The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.

Proteinuria, high serum creatinine, and reduced glomerular filtration rate (GFR) have been associated with increased mortality from cardiovascular disease (CVD) and all causes. However, the combined effect of proteinuria with serum creatinine and GFR on CVD or all-cause mortality has not been well investigated. We conducted a 10-year prospective cohort study of 30,764 men and 60,668 women aged 40-79 years who participated in annual health checkups in 1993. The Cox proportional hazards model was used to estimate the relative risk (RR) after adjusting for age, smoking, and other cardiovascular risk factors. The multivariable RR (95% confidence interval (CI)) of CVD death for positive vs negative proteinuria was 1.38 (1.05-1.79) among men and 2.15 (1.64-2.81) among women. The respective RR for the highest vs lowest creatinine groups (> or = 1.3 vs < or = 0.8 mg/dl for men and > or = 1.1 vs < or = 0.6 mg/dl for women) was 1.56 (1.19-2.04) among men and 2.15 (1.58-2.93) among women. The respective RR for GFR < 60 vs > r = 100 ml/min/1.73 m2 was 1.65 (1.25-2.18) among men and 1.81 (1.39-2.36) among women. For individuals with proteinuria combined by hypercreatininemia or reduced GFR, the risk of CVD death was two-fold higher in men and 4-6-fold higher in women compared to those without proteinuria and with normal creatinine level or GFR. Similar associations were observed for stroke, coronary heart disease, and all-cause mortality. Proteinuria, and hypercreatininemia or reduced GFR and their combination were significant predictors of CVD and all-cause mortality.

Non-invasive diagnosis of a Schwannoma by ultrasonography: a case study.

A 52-year-old female came to this institution complaining of a right leg mass lesion. Ultrasonography showed a 16 x 12 x 20mm hypoechoic solid mass lesion in the right leg. The patient underwent surgery during the diagnosis of Schwannoma. Preoperative diagnosis of Schwannoma is difficult by examination. Computerized tomography and magnetic resonance imaging, showed the origin of Schwannoma. However, the lesion was noted to be in a direct continuity with the cord-like echogenic structure consistent with a nerve by echography. We prefer to conduct preoperative examination by ultrasonography in patients with Schwannoma. In conclusion, we have reported a case of Schwannoma diagnosed by non-invasive ultrasonography.

Elevated serum granulocyte colony-stimulating factor levels in patients with Graves' disease.

OBJECTIVE: Agranulocytosis is a serious side effect of anti-thyroid drugs (ATD). Granulocyte colony-stimulating factor (G-CSF) is one of the cytokines that increase granulocyte number. The aim of this study was to examine the sequential variation of serum G-CSF levels in patients with Graves' disease before and after ATD therapy. PATIENTS: Sixty-three patients with Graves' disease were studied before, during and after treatment with methimazole (MMI). Serum samples from 71 healthy subjects were used as controls. DESIGN AND MEASUREMENTS: Serum levels of G-CSF were measured by a novel chemiluminescent enzyme immunoassay, which was sensitive enough to determine G-CSF levels in healthy subjects. Blood granulocyte counts, serum, thyroid hormone and TSH levels, and titres of thyroid autoantibodies were also measured. RESULTS: Serum G-CSF levels in Graves' patients before and 2 weeks after MMI were significantly higher than in healthy subjects. There was a significant correlation between serum G-CSF levels and granulocyte counts in untreated patients with Graves' disease. Untreated patients with granulocyte counts less than 2 x 10(9)/I had significantly lower serum G-CSF levels as compared with other untreated patients. Serum G-CSF levels gradually decreased thereafter. No correlation was observed between serum G-CSF levels and serum thyroid hormone levels or titres of thyroid autoantibodies. After ATD treatment, no correlation was found between serum G-CSF levels and granulocytes counts. There was no significant correlation between the change of serum G-CSF levels and that of granulocyte counts before and after MMI treatment. Graves' patients with mild agranulocytosis had normal or elevated serum G-CSF levels. CONCLUSIONS: Significantly elevated serum G-CSF levels were observed in patients with Graves' hyperthyroidism. During ATD therapy, deficiency of G-CSF was not identified as a cause of agranulocytosis in this study.

Transplantable rat thyroid cancer cell line FRTC transformed with muramyl dipeptide.

A rat thyroid cancer cell line, FRTC, was established from the normal rat thyroid cell line, FRTL-5. FRTL-5 cells were cultured in vitro with N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) for 4 days and were transplanted intraperitoneally into Fisher rats. Disseminated tumour formation in the peritoneum was found in ten out of ten rats in which MDP-treated FRTL-5 cells were transplanted. Colloid-like structures stained with anti-thyroglobulin (Tg) antibodies were observed in the tumours. On the other hand, no tumour was found in any of the rats in which untreated FRTL-5 cells were transplanted. No morphological changes were observed in FRTL-5 cells after long-term in vitro culture in the presence of MDP. MDP had no effect on thymidine incorporation, the production of cAMP or the expression of c-myc in FRTL-5 cells in vitro. Cells from the tumour (FRTC) secreted Tg in vitro and expressed Tg, thyroid peroxidase (TPO) and thyrotropin (TSH) receptor mRNA. The expression of TSH receptor mRNA increased in FRTC cells after TSH stimulation. FRTC cells produced cAMP in response to TSH stimulation in a dose-dependent manner. However, the growth of FRTC cells was TSH independent. Expression of c-myc and c-fos was observed in FRTC cells in vivo as well as in vitro. FRTC cells formed tumours in Fisher rats when transplanted subcutaneously. FRTC cells have several characteristics of differentiated thyroid cancer cells and may provide a good model for the study of human differentiated thyroid cancers.

Decrease in serum levels of thyroid hormone in patients with coronary heart disease.

The aim of this study was to evaluate the relationship between subclinical hypothyroidism and/or autoimmune thyroid disease and coronary heart disease (CHD). Ninety seven patients diagnosed as having CHD by a coronary angiography (CHD group) and 103 healthy subjects matched for age, sex and body mass index (control group) were included in the study. Thyroid function, thyroid autoantibodies and serum lipid concentrations were measured in the CHD and control groups. The CHD group exhibited significantly decreased serum free T3 (FT3) and free T4 (FT4) levels, and significantly increased serum TSH levels as compared with the control group, indicating a significant decrease in thyroid function in the CHD patients. Serum high density lipoprotein cholesterol (HDL-C) levels were significantly decreased in the CHD group. The incidence of subclinical hypothyroidism and thyroid autoantibodies was similar in both two groups. These observations were also true of women even after those who had diabetes mellitus (DM), hypertension (HT) and a smoking habit were excluded. This was not the case, however, in men without DM, HT, or a smoking habit. Patients with CHD had significantly lower serum levels of HDL-C than the control subjects, regardless of gender (P < 0.01). In the group with CHD, there was no difference between the serum lipid levels in patients with subclinical hypothyroidism and those with normal thyroid function. Female patients with CHD had significantly lower serum levels of thyroid hormone and HDL-C, but their subclinical hypothyroidism or thyroid autoimmunity did not seem to be related to the development of CHD.

Thyroid involvement by malignant histiocytosis of Langerhans' cell type.

Involvement of the thyroid gland by Langerhans' cell histiocytosis is quite rare. We describe the case of a 58-year-old man referred for treatment of a progressively enlarging goitre. The trachea was severely stenotic and adjacent structures such as the left carotid vein and the thyroid cartilage were also involved. Central diabetes insipidus and severe combined immunodeficiency were associated. Although fine needle aspiration biopsy of the thyroid was initially interpreted as papillary carcinoma, anaplastic thyroid cancer was suspected. Treatment with prednisolone, doxorubicin and irradiation controlled the tracheal compression. A diagnosis of thyroid Langerhans' cell histiocytosis was finally made on the basis of the presence of Birbeck granules and CD1a and CD4 antigen in the thyroid tumour cells. Furthermore, positive staining for CD68 and lysozyme suggested that the tumour cells may have had the character of phagocytic cells in addition to their dendritic cell nature. This is the first case of thyroid involvement by malignant histiocytosis of Langerhans' cell type with unusual phagocytic markers.

Axial parameters affecting lower limb alignment after high tibial osteotomy.

Lower limb alignment of 46 knees treated with high tibial osteotomy was studied to find a method for determining the precise correction angle. The femorotibial angle was divided into several axial alignment parameters. Before the operations, the femorotibial angle correlated with the tilting angle of the femoral shaft toward the horizontal (femoral shaft-horizontal angle) and that of the tibial shaft toward the horizontal (tibial shaft-horizontal angle). After the operations, the femorotibial angle correlated with the tibial shaft-horizontal angle, but not with the femoral shaft-horizontal angle. The postoperative femoral shaft-horizontal angle tends to be constant regardless of the degree of valgus. In preoperative varus knees, the varus deformity increases the degree of shift of the femoral and tibial shaft toward the varus direction. In postoperative valgus knees, the more valgus the knee the more the tibial shaft shifted toward the valgus direction, which was not true for the femoral shaft. The femorotibial angle was influenced more by the tibial axial alignment in the postoperative valgus knee. The slope of the distal femoral articular surface influenced the tilt of tibial articular surface toward the horizontal which, in turn, influenced the tibial shaft-horizontal angle. The authors recommend relying on the tibial axial alignment parameter to determine the amount of correction. The slope of the distal femoral articular surface should be considered in preoperative planning.

Clinical and arthroscopic findings of acute anterior cruciate ligament tears of the knee.

Clinical, arthrographic, and arthroscopic findings in 53 patients with acutely torn anterior cruciate ligaments (ACLs) were documented. Arthroscopy and instability tests under anesthesia were performed on all patients within 2 weeks after the initial injury. Twenty-three patients complained of extension blocks, and localized tenderness on the medial side was revealed in 26 patients at the initial examination. Aspiration from joints exhibited hemarthrosis in 52 patients. Arthroscopy revealed ACL ruptures in all patients. Four Segond's fractures, 26 meniscus tears (8 medial and 18 lateral), 1 osteochondral fracture, and 19 medial collateral ligament ruptures were revealed. Arthroscopy detected only 1 of the 5 ruptures of the posteromedial corner of the medial meniscus, which were noted on arthrography. Three ACL stumps were protruding among the femorotibial joint, which seemed to be restricting full extension. Statistical analysis showed that tenderness on the medial side was not revealed more frequently in knees with medial collateral ligament injuries than in the others. The volume of aspirated fluids in knees with no leakage in arthrography significantly increased over those with leakages (p < 0.05). Diagnosis of ACL injuries should be completed by clinical, arthrographic, and arthroscopic examinations.

Untreated acute anterior cruciate ligament tears of the knee: progression and the influence of associated injuries.

Arthroscopy was performed on 53 consecutive patients with acutely torn ACL within two weeks after the initial injury. Arthrography was performed on 42 of the 53 patients prior to arthroscopy. Four Segond's fractures, twenty-six meniscus tears (eight medial, eighteen lateral) and nineteen medial collateral ligament (MCL) ruptures were revealed. One medial meniscectomy was performed under arthroscopy, and ten MCL tears were repaired in the acute phase. No surgical procedure was done on the torn ACL, but three excisions of ACL stubs were performed due to a restriction of full extension. The patients were re-examined clinically and radiographically after a period of from 3 years 7 months to 11 years 1 month, averaging 6 years 2 months. Four late meniscectomies were performed on the medial menisci in the chronic phase. Anterior translations of the tibia and knee rating scores of the patients with MCL tears and with Segond's fractures did not differ from those of the others. Anterior translations of the tibia in patients with medial meniscectomies increased (P < 0.05), and their functional scores significantly decreased (P < 0.01) more than those of the other patients. Patients with repaired MCL tears showed significantly higher functional scores than those of the patients with unrepaired MCL ruptures (P < 0.05).

Disturbed lipid metabolism in patients with subclinical hypothyroidism: effect of L-thyroxine therapy.

To evaluate whether patients with subclinical hypothyroidism have a disturbance in lipid metabolism, and whether supplemental L-thyroxine (L-T4) therapy would improve their lipid parameters, we measured serum levels of thyroid hormones, TSH and lipid parameters in 34 patients with subclinical hypothyroidism before and 2 months after treatment with L-T4. Before treatment, patients with subclinical hypothyroidism had elevated serum low density lipoprotein cholesterol (LDL-C) concentrations compared with control subjects (P < 0.05). Overall, L-T4 therapy significantly decreased the serum level of TSH (P < 0.01), total cholesterol (TC; P < 0.02), high density lipoprotein cholesterol (P < 0.02), LDL-C (P < 0.05), and the ratio of apolipoprotein B to apolipoprotein A1 (P < 0.05). Lipid values in patients with basal serum TSH levels below 10 mU/l were not affected by L-T4 therapy, whereas serum levels of TC and LDL-C decreases significantly (P < 0.01) in patients with serum TSH levels above 10 mU/l. Thus, the L-T4 treatment appears to have a preventive effect on the disturbance of lipid metabolism in patients with subclinical hypothyroidism, especially in patients with serum TSH levels above 10 mU/l.

[The effect of arotinolol on the thyroid function and the autonomic nerve systems].

beta-blockers have been accepted as a reasonable adjunct therapy for the treatment of hyperthyroidism. They lessen the sympathetic symptoms such as tachycardia and finger tremor. On the other hand, many studies have demonstrated a decrease in 3, 3', 5-triiodothyronine (T3) during treatment with beta-blockers (especially propranolol). The purpose of this study is to clarify the effect of arotinolol (alpha 1, beta-blocker) on the thyroid functions and autonomic nerve systems (ANS) of patients with Graves' disease. Arotinolol 20mg a day p.o. was given to untreated patients with Graves' disease (n = 16) for 2 weeks. Blood sampling and the ANS function-tests were done before and after the treatment. In addition, the in vitro effects of arotinolol on the cAMP production and the radioactive iodine uptake (RAIU) using rat thyroid cell line FRTL5 were evaluated to examine the direct influence on thyroid cells. Arotinolol improved hyperthyroid symptoms including tachycardia, but had no effect on ANS function-tests. It is of interest that not only T3 but also T4 decreased after the arotinolol treatment. We therefore suspected the direct suppressive effects of arotinolol on the thyroid. There were, however, no in vitro inhibitory effects on the cAMP production and the RAIU in TSH-stimulated FRTL5 cells. The reason why serum T4 levels in patients with untreated Graves' disease have decreased after the treatment of arotinolol could not be clarified. In conclusion, arotinolol is a very useful drug for the initial therapy of patients with Graves' disease to reduce the serum thyroid hormone levels and symptoms of hyperthyroidism when combined with antithyroid drugs.

Incidence of anti-mouse IgG in normal subjects and patients with autoimmune thyroid disease.

Serum antibodies to mouse IgG occasionally interfere with two-site immunometric assays in which mouse monoclonal antibodies are used. We examined the titers of antibodies to mouse IgG in serum samples from normal subjects and patients with autoimmune thyroid disease (AITD) using an enzyme-linked immunosorbent assay. Anti-mouse IgG antibodies were positive in 7/119 patients with Graves' disease (5.9%) and 3/60 patients with Hashimoto's thyroiditis (5.0%). One of the 15 patients with a thyroid neoplasm (6.7%) also had antibodies to mouse IgG, as did 5/60 healthy subjects (8.3%). These antibodies were either of the IgG or IgM class. There was no significant difference in the incidence of positive anti-mouse IgG antibody between normal subjects and patients with AITD. It is important to note this high incidence of antibodies to mouse IgG due to the potential of interference with immunometric assays employing mouse monoclonal antibodies.

Disturbance of thyroidal iodine metabolism in BB/W rat.

To investigate the thyroid function in Bio-Breeding Worcester (BB/W) rats, we have examined the iodine metabolism, serum TSH and thyroid hormone levels in 8- and 16-week-old BB/W and normal Wistar (W) rats. At 8 weeks of age, serum TSH levels were significantly higher in BB/W rats than in W rats, although there was no difference in the serum levels of free T3 and free T4. Furthermore, the thyroidal radioactive iodine incorporation at 48 h was significantly lower in BB/W rats, suggesting that they might have some defects in iodine organification. At 16 weeks of age, serum TSH levels were also significantly higher in BB/W rats than in W rats. Furthermore, serum TSH levels in 16-week-old BB/W rats were significantly higher than in 8-week-old BB/W rats. The thyroid weight was significantly greater in BB/W rats, probably due to the increased serum TSH. The thyroidal radioactive iodine uptake at 48 h and the iodine content in the thyroid homogenates were significantly lower in BB/W rats. These results suggest that BB/W rats have some defect in iodine metabolism resulting in impaired thyroid hormone synthesis.

[Studies on the iodide metabolism and the expression of thyroglobulin and thyroid peroxidase mRNA in the thyroid of BB/W rats].

BioBreeding/Worcester (BB/W) rats develop insulin dependent diabetes mellitus (IDDM) and lymphocytic thyroiditis (LT) spontaneously. Our previous studies have shown that BB/W (Saitama-Tokyo colony) rats develop LT at about 10 weeks of age. Their serum TSH values increase as LT extends, although their serum thyroid hormone levels remain normal. This indicates that BB/W rats suffer from subclinical hypothyroidism. To investigate whether BB/W rats have a defect in iodide metabolism, the thyroidal radioactive iodine uptake (RAIU) in BB/W rats was examined. Thyroidal RAIU at 3hr in both 8 and 16 week-old BB/W rats was significantly higher than that in age-matched normal Wistar rats. On the other hand, BB/W rats had significantly lower 48hr thyroidal RAIU than normal Wistar rats. This suggests that BB/W rats appear to have some defects in iodide metabolism, especially in iodide organification even before the development of LT. The expression of thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA in BB/W and Wistar rats was then examined using the Northern blot analysis. The expression of both TPO and Tg mRNA was greatly decreased in BB/W rats compared with that in Wistar rats despite the high serum TSH levels in BB/W rats. This indicates that BB/W rats may have pretranslational defects in TPO and Tg synthesis, resulting in the impaired thyroid hormone synthesis. In the present study, it has been demonstrated that BB/W rats appear to have a defect(s) in iodide metabolism possibly due to some abnormalities in TPO and Tg synthesis.

Effect of cholera toxin on serum levels of thyrotropin and thyroid autoantibodies in biobreeding/Tokyo (BB/TKY) rats.

The effect of cholera toxin (CT) on the thyroid-pituitary axis and the immune system was examined in Bio-Breeding/Tokyo (BB/TKY) rats, which spontaneously develop insulin-dependent diabetes mellitus (DM) and lymphocytic thyroiditis (LT). Intravenous administration of CT (5 micrograms/100 g body weight) every other week starting at 6 weeks of age resulted in a significant decrease in the serum thyrotropin (TSH) level at 12 and 14 weeks of age when compared with saline treated littermates. CT stimulated rat thyroid cells to proliferate in vitro. Furthermore, serum anti-thyroglobulin antibody (ATA) titers were also significantly decreased in 14-week-old rats treated with CT. In vitro ATA production by spleen cells from BB/TKY rats was inhibited by CT. Antibodies to thyroxine were detected in both CT-treated and control rats. It is of interest that the ratio of W3/25+ helper/inducer cells to OX8+ suppressor/cytotoxic cells was significantly decreased in CT-treated rats. However, there was no significant difference in the incidence of DM and LT between the two groups of rats. The present study showed that CT suppressed ATA production both in vivo and in vitro, and had a stimulatory effect on thyrocytes in BB/TKY rats.

[Studies on thyroid hormone autoantibody (THAA) in 2 cases of Graves' disease with spuriously high free thyroxine values].

Two patients with Graves' disease treated with methimazole (MMI) showed a discrepancy between serum free T4 (FT4) values and other hormone values (especially total T4) which was due to the presence of potent binding activity to labelled T4 analogue (125I-aT4) in their serum. This activity was demonstrated to be in immunoglobulin G (IgG) with kappa light chain isotype in both patients. The binding of 125I-aT4 to their serum was inhibited by unlabelled T4 in a dose-dependent manner. Autoantibodies had almost identical binding affinity to T4 and aT4, although they precipitated more radioactivity when 125I-aT4 was used. The binding of IgG purified from patients' sera to labelled T4 or aT4 was not greater than the corresponding sera, suggesting that the thyroxine binding proteins did not interfere with the assay. Since the specific radioactivity of 125I-aT4 is almost 10 times higher than that of 125I-T4, autoantibodies can precipitate almost 10 times more radioactivity in the FT4 assay than the total T4 assay, thus leading to the spuriously high FT4 values and large discrepancy between FT4 and TT4 values.

The mechanism for the discrepancy between serum total and free thyroxine values induced by autoantibodies: report on two patients with Graves' disease.

The sera from two patients with Graves' disease gave abnormally high serum free T4 values as compared with the total T4 and other hormone values, suggesting the presence of autoantibodies to labelled T4 analogue used in the Amersham free T4 assay kit. The autoantibodies appeared to develop after the initiation of methimazole therapy and disappeared again after the cessation of methimazole. This binding activity to labelled T4 analogue was demonstrated to be in the immunoglobulin G with a kappa light chain isotype in both sera, and was displaced by unlabelled T4 in a dose-dependent manner. The binding of immunoglobulin G purified from these sera to labelled T4 or T4 analogue was found to be almost identical to that of the corresponding serum binding. Since the specific radioactivity of labelled T4 analogue used in the Amersham free T4 assay kit is about 10 times higher than that of the labelled T4 in the Amersham total T4 assay kit, serum free T4 determinations are much more vulnerable to thyroid hormone autoantibodies. Thus, in the presence of autoantibodies, a large discrepancy develops between free T4 and total T4 values.