Thiazolidinediones, synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), are reported to have direct beneficial effects on diabetic nephropathy without lowering blood glucose levels in human and rat. We hypothesized these effects of thiazolidinediones might be derived from PPARgamma activation of kidney cells, and we examined the expression of PPARgamma and the effect of PPARgamma agonists, troglitazone and 15-deoxy-delta-prostaglandin J2 (15d-PGJ2), on the proliferation and differentiation in rat mesangial cells. A single band of mRNA of PPARgamma with a predicted size was detected in reverse transcription-polymerase chain reaction products (RT-PCR) using established PCR probes of PPARgamma. PPARgamma protein in rat mesangial cells was identified as PPARgamma1 by a Western blot. In a gel mobility shift assay to determine a binding activity of PPARgamma, the nuclear protein from rat mesangial cells bound to a (32)P-labeled oligonucleotide probe, including PPAR response elements. A synthetic and a natural ligand of PPARgamma, troglitazone and 15d-PGJ2, decreased thymidine incorporation in a dose dependent manner. After 7 days incubation with troglitazone and 15d-PGJ2, alpha-smooth muscle actin expression, a marker of mesangial cell de-differentiation, was decreased significantly compared to that of control. These results indicate that PPARgamma1 is expressing in rat mesangial cells, and PPARgamma1 activation with its agonists modulates the proliferation and differentiation of cultured rat mesangial cells.

The duration of action of methimazole (MMI) was studied in patients with hyperthyroidism due to Graves' disease. Perchlorate discharge tests performed 24 h after MMI administration revealed greater than 10% discharge in 77% of 53 patients who received a single dose of 15 mg MMI and in 74% of 23 patients who received 30 mg. The mean percent discharges were 41.5 +/- 26.4% (+/- SD) and 35.4 +/- 28.0, respectively. Based on these results, hyperthyroidism was treated with a single daily dose (SDD) of 15 mg in 43 patients and with 30 mg in 32 patients, and the results were compared with retrospective analysis of 50 patients who were treated with divided doses of MMI (10 mg, 3 times daily). Within 12 weeks, 93% of the patients treated with 15 mg SDD, 91% treated with 30 mg SDD, and 86% treated with divided doses were euthyroid. The mean times to achieve euthyroidism in these patients were 5.3 +/- 3.6 (+/- SD), 5.3 +/- 3.1, and 5.6 +/- 3.0 weeks, respectively. Side-effects occurred in 2 patients treated with 15 mg SDD and in 6 treated with 30 mg SDD. We conclude that a single daily dose of 15 mg MMI is not only effective in most patients with Graves' hyperthyroidism, but also less frequently causes adverse effects.

OBJECTIVE -The prevalence and clinical importance of orthostatic hypertension (OHT) in diabetic patients has not been elucidated, in contrast to orthostatic hypotension, which is occasionally found in diabetic patients with autonomic neuropathy.RESEARCH DESIGN AND METHODS -The prevalence and severity of orthostatic hypertension was investigated in 277 Japanese male patients with type 2 diabetes, including 90 hypertensive patients and 128 nondiabetic age-matched male subjects. Patients treated with antihypertensive drugs were excluded from the study. OHT was defined as an increase in diastolic blood pressure (DBP) from Ͻ90 to Ն90 mmHg and/or an increase in systolic blood pressure (SBP) from Ͻ140 to Ն140 mmHg after standing from supine position. Clinical profiles and several serum biochemical parameters were determined in addition to chest X-rays and electrocardiograms.RESULTS -The prevalence of OHT in normotensive and hypertensive diabetic patients was significantly higher than in control subjects (12.8 vs. 1.8%, P Ͻ 0.01, for normotensive patients; 12.6 vs. 11.1%, not significant, for hypertensive patients). Orthostasis induced a mean increase of 6.8 Ϯ 11.4 mmHg in SBP and 9.1 Ϯ 5.2 mmHg in DBP in diabetic patients with OHT compared with those without OHT (Ϫ1.0 Ϯ 9.0 and 3.8 Ϯ 6.6 mmHg, respectively). Vibration sensation in the lower limb was reduced in diabetic patients with OHT, but the percent coefficient of variation of RR interval, cardio-to-thoracic ratio on chest X-ray, and serum triglyceride levels were higher in these patients compared with normotensive diabetic patients without OHT.CONCLUSIONS -Orthostatic hypertension is a novel complication in normotensive diabetic patients and may associate with early stage neuropathy and development of sustained hypertension.

Recovery of thyroid function in patients with both thyroid and renal dysfunction was studied. Among 245 patients with primary hypothyroidism (serum TSH >10 mU/l), 36 had mild to severe renal dysfunction (serum urea nitrogen >7.1 mmol/l and creatinine >106 μmol/l). Of these 36 patients, recovery of the thyroid function after iodine restriction was observed in 30(83%), in whom an elevated serum non-hormonal iodine level (median 236, range 67–15591 μg/l, N=19) and a high thyroidal radioactive iodine uptake (51.5±29.3%at24h, N = 26) were observed. The perchlorate discharge test was positive in 7 of 13 patients examined, suggesting an iodide organification defect rather than an atrophic or destructive change in the thyroid. Antithyroid antibodies were negative in 22 patients (73%) and an almost normal thyroid gland or colloid goitre was confirmed histologically in 8 of them. After a 13.2 mg potassium iodide loading test, 24 h urinary excretion of iodine was about 60% in normal controls, but only 10% in a different group of six euthyroid patients with renal dysfunction. These findings suggest that impaired renal handling of iodine rather than autoimmune mechanism may have a significant role in the pathogenesis of reversible hypothyroidism found in patients with renal dysfunction, probably through a prolonged Wolff-Chaikoff effect.

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The clinical significance of the thyroidal radioactive iodine uptake (RAIU) test was reevaluated in patients with various thyroid disorders. Compared with 262 normal subjects or 194 patients with euthyroid diffuse goiter with normal serum TSH levels, RAIU values were significantly higher in 100 patients with latent primary hypothyroidism (serum TSH, 5-40 mU/L). In 126 patients with overt primary hypothyroidism (serum TSH, greater than 40 mU/L), RAIU values were either extremely high (49 patients with reversible hypothyroidism and 10 patients with postpartum hypothyroidism) or low (67 patients with irreversible hypothyroidism). The increase in RAIU values in latent, or reversible overt hypothyroidism was TSH dependent, and there was a good correlation between RAIU values and serum TSH levels (r = 0.6203; P less than 0.001). In overt primary hypothyroidism, spontaneous recovery of thyroid function during iodide restriction alone occurred in 52 of 53 patients with RAIU values above 35%, in only 7 of 23 patients with RAIU values between 10-35%, and in none of 50 patients with RAIU below 10%. Thus, recovery was predicted by high RAIU values (P less than 0.001; prediction rate, 91.4%). Goiter was found in about 80% of the patients with reversible hypothyroidism, compared with only 34% of the patients with irreversible hypothyroidism. Recovery of thyroid function during iodide restriction also occurred in 71% of the patients with latent hypothyroidism. However, RAIU measurements did not predict the prognosis of patients with latent hypothyroidism. We conclude that iodine-induced reversible hypothyroidism is common in our patient population, and RAIU measurements may be helpful in determining the prognosis of patients with overt primary hypothyroidism.

The use of a screening test for thyroid functional disorder by sensitive thyroid stimulating hormone assay in the elderly was investigated. The basal thyroid stimulating hormone levels predicted the response of thyroid stimulating hormone to thyrotropin releasing hormone; it was suppressed in 99 (99.0%) of 100 hyperthyroid patients. Therefore, not only primary hypothyroidism but also hyperthyroidism can be excluded when the serum thyroid stimulating hormone levels are normal. An epidemiological study was then performed on 2,421 (76.7%) of the Japanese general population aged 40 or over recruited from the residents in Hisayama town and also in 122 residents between 20 and 40 years of age. Additional free T4 measurement was necessary in about 10% of the residents with abnormal TSH levels to confirm the diagnosis of hyperthyroidism or distinguish latent from overt hypothyroidism. There was a significant correlation between age and serum thyroid stimulating hormone levels after logarithmic conversion (r = 0.1533, P less than .001). The prevalence of thyroid dysfunction found in 1,026 males and in 1,395 females aged 40 or over was, respectively: hyperthyroidism, less than 0.1% and 0.2%, latent (subclinical) hypothyroidism, 3.2% and 5.5%, and overt hypothyroidism, 0.4% and 0.7%. We conclude that the screening with this sensitive thyroid stimulating hormone assay and additional free T4 measurement is useful for detection of patients with thyroid functional disorder.