse of Graves' thyrotoxicosis were positive for TRAb. Eleven (91.7%) of 12 patients with development of painless thyroiditis after ATD treatment for Graves' disease were negative for TRAb. Levels of TRAb were significantly different between patients with relapse of Graves' thyrotoxicosis (4.86 +/- 6.45 IU/L) and those with painless thyroiditis (0.62 +/- 0.61 IU/L) (P<0.001). The 2nd generation assay for TRAb was useful to differentiate relapse of Graves' thyrotoxicosis from development of painless thyroiditis in patients who seemed to be in remission after ATD treatment for Graves' disease.

[Differential diagnosis of hepatitis: development of new laboratory tests for autoimmune hepatitis and progress in pathophysiology].

Liver dysfunction has been found in 8.1% of postpartum women in the general population. This dysfunction was speculated to be developed by postpartum aggravation of subclinical autoimmune hepatitis. Therefore, we developed two methods for detection of autoantibodies to liver-specific antigens: an ELISA for anti-liver-specific arginase antibodies, and a highly sensitive radioligand assay for anti-CYP2D6 antibodies. Basic examinations of dilution curve, inhibition study and reproducibility were satisfactory for clinical application in both assays. Anti-arginase antibodies and anti-CYP2D6 antibodies were found in 28.6% and 42.6% of patients with autoimmune hepatitis, respectively. There was no correlation between the two autoantibodies and thus, combined use of these antibodies detects 55.3% of autoimmune hepatitis. Autoimmune hepatitis exists frequently when we include mild cases.

Relation between post-partum liver dysfunction and anti-cytochrome 2D6 antibodies.

PROBLEM: Autoimmune thyroid disease frequently aggravates or develops after delivery through the immune rebound mechanism. However, little is known about the post-partum development of autoimmune hepatitis (AIH). METHOD OF STUDY: We examined 18 patients who developed liver dysfunction after delivery or abortion. Serial examinations were performed in 10 of these cases. Anti-cytochrome 2D6(CYP2D6) antibodies, which are liver-specific autoantibodies, were measured using a sensitive radioligand assay. RESULTS: Liver dysfunction developed between 1 and 5 months after delivery and was mild and transient except in one case. One patient developed liver dysfunction after abortion. Eight of 10 patients who underwent serial serologic examinations were positive for anti-nuclear antibodies, but anti-smooth muscle antibodies were positive in only three patients, and were present only at low titer. None of the patients had anti-mitochondrial antibodies. Nine of these 10 cases were diagnosed as definite or probable AIH according to the international scoring system of AIH. Nine of these 10 patients were positive for anti-CYP2D6 antibodies. The increase of anti-CYP2D6 antibodies was slightly delayed compared to increase of aminotransferase. Of the 18 patients who developed liver dysfunction, 15 cases (83.3%) were positive for anti-CYP2D6 antibodies. Of the 77 post-partum control subjects only three (3.9%) had positive antibodies. CONCLUSIONS: Autoimmune hepatitis developed after delivery, similarly to the development of post-partum autoimmune thyroid disease. Measurement of anti-CYP2D6 antibodies by a sensitive radioligand assay could provide information important for the detection of post-partum AIH.

No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease.

Serial changes in serum levels of anti-TSH receptor antibodies were examined during and after pregnancy in six patients with Graves' disease receiving no or minimal maintenance doses of antithyroid drugs. During pregnancy, serum levels of TSH-binding inhibitory Igs (P < 0.001) and thyroid-stimulating antibodies (TSAbs) (P < 0.01) decreased gradually but increased after delivery in all patients. Activities of thyroid-stimulation blocking antibodies (TSBAbs) were lower than the cut-off value in early pregnancy, and values significantly decreased in four patients during pregnancy. The other two patients showed no significant change during pregnancy. In contrast, TSBAb levels increased significantly (P < 0.01) after delivery in all patients. We found that activities of TSH-binding inhibitory Igs, TSAb, and TSBAb decrease during pregnancy and increase after delivery, suggesting that amelioration of Graves' disease during pregnancy is induced by decrease of TSAb but not by the appearance of TSBAb.

Association of seasonal allergic rhinitis is high in Graves' disease and low in painless thyroiditis.

Hashimoto's thyroiditis is thought to be a T-helper cell type 1 (TH1)-dependent disease, but it is not clear whether Graves' disease is T-helper cell type 2 (TH2)-predominant or not. TH1-predominant diseases are infrequently and TH2-predominant diseases are frequently associated with allergic diseases. We examined the prevalence of seasonal allergic rhinitis to Japanese cedar pollen, a typical TH2-associated disease, in patients with Graves' disease (n = 126), painless thyroiditis (n = 46) and Hashimoto's thyroiditis (n = 88), and compared them to healthy controls (n = 766). Gender and age distribution were not different among patient groups and healthy controls, except for the higher age of patients with Hashimoto's thyroiditis. The prevalence of seasonal allergic rhinitis was significantly high in patients with Graves' disease (42.9%, p < 0.05) and low in patients with painless thyroiditis (13.0%, p < 0.01) but was not different in patients with Hashimoto's thyroiditis (26.1%) compared to that of healthy controls (32.6%). When patients with painless thyroiditis were included in Hashimoto's thyroiditis group, the prevalence of seasonal allergic rhinitis was 21.6% and significantly different from that of healthy controls (p < 0.05). These data indicate that Graves' disease is TH2 predominant and painless thyroiditis is a TH1-predominant disease. Our findings suggest that the shift from TH2 toward TH1 immunogenesis may be important for achieving earlier remission of Graves' disease.

Possible induction of Graves' disease and painless thyroiditis by gonadotropin-releasing hormone analogues.

Prolonged administration of gonadotropin-releasing hormone (GnRH) analogues induce a decrease in serum estrogen level, which may aggravate subclinical or mild autoimmune thyroid disease. Two patients developed Graves' thyrotoxicosis in association with an increase in anti-thyrotropin (TSH) receptor antibody activities at 4 months after initiation of buserelin acetate. GnRH analogue therapy was discontinued at the time of diagnosis but it took more than 2 years of methimazole therapy to obtain remission of Graves' disease. Another patient developed painless thyroiditis in association with an increase in antithyroid microsomal antibodies at 4 months after initiation of leuprolide acetate. These results indicate that GnRH analogues possibly induce clinical onset of Graves' thyrotoxicosis or destruction-induced thyrotoxicosis. Clinicians should be aware of this phenomenon. All patients who are to receive GnRH analogue therapy should be examined for antithyroid antibodies and family history of autoimmune thyroid disease, and should be followed accordingly.

Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease.

Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves' disease during or after anti-thyroid drug therapy, there is no reliable one to assure the complete remission. We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Fifty-seven patients with Graves' disease were treated with anti-thyroid drugs at the initial dose of 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU). Then, doses were gradually decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI 5 mg every other day or PTU 50 mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBII) were measured every one to two months for the first 6 months and every 3-4 months for the next 18 months to confirm continuous remission. After 2 years of drug cessation, 46 (81%) of 57 patients were in remission and the other 11 patients had relapsed into thyrotoxicosis. At the time of drug discontinuation, the serum concentration of FT4, FT3 and TSH, titers of anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies, goiter size were not different between the remission and relapse groups. At the time of drug cessation, the activities of TBII and thyroid-stimulating antibodies (TSAb) overlapped between the two groups, although they were significantly lower in the remission group than in the relapse group (p<0.01). Forty percent (4/10) of TBII positive patients and 71% (23/32) of TSAb positive patients continued to be in remission. On the other hand, thyrotoxicosis relapsed in 5 (11%) of 47 TBII negative and 2 (8%) of 25 TSAb negative patients. These data indicate that minimum maintenance therapy to keep euthyroid (normal FT4 and TSH) for 6 months is a practical measure for 81% prediction of remission in Graves' disease. The measurement of TBII or TSAb gave little additional information for predicting remission.

Increased serum concentration of eosinophil-derived neurotoxin in patients with Graves' disease.

Eosinophil-derived neurotoxin (EDN) is released after activation and stimulation of eosinophils in allergic disease, which is a T(H)2-predominant condition. We previously reported that Graves' thyrotoxicosis develops or relapses after an attack of allergic rhinitis. In this study, to confirm the relation between Graves' disease and the allergic condition, we determined the serum level of EDN in 30 untreated patients with Graves' disease, 50 patients with Hashimoto's thyroiditis, and 39 normal controls. Compared to the serum level in normal subjects (30.1 +/- 15.6 ng/mL), EDN was increased in untreated patients with Graves' disease (52.4 +/- 27.6 ng/mL), but not in patients with Hashimoto's thyroiditis (thyrotoxic, 30.9 +/- 13.4 ng/mL; euthyroid, 30.0 +/- 11.9 ng/mL; hypothyroid, 23.4 +/- 10.2 ng/mL). A significant correlation was observed between the EDN level and the serum activity of thyrotropin (TSH) receptor antibody (r = 0.541, p < 0.0001). These data suggest that the allergic condition is closely related to Graves' disease and that a T(H)2-type immune response is crucial in the pathogenesis of Graves' disease.

Blocking-type anti-TSH receptor antibodies and relation to responsiveness to antithyroid drug therapy and remission in Graves' disease.

OBJECTIVE: Antithyroid drugs are effective in some patients with Graves' disease but not in others. The factors responsible for this difference are still unknown. We examined the relationship between the nature of anti-TSH receptor (TSH-R) antibodies and responsiveness to drugs in Graves' disease. PATIENTS: Twenty-eight untreated patients with Graves' disease were treated with thiamazole and followed for up to 13 years. MEASUREMENT: Antithyroid microsomal antibodies (MCHAs) and antithyroglobulin antibodies (TGHAs) were measured by the passive haemagglutination method. Anti-TSH-R antibodies were measured by a radioreceptor assay (TBII), and thyroid-stimulating antibodies (TSAbs) and TSH-stimulation blocking antibodies (TSBAbs) were measured by bioassays using FRTL-5 cells. Blocking antibodies were also measured by the conversion assay. In order to confirm the usefulness of the conversion assay, in vitro experiments using mixtures of TSAb serum and TSBAb serum were performed. RESULTS: In in vitro conversion experiments, the conversion assay sensitively detected coexisting blocking antibodies. TSBAb was found in seven patients and a positive conversion ratio was found in four patients, and, of these, three patients had both antibodies. Finally, eight patients (28.6%) had blocking antibodies and 25 of 28 patients (89.3%) had stimulating antibodies. These patients with blocking antibodies (Group A) responded well initially to antithyroid drugs and showed earlier normalization of the serum T4 level (3.0 +/- 1.2 weeks) than patients without blocking antibodies (Group B, 10.7 +/- 8.5, P < 0.001). Unexpectedly, remission of Graves' thyrotoxicosis was earlier in Group B (5.1 +/- 4.4 years) than in Group A (8.0 +/- 4.3 years, P < 0.05). Other parameters, including serum T4, goitre size, ophthalmopathy, TBII, TSAb, TGHA and MCHA, were not different between the two groups. CONCLUSIONS: Graves' patients with coexisting blocking antibodies initially respond well to thiamazole but are relatively slow to achieve remission. Measurement of blocking antibodies may be useful for selection of treatment options in Graves' disease.

Simple and practical parameters for differentiation between destruction-induced thyrotoxicosis and Graves' thyrotoxicosis.

OBJECTIVE: Differentiation of destruction-induced thyrotoxicosis from Graves' thyrotoxicosis is important for selection of therapy. It is, however, often difficult to make this distinction without measurement of radioactive iodine uptake. We searched for simple and practical parameters that might allow differentiation between the two entities. PATIENTS: One hundred and eleven untreated patients with thyrotoxicosis (69 Graves' disease, 21 painless thyroiditis, 21 subacute thyroiditis) and 45 normal controls were examined. MEASUREMENTS: Serum levels of free T4 (FT4) and free T3 (FT3) were measured by radioimmunoassay, and anti-TSH receptor antibodies (TBII) were measured by radioreceptor assay. Peripheral leucocyte counts and the percentages of eosinophils and monocytes were measured using an automated leucocyte differential system. RESULTS: Peripheral eosinophils were significantly higher in Graves' disease (3.54 +/- 4.18%, P < 0.05) and lower in subacute thyroiditis (1.08 +/- 1.03%, P < 0.001) than in normal controls (2.26 +/- 1.33%). Peripheral monocytes were significantly higher in painless thyroiditis (6.87 +/- 2.85%, P < 0.01) than that in normal controls (4.63 +/- 2.14%). In comparison between groups, FT3 was higher with Graves' disease (20.55 +/- 10.29 pmol/l) than both painless thyroiditis (11.59 +/- 8.22 pmol/l, P < 0.001) and subacute thyroiditis (15.27 +/- 8.63 pmol/l, P < 0.05). The eosinophil to monocyte (Eo/Mo) ratio, FT3/FT4 ratio and Eo/Mo ratio multiplied by FT3 (pmol/ml) (Eo/Mo.FT3) were calculated and compared in these three disease groups. The Eo/Mo ratio, FT3/FT4 ratio and Eo/Mo.FT3 were significantly higher in patients with Graves' thyrotoxicosis (0.782 +/- 0.759, 0.399 +/- 0.089, 16.7 +/- 23.5 pmol/l, respectively) than in those with painless thyroiditis (0.259 +/- 0.157, 0.304 +/- 0.072, 2.43 +/- 1.49 pmol/l, respectively) and subacute thyroiditis (0.234 +/- 0.241, 0.335 +/- 0.057, 2.98 +/- 3.51 pmol/l, respectively). Twenty-two of 24 (91.7%) thyrotoxic patients with Eo/Mo < 0.2 had destruction-induced thyrotoxicosis (painless or subacute thyroiditis). Twenty-two of 28 (78.6%) thyrotoxic patients with FT3/FT4 < 0.3 had destruction-induced thyrotoxicosis. Thirty-six of 42 (85.7%) thyrotoxic patients with Eo/Mo.FT3 < 4.5 had destruction-induced thyrotoxicosis. The Eo/Mo ratio, FT3/FT4 ratio and Eo/Mo.FT3 were found to be similarly useful for differentiation between the two types of thyrotoxicosis. All thyrotoxic patients with TBII > or = 20% had Graves' disease and 76.4% of patients with TBII < 20% had destruction-induced thyrotoxicosis. CONCLUSION: The Eo/Mo ratio, FT3/FT4 ratio, and Eo/Mo.FT3 are simple, practical parameters and were as effective as TBII for differentiation of destruction-induced thyrotoxicosis (painless or subacute thyroiditis) from Graves' thyrotoxicosis. Eo/Mo < 0.2 and/or Eo/Mo.FT3 < 4.5 in untreated thyrotoxic patients are laboratory signals of destruction-induced thyrotoxicosis, and if these are determined, the radioactive iodine uptake test can be omitted for differential diagnosis of these two types of thyrotoxicosis.

Anti-CYP2D6 antibodies detected by quantitative radioligand assay and relation to antibodies to liver-specific arginase in patients with autoimmune hepatitis.

BACKGROUND: Antibodies to cytochrome P4502D6 (CYP2D6) were measured and their prevalence compared with that of antibodies to liver-specific arginase in patients with autoimmune hepatitis (AIH). METHODS: Anti-CYP2D6 antibodies were measured by sensitive radioligand assay and enzyme-linked immunosorbent assay (ELISA), and anti-arginase antibodies were measured by ELISA in 132 patients (definite AIH 11, probable AIH 36, hepatitis C 20, hepatitis B 23, other autoimmune diseases 42) and 50 healthy controls. RESULTS: CYP2D6 index (radioligand assay) was significantly higher in all groups of patients than those in healthy controls. A higher index than the cut-off value (mean+3 S.D. in healthy controls) was found in 36.4%, 44.4%, 25.0%, 17.4% and 28.6% of patients with definite AIH, probable AIH, hepatitis C, hepatitis B and other autoimmune diseases, respectively. CYP2D6 index was not related to serum IgG, anti-nuclear antibody or AIH scores, and was weakly correlated with anti-arginase antibody activity. When CYP2D6 index and anti-arginase antibodies were combined, 55.3% of AIH patients were positive for either one or both antibodies. CONCLUSIONS: Anti-CYP2D6 antibodies by radioligand assay were frequently present in patients with AIH. Combined tests for anti-CYP2D6 radioligand assay and anti-arginase antibodies resulted in detection of 55% of AIH patients.