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Objective: The goal of this study was to know the fate of albuminuria in Japanese patients with type 2 diabetes under tight blood pressure and glycemic control.Research Design and Methods: Patients having normoalbuminuria (urinary albumin excretion <30 mg/g creatinine, n = 179) or microalbuminuria (albumin excretion 30-299 mg/g creatinine, n = 94) at baseline have been followed up for 8 years: ratio of men to women was 160/113, the mean age was 58 years, pretreatment HbA(1c) (A1C) was 8.8%, and blood pressure was 136/76 mmHg. A1C <6.5% and blood pressure <130/80 mmHg were targeted, and the A1C of 6.5 +/- 0.7% (mean +/- SD) and blood pressure of 127 +/- 11/72 +/- 6 mmHg have been maintained during the 8 years. Development of microalbuminuria or macroalbuminuria (albumin excretion > or =300 mg/g creatinine) in initially normoalbuminuric patients and progression to macroalbuminuria or regression to normoalbuminuria in initially microalbuminuric patients were assessed at year 8.Results: Development occurred in 27 (15%) of the normoalbuminuric patients and progression and regression in 16 (17%) and 20 (21%), respectively, of the microalbuminuric patients. Significant independent relationships existed between development and higher achieved mean systolic blood pressure (SBP) and regression and lower achieved mean SBP. In the patients with achieved mean SBP <120 mmHg, development was 3%, progression was 11%, and regression was 44% during 8 years. Prediction for nephropathy by blood pressure and glycemia alone was limited. Nevertheless, albumin excretion at year 8 was positively correlated with achieved mean SBP and baseline albuminuria.Conclusions: Development and progression were low and regression was high with SBP of 120 mmHg, provided A1C was maintained at 6.5%. [ABSTRACT FROM AUTHOR]

Aim/hypothesis. We analysed Japanese MODY patients for mutations in the HNF-1α gene. Methods. Fifty unrelated Japanese patients with early-onset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1α gene. Functional studies of the mutant HNF-1α were carried out. Results. We identified three new mutations in the HNF-1α gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC→A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1α. By increasing the amount of L518P519fsTCC→A-HNF-1α, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1α or V617I-HNF-1α mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control. Conclusion/interpretation. The L518P519fsTCC→A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1α gene needs to be screened for mutations in patients either with early-onset diabetes or with a strong family history for diabetes. [ABSTRACT FROM AUTHOR]

Background: Small, dense low-density lipoprotein (sd-LDL) increases in type 2 diabetes patients and causes arteriosclerosis. Non-high-density-lipoprotein cholesterol (non-HDL-C) is thought to be useful for predicting arteriosclerosis and sd-LDL elevation; however, there are no data about whether the triglyceride /low-density-lipoprotein cholesterol (TG/LDL-C) ratio is a valuable predictor for sd-LDL., Methods: A total of 110 type 2 diabetes patients with hypertriglyceridemia were analyzed. No patients were treated with fibrates, but 47 patients were treated with statins. LDL-C was measured by the direct method. LDL-migration index (LDL-MI) using electrophoresis (polyacrylamide gel, PAG) was calculated, and a value ≥0.400 was determined to indicate an increase in sd-LDL. Simple regression analyses were carried out between LDL-MI and lipid markers. Receiver operating characteristic curves of lipid markers for predicting high LDL-MI were applied to determine the area under the curve (AUC), sensitivity, specificity, and cut-off point., Results: LDL-MI correlated negatively with LDL-C (P = 0.0027) and PAG LDL fraction (P < 0.0001) and correlated positively with TGs, non-HDL-C, TG/LDL-C ratio, TG/HDL-C ratio, and non-HDL-C/HDL-C ratio among all study patients. Similar results were obtained for patients analyzed according to statin treatment. The AUCs (95% confidence interval) were 0.945 (0.884-1.000) for TG/LDL-C ratio and 0.614 (0.463-0.765) for non-HDL-C in patients without statins (P = 0.0002). The AUCs were 0.697 (0.507-0.887) for TG/LDL-C and 0.682 (0.500-0.863) for non-HDL-C in patients treated with statins. The optimal cut-off point for TG/LDL-C ratio for increased LDL-MI was 1.1 (molar ratio) regardless of statin treatment. The sensitivity and specificity of the TG/LDL-C ratio (90.0 and 93.9%, respectively) were higher than those of non-HDL-C (56.7 and 78.8%, respectively) in patients without statins., Conclusions: The TG/LDL-C ratio is a reliable surrogate lipid marker of sd-LDL and superior to non-HDL-C in type 2 diabetes patients not treated with statins., (© 2021. The Author(s).)

Aims/introduction: Type 2 diabetes mellitus is caused by a relative imbalance between insulin secretion and sensitivity related to the body mass index (BMI). Seven categories of oral antidiabetic drugs (OADs) are available in Japan. It is important to assess the OAD utilization patterns based on patients' BMI levels., Materials and Methods: OAD prescribing patterns from 2002 to 2019 were analyzed using the data collected in the computerized diabetes care database provided by the Japan Diabetes Clinical Data Management Study Group; OAD utilization patterns in 25,751 OAD-treated type 2 diabetes mellitus patients registered in 2019 were analyzed after classifying them into five categories of BMI., Results: Comparing OAD usage between 2002 and 2019, sulfonylureas decreased from 44.5 to 23.2%, and biguanides (BGs) increased from 19.3 to 50.3%. Dipeptidyl peptidase-4 inhibitors (DPP4is) increased to 56.9% in 2019. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) increased to 23.6% in 2019. About 90% of type 2 diabetes mellitus patients had BMI < 30 kg/m 2 . DPP4is were the most used OADs in 2019. When BMI exceeded 30 kg/m 2 , use of BGs and sodium-glucose cotransporter 2 inhibitors increased, and use of sulfonylureas and DPP4is decreased. Although DPP4is were the most used OADs for patients with BMI <30 kg/m 2 , they were the third most prescribed OADs for patients with BMI >35 kg/m 2 after BGs and sodium-glucose cotransporter 2 inhibitors ., Conclusions: DPP4i usage was as high as that of BG in the analysis of Japanese type 2 diabetes mellitus patients with relatively low BMI. This was considered to be a treatment option appropriate for the pathophysiology in Japanese patients., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: There have been several reports of secondary anemia associated with Graves' disease. There are no reports of secondary anemia resulting from thyrotoxicosis due to painless thyroiditis (silent thyroiditis). We report the case of a patient with pancreatic diabetes who developed anemia caused by thyrotoxicosis due to painless thyroiditis., Case Presentation: The patient was a 37-year-old man who visited the hospital complaining of fatigue, palpitations, and dyspnea. His hemoglobin was 110 g/l (reference range, 135-176), and mean corpuscular volume was 81.5 fl (81.7-101.6). His free thyroxine (FT4) was high, at 100.4 pmol/l (11.6-21.9); the free triiodothyronine (FT3) was high, at 27.49 pmol/l (3.53-6.14); TSH was low, at < 0.01 mIU/l (0.50-5.00); and TSH receptor antibody was negative. Soluble IL-2 receptor (sIL-2R) was high, at 1340 U/ml (122-496); C-reactive protein (CRP) was high, at 6900 μg/l (< 3000); and reticulocytes was high, at 108 10 9 /l (30-100). Serum iron (Fe) was 9.5 (9.1-35.5), ferritin was 389 μg/l (13-401), haptoglobin was 0.66 g/l (0.19-1.70. Propranolol was prescribed and followed up. Anemia completely disappeared by 12 weeks after disease onset. Thyroid hormones and sIL-2R had normalized by 16 weeks after onset. He developed mild hypothyroidism and was treated with L-thyroxine at 24 weeks., Conclusions: This is the first case report of transient secondary anemia associated with thyrotoxicosis due to painless thyroiditis. The change in sIL-2R was also observed during the clinical course of thyrotoxicosis and anemia, suggesting the immune processes in thyroid gland and bone marrow.

Background: Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated., Methods: Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4-8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL., Results: Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (- 3.8-19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96-3.26] vs. 3.36 [3.05-3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62-6.69] vs. 3.25 [2.64-3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391-0.450] vs. 0.354 [0.341-0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs., Conclusions: Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

Low concentrations of high-density lipoprotein cholesterol (HDL-C) have been reported in patients with hematological malignancies. However, the proof of decreased HDL-C in hematological malignancies and its association with clinical outcomes remain unclear. We analyzed 140 Japanese patients with malignant lymphoma (ML) and adult T-cell leukemia-lymphoma (ATLL). HDL-C, LDL-C and soluble interleukin-2 receptor (sIL-2R) were measured. Treatment decisions were determined with established protocols. HDL-C was 0.98 ± 0.45 mmol/l in patients and 1.51 ± 0.35 mmol/l in controls (P < 0.001). LDL-C was lower in patients than in controls (2.76 ± 0.96, 3.16 ± 0.76 mmol/l, respectively, P < 0.001). HDL-C was the lowest in ATLL (0.81 ± 0.37 mmol/l), modest in non-Hodgkin lymphoma (1.09 ± 0.42 mmol/l) and the highest in Hodgkin's disease (1.14 ± 0.68 mmol/l), (P = 0.0019). Inverse correlation was found between HDL-C and sIL-2R (r = -0.6584, P < 0.001). Categorized patients into 3 subgroups according to HDL-C (<0.52, 0.52-1.02 and ≥1.03 mmol/l), sIL-2R were the highest (median, 36,675; IQR, 17,180-92,600 U/mL) in patients with HDL-C < 0.52 mmol/l, modest (2386, 1324-8340) in HDL-C 0.52-1.02 mmol/l and the lowest (761, 450-1596) in HDL-C ≥ 1.03 mmol/l (P < 0.001). In Cox regression model, the lowest HDL-C levels, <0.52 mmol/l, were associated with poorer clinical outcome and the hazard ratio was 5.73 (95%CI, 3.09-10.50; P < 0.001). In Kaplan-Meier analysis according to HDL-C tertiles (<0.78, 0.78-1.10 and ≥1.11 mmol/l), patients with lowest HDL-C tertile showed inferior overall survival with a median follow-up of 23 months (P < 0.001). We concluded that cytokine-induced low levels of HDL-C in patients with ML and ATLL has independent prognostic significance, and suggesting an early indicator of poorer outcome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Unlabelled: The aim of this study was to evaluate differences in dopamine transporter SPECT images among different SPECT/CT devices and to determine the most appropriate region of interest (ROI) for semiquantitative evaluation., Methods: An anthropomorphic striatal phantom was filled with (123)I solutions of different striatum-to-background radioactivity ratios. Data were acquired using 2 SPECT/CT devices equipped with low- to medium-energy general-purpose and low-energy high-resolution (LEHR) collimators. The SPECT images were reconstructed by filtered backprojection with both attenuation and scatter correction and then were analyzed using specific binding ratio (SBR). The most appropriate of 7 ROI types was determined, and we then compared the linearity and recovery of SBR among the different SPECT/CT devices and collimators., Results: The linearity of SBR was excellent for all types of ROIs. The ROI contouring the striatum based on the CT images showed the best recovery of SBR using mean activity in the striatal ROI (SBRmean) (47.8%). For this ROI, the recovery of SBRmean for SPECT/CT with a LEHR collimator with thick septa and a long hole length was 61.6%-significantly higher than that of other devices., Conclusion: The ROI contouring the striatum based on CT images was considered appropriate for evaluating dopamine transporter SPECT/CT. Among the different SPECT/CT devices, an LEHR collimator designed for (123I)I imaging is recommended., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Aims/introduction: Although male diabetic patients have an increased risk of fracture, there is little information about this in the literature. The association between heel bone stiffness and the lifestyle of male patients with diabetes was evaluated., Materials and Methods: The study included 108 participants with type 2 diabetes mellitus patients and 168 age-adjusted, healthy male volunteers. None of the participants had a history of osteoporosis or other severe diseases. Heel bone stiffness was examined by quantitative ultrasound, and each participant completed a health interview survey questionnaire. Bone stiffness was taken as an indicator of bone strength. Stepwise regression analysis was used to investigate associations between bone stiffness and lifestyle-related factors, such as sunlight exposure, intake of milk or small fish, regular exercise, cigarette smoking, consumption of alcohol, and number of remaining teeth., Results: Bone stiffness showed a significant negative association with cigarette smoking [standardized coefficient (SC) = -0.297, F-value (F) = 10.059] and age (SC = -0.207, F = 7.565) in diabetic patients. Bone stiffness showed a significant negative association with age (SC = -0.371, F = 12.076) and height (SC = -0.193, F = 7.898), as well as a significant positive association with sunlight exposure (SC = 0.182, F = 9.589) and intake of small fish (SC = 0.170, F = 7.393) in controls., Conclusions: These findings suggest that cigarette smoking and age are negatively associated with bone stiffness in Okinawan male patients with type 2 diabetes mellitus.

Objective: Compact medical cyclotrons have been set up to generate the nuclides necessary for positron emission tomography. In accelerator facilities, neutrons activate the concrete used to construct the vault room; this activation increases with the use of an accelerator. The activation causes a substantial radioactive waste management problem when facilities are decommissioned. In the present study, several concrete cores from the walls, ceiling and floor of a compact medical cyclotron vault room were samples 2 years after the termination of operations, and the radioactivity concentrations of radionuclides were estimated., Methods: Cylindrical concrete cores 5 cm in diameter and 10 cm in length were bored from the concrete wall, ceiling and floor. Core boring was performed at 18 points. The gamma-ray spectrum of each sample was measured using a high-purity germanium detector. The degree of activation of the concrete in the cyclotron vault room was analyzed, and the range and tendency toward activation in the vault room were examined., Results: (60)Co and (152)Eu were identified by gamma-ray spectrometry of the concrete samples. (152)Eu and (60)Co are produced principally from the stable isotopes of europium and cobalt by neutron capture reactions. The radioactivity concentration did not vary much between the surface of the concrete and at a depth of 10 cm. Although the radioactivity concentration near the target was higher than the clearance level for radioactive waste indicated in IAEA RS-G-1.7, the mean radioactivity concentration in the walls and floor was lower than the clearance level., Conclusion: The radioactivity concentration of the inner concrete wall of the medical cyclotron vault room was not uniform. The areas exceeding the clearance level were in the vicinity of the target, but most of the building did not exceed the clearance levels.

Objective: We evaluated the accuracy of amplitude gating PET (AG-PET) compared with phase gating PET (PG-PET) in relation to respiratory motion patterns based on a phantom analysis., Method: We used a NEMA IEC body phantom filled with an (18)F solution with a 4:1 sphere-to-background radioactivity ratio (12.6 and 2.97 kBq/mL). PET/CT scans were acquired in a motionless and moving state on a Biograph mCT. The respiratory movements were simulated by four different waveform patterns consisting of ideal breathing, breathing with a pause period, breathing with a variable amplitude and breathing with a changing baseline. AG-PET selects the narrow bandwidth containing 20 % of the respiratory cycle. PG-PET was reconstructed with five gates. The image quality was physically assessed using the percent contrast (Q H,10mm), background variability (N 10mm) recovery coefficient (RC), and sphere volumes., Result: In regular motion patterns with ideal breathing and breathing with a pause period, the Q H,10mm, RC and sphere volumes were not different between AG-PET and PG-PET. In the variable amplitude pattern, the Q H,10mm of AG-PET was higher than that of PG-PET (35.8 vs 28.2 %), the RC of AG-PET was higher than that of PG-PET and sphere volume of AG-PET was smaller than that of PG-PET (6.4 vs 8.6 mL). In the changing baseline pattern, the Q H,10mm of AG-PET was higher than that of PG-PET (42.4 vs 16.7 %), the RC of AG-PET was higher than that of PG-PET and sphere volume of AG-PET was smaller than that of PG-PET (6.2 vs 9.8 mL). The N 10mm did not differ between AG-PET and PG-PET, irrespective of the motion pattern., Conclusion: Amplitude gating PET is considered to be more accurate than phase gating PET for examining unstable respiratory motion patterns, such as those involving a variable amplitude or changing baseline.

Background: Hypertension is a major risk factor for death and cardiovascular disease (CVD) in patients undergoing chronic haemodialysis (HD), but there is uncertainty surrounding the effects of blood pressure (BP) lowering on this high-risk patient group., Methods: In a multicenter, prospective, randomized, open-label, blinded-endpoint trial, 469 patients with chronic HD and elevated BP (140-199/90-99 mmHg) were assigned to receive the angiotensin receptor blockade (ARB) olmesartan (at a dose of 10-40 mg daily; n = 235) or another treatment that does not include angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors (n = 234). The primary outcomes were the following: (i) composite of death, nonfatal stroke, nonfatal myocardial infarction and coronary revascularization and (ii) all-cause death., Results: During a mean follow-up of 3.5 years, the mean BP was 0.9/0.0 mmHg lower in the olmesartan group than in the control group (not significant). A total of 68 patients (28.9%) in the olmesartan group and 67 patients (28.6%) in the control group had subsequent primary composite endpoints [hazard ratio (HR) in the olmesartan group 1.00, 95% confidence interval (CI) 0.71-1.40, P = 0.99]. All-cause deaths occurred in 38 patients (16.2%) in the olmesartan group and 39 (16.7%) in the control group (HR, 0.97; 95% CI, 0.62-1.52, P = 0.91). Olmesartan did not alter the risks of serious adverse events., Conclusions: BP-lowering treatment with an ARB did not significantly lower the risks of major cardiovascular events or death among patients with hypertension on chronic HD. (Cochrane Renal Group Prospective Trial Register number CRG010600030).

Acute renal failure (ARF) induced by dextran or mannitol is a lethal adverse effect, and hemodialysis or plasma exchange is recommended to avoid fatal ARF. This report describes 2 cases of ARF; one caused by dextran and the other by mannitol. Both showed decreases in the blood urea nitrogen (BUN)/creatinine ratios after the administration of these reagents. They immediately recovered to the level of creatinine on admission after the administration of these reagents was stopped, without hemodialysis or plasma exchange. Decreases in the BUN/creatinine ratio might be a useful index for the diagnosis of ARF is caused by these reagents.

Background: Motorization and supermarket-proliferation affect lifestyles. About 15 years ago, Okinawans went to several shops on foot, but now they go to supermarkets by car. The influences of these changes on the prevalence of diabetes are uncertain. OBJECTIVE AND MEASUREMENTS: The influence of motorization and supermarket-proliferation on the prevalence of diabetes was studied in the inhabitants of a town on Okinawa, Japan. Measurements were composed of anthropometry and blood chemistry. Participants were asked where they buy food and daily necessities (several shops or a supermarket) and how they get there (by car or on foot)., Design: Serial cross-sectional., Participants: Inhabitants of the island of Okinawa were studied., Results: In 1991, 24% went to several shops and 20% to a supermarket. However, in 2004, only 3.1% went to several shops and 83% to a supermarket. In 1991, 55% went to shopping places on foot and 38% by car. However, in 2004, only 14% went on foot and 76% by car. The prevalence of diabetes in Okinawa increased from 4.7% in 1991 to 8.4% in 2004. The prevalence of diabetes correlated positively with the percent of inhabitants going to supermarkets, and those going there by car. In 1991, the prevalence of type 2 diabetes was 4.7% in men and 4.6% in women; no difference was noted between men and women. In 2004, the prevalence of type 2 diabetes increased to 9.2% in men and to 7.5% in women. The increase in the prevalence of type 2 diabetes from 1991 to 2004 was higher in men than in women., Conclusions: About 15 years ago, Okinawans went to shops on foot, but now they go to supermarkets by car. The prevalence of diabetes is increasing. Motorization and supermarket-proliferation are associated with the increases of the prevalence of diabetes. The increase in diabetes prevalence was higher in men than in women.

In this study we confirmed our previous findings on the importance of IgE in Graves' disease and further investigated the relationships existing among Graves' disease, IgE, and interleukin-4. Two hundred and thirty-two newly diagnosed Graves' disease patients were treated with methimazole for 2 years, and were classified into 3 groups according to their response to the therapy. Incidence of IgE elevation (IgE> or =170 IU/ml) before treatment was lowest, 23.8%, in the group who achieved remission without recurrence, while it was 41.7% in the group who achieved remission but recurrence occurred within 4 years. Incidence of IgE elevation before treatment was highest, 60.7%, in the group who failed to achieve remission, significantly higher than that of the group without recurrence. Incidence of IgE elevation before treatment in all these patients of Graves' disease were 35.3%, significantly higher than those of Hashimoto's thyroiditis (17.5%) and of simple goiter (7.0%). Serum IL-4 levels before treatment were significantly higher in the patients of Graves' disease with IgE elevation than in those without IgE elevation. Serum T4 concentration and TSAb titration before treatment were also significantly higher in elevated IgE group than in normal IgE group. These results support our previous findings and suggest that IL-4 may play important roles in the elevation of IgE, TBII, and TSAb in patients of Graves' disease, and that IL-4 and IgE may be involved in the development, progression, and maintenance of Graves' disease.

To explore the relationship between pituitary morphology and function, we performed mid-sagittal MRI and endocrinological evaluation in 38 patients with asthenia. Six patients were diagnosed as having complete empty sella (ES) and 16 patients partial empty sella (PES). BMI, blood pressure, serum Na, ACTH, cortisol, TSH and T(4) were lower in ES group and PES group than in the group with normal pituitary size. Age in the patients with ES was oldest. Multiple regression analysis revealed that serum cortisol level was independently correlated with the size of the pituitary (beta = 0.586, p = 0.0069). Other variables, including age, BMI, blood pressure, serum Na, ACTH, TSH and T(4), were not correlated with the pituitary size when multivariate analysis was employed. In conclusion, there is a close relationship between the reduction of size of pituitary gland and the degree of adrenocortical dysfunction in asthenic patients. It is suggested that the pituitary-adrenal axis is especially vulnerable in empty sella syndrome, and therefore, meticulous evaluation of the hypophysial adrenal axis is recommended in subjects with reduced pituitary size even in elderly population.

Fosfomycin is clinically recognized to reduce the aminoglycoside antibiotics-induced nephrotoxicity. However, little has been clarified why fosfomycin protects the kidney from the aminoglycosides-induced nephrotoxicity. Gentamicin, a typical aminoglycoside, is reported to cause lipid peroxidation. We focused on lipid peroxidation induced by gentamicin as a mechanism for the aminoglycosides-induced nephrotoxicity. The aim of this study is to investigate the effect of fosfomycin on the gentamicin-induced lipid peroxidation. In rat renal cortex mitochondria, fosfomycin was shown to depress the gentamicin-induced lipid peroxidation, which was evaluated by formation of thiobarbituric acid reactive substances (TBARS). Interestingly, this effect was observed in rat renal cortex mitochondria, but not in rat liver microsomes. However, fosfomycin did not affect lipid peroxidation of arachidonic acid caused by gentamicin with iron. Fosfomycin inhibited the gentamicin-induced iron release from rat renal cortex mitochondria. These results indicated that fosfomycin inhibited the gentamicin-induced lipid peroxidation by depressing the iron release from mitochondria. This may possibly be one mechanism for the protection of fosfomycin against the gentamicin-induced nephrotoxicity.

To investigate the possible involvement of IDDMK1,2 22/HERV-K18 in childhood type I diabetes mellitus, we identified two nonsynonymous A/G polymorphisms in the superantigen-coding region of IDDMK1,2 22 at the 290- and 461-nucleotide (nt) positions from the initial methionine codon and compared their frequencies in 74 Japanese patients with type 1 diabetes and in 54 nondiabetic controls. Although the G substitution was observed more frequently at either site in the patients than it was in the controls (7% vs. 4% at 290 nt, and 29% vs. 20% at 461 nt), the differences were not statistically significant. A weak significance of difference in the frequency of 461G was obtained only in an early-onset group of patients manifesting the disease at 5 years of age or less (n = 24) when compared with controls (38% vs. 20%; P = 0.03). However, in addition to the common absence of a particular allele among the expected four alleles, remarkable differences in allele frequencies were present between Japanese and European populations. This first trial investigating the association of IDDMK1,12 22 with type 1 diabetes presents intriguing suggestions for the role of this region in the etiology of autoimmune and infectious diseases.

We analyzed the association of 2 biallelic polymorphisms of CYP11B2 (P450c11AS) gene (1 in the Lys(173)Arg of exon 3 and the other in the promoter at position -344T/C) with hypertension in 73 hypertensive patients and 134 normotensive subjects. The association between low-renin hypertension and angiotensin I-converting enzyme (ACE) gene was also analyzed. An elevated ratio of plasma aldosterone concentration to plasma renin activity was used to identify low-renin hypertension. Genotypes for CYP11B2 and ACE were determined through polymerase chain reactions. The Arg(173) allele frequency did not differ between hypertensive patients considered as 1 group (34%) and normotensive control subjects (37%). However, only 22% of 58 CYP11B2 alleles studied in 29 patients with low-renin hypertension were Arg(173) alleles, whereas the frequency of this allele was 41% in patients with normal- or high-renin hypertension (P=0.033). An analysis of the distribution of -344C and Arg(173) genotypes indicated that these 2 variants were in complete linkage disequilibrium: -344C was present in a subset of chromosomes carrying the Arg(173) (P<0.001 in low-renin hypertension). Therefore, the frequency of the -344C allele was low in the patients with low-renin hypertension compared with those with normal- or high-renin hypertension. Deletion (D) allele frequencies of the ACE gene were 31% in the patients with low-renin hypertension, 39% in the patients with normal- or high-renin hypertension, and 29% in normotensive control subjects. We detected an association between the CYP11B2 gene polymorphisms and low-renin hypertension with inappropriate elevation of aldosterone. The decreased frequencies of the Arg(173) and -344C variants in the CYP11B2 appear to be genetically linked to low-renin hypertension in the Japanese population studied.

Excess iodine intake may affect the development of Hashimoto's thyroiditis. Kelp consumption is very high in Okinawa. We expected a high prevalence of Hashimoto's thyroiditis in Okinawa. We studied urinary iodine excretion and the positivities of anti-thyroglobulin antibodies (TGAb) and anti-thyroid peroxidase antibodies (TPOAb) in the residents of Nishihara in Okinawa, Yamagata in Yamagata, Kobe in Hyogo, and Hotaka in Nagano, Japan. TGAb and/or TPOAb were positive in 142 (13.7%) of 1039 subjects in Nishihara, in 16 (16.0%) of 100 subjects in Yamagata, in 31 (13.4%) of 232 subjects in Kobe, and in 35 (13.9%) of 252 subjects in Hotaka; TGAb and/or TPOAb positivity was about the same in these 4 areas. One tenth of the subjects with positive TGAb and/or TPOAb had hypothyroidism; the frequencies of hypothyroidism in those with positive TGAb and/or TPOAb were about the same in Nishihara, Yamagata, Kobe, and Hotaka. The iodine concentration in samples of morning urine correlated well with the 24-h urine iodine excretion. The urinary iodine excretion was 1.5 mg/day in Nishihara. There were no differences between Nishihara and Yamagata in the urinary iodine concentration, but the urinary iodine concentrations in Kobe and Hotaka were less than those in Nishihara or Yamagata. The amounts of iodine excretion in Kobe and Hotaka were moderate, and less than those in Nishihara or Yamagata. The amounts of iodine intake in Kobe and Hotaka were less than those in Nishihara or Yamagata, but TGAb and/or TPOAb positivity was about the same in Nishihara, Yamagata, Kobe, and Hotaka. The differences in dietary iodine intake do not affect TGAb and/or TPOAb positivity.

Sixty-four patients with acromegaly were retrospectively analyzed to study the incidence and cause of hypertension in acromegaly. WHO criteria indicate that 37.5% patients with acromegaly have hypertension. The blood pressure was positively correlated with age, the insulin-like growth factor I (IGF-I) and serum sodium (Na) concentration. In addition, IGF-I and Na were significantly different in hypertensive and normotensive groups. Seventy-five percent of hypertensive patients had a family history of hypertension. IGF-I, Na and blood pressure were significantly higher in patients with a family history of hypertension than in those without it. In patients with a family history of hypertension, blood pressure was positively correlated with IGF-I and serum Na, but IGF-I was not correlated with serum Na. In patients without such a family history, blood pressure had a good correlation only with age, and IGF-I was not significantly correlated with blood pressure. In addition, the incidence of hypertension in this group was the same as or lower than that in the general population. The above results suggest that the genetic factor produces hypertension in acromegaly by two ways, by increasing Na and enhancing IGF-I production by GH.

In an attempt to study the natural course of Hashimoto's thyroiditis and simple goiter, 74 euthryroid patients with Hashimoto's thyroiditis and 212 patients with simple goiter were followed for 10 years. In 204 patients with simple goiter (96.2%) it remained as a simple goiter throughout the observation period, whereas 8 patients (3.8%) later had Hashimoto's thyroiditis as evidenced by the appearance of circulating thyroid autoantibodies. These 8 patients had HLA typing significantly different from that of control subjects. None of the patients with simple goiter had hyperthyroid Graves' disease despite the fact that 17.5% of those patients had mild to moderate exophthalmos with either Moebius' sign or von Graefe's sign. In contrast, 12 patients with Hashimoto's thyroiditis (16.2%) had exophthalmos with Moebius' sign and/or von Graefe's sign, and 4 of 12 such patients later had hyperthyroid Graves' disease. TSH binding inhibitory immunoglobulin was detected in 3 of 4 such patients with hyperthyroid Graves' disease. Forty-nine patients with Hashimoto's thyroiditis (66.2%) still remained euthyroid but 20 of those (27.0%) turned into hypothyroidism during the 10-year follow-up.

We assessed the usefulness and reliability of computed tomography (CT scan) in evaluating adrenal hyperplasia in 38 patients, including 14 with Cushing's disease, 17 with idiopathic hyperaldosteronism (IHA), and 7 with the adrenogenital syndrome (AGS). Eighty-two normal subjects were also examined. We analyzed the shape of the adrenal gland and quantitated its thickness, width and length. Visual inspection revealed V-shaped right adrenal glands in 100% of patients with Cushing's disease, 94% of patients with IHA, 100% of patients with AGS and in 41% of the normal subjects. Triangular left adrenal glands were observed in 100% of patients with Cushing's disease, 82% of patients with IHA, 67% of patients with AGS and in 12% of the normal subjects. Quantitative analysis showed that the right adrenal gland was significantly thicker and longer in patients with Cushing's disease, IHA and in those with AGS than in normal subjects. The right adrenal gland was significantly wider in the patients with Cushing's disease and AGS than in control subjects. The left adrenal gland was significantly wider and longer in patients with Cushing's disease and AGS than in the normal controls. Analysis of individual data indicated that the upper limit of normal for thickness of the right adrenal was 7 mm. Therefore, adrenal hyperplasia was strongly suggested when the right adrenal gland was more than 7 mm thick. Our findings suggest that the CT scan is useful and reliable in diagnosing adrenal hyperplasia.

Carney's complex is composed of myxoma, spotty pigmentation and endocrine overactivity. A 27-year-old male was diagnosed to have Carney's complex on the basis of intense spotty pigmentations on his face, soles and palms, and bilateral adrenal nodular hyperplasia on computed tomography scanning (CT) and magnetic resonance imaging (MRI). Total bilateral adrenectomy was done; histological findings were compatible with primary pigmented adrenocortical disease (PPNAD). Recently, his sister and one of his brothers were suspected to have Carney's complex with PPNAD. We report the first familial case of Carney's complex with PPNAD and spotty pigmentations in Japan.

Ninety-four overweight subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) were followed for 10 years. No one from the NGT group developed diabetes, however 32% of the IGT subjects did develop diabetes. Initial data of the IGT subjects who developed diabetes were significantly different from those who did not develop diabetes. Fasting, peak and/or sigma plasma glucose (PG), IRI and CPR at 180 minutes and CPR/IRI at 0 and 180 minutes were increased, and the peak time of PG was delayed; also the prevalence of a positive family history was higher, and the body weight heavier. Seventy-nine percent of IGT subjects with the initial sigma PG of greater than or equal to 40 mM or a positive family history developed diabetes whereas only 3% of those with sigma PG of less than 40 mM and a negative family history developed diabetes. Therefore, it might be considered that among the overweight adults with IGT, those with sigma PG of greater than or equal to 40 mM or a positive family history are diabetes prone and those with sigma PG of less than 40 mM and a negative family history are diabetes resistant.

A patient with hypogonadotropic hypogonadism and anosmia (Kallmann's syndrome) is described. Anosmia has been believed to be due to hypoplasia of the rhinencephalon. This anatomical defect was demonstrated in vivo in a patient with Kallmann's syndrome by magnetic resonance imaging (MRI).

The LD50 values of dibekacin to mice were determined following three different methods of administration, namely, intravenous constant infusion, intravenous bolus injection, and intramuscular injection. The serum levels of dibekacin were pharmacokinetically analyzed. The differences in LD50 values between the methods of administration were discussed from the viewpoints of pharmacokinetics. 1) The LD50 value following the intravenous constant infusion was higher than that following the intravenous bolus injection and approached the level of that following the intramuscular injection, when the infusion rate of the drug was decreased by increasing the infusion period. 2) The biological half-life of dibekacin in mice was 24--45 min. 3) The volume of distribution increased as its dose increased, and a linear correlation was noted between log Vd and log (dose). 4) The difference among the maximum serum concentrations calculated with dibekacin following the administration of LD50 was small, which coincided with the results of the experiment that the serum concentrations of dibekacin at the death following the administration of LD100 were almost the same regardless of the method of administration.

The behaviors of dibekacin after three administration methods to rabbits and dogs were pharmacokinetically analysed. 1) In both rabbits and dogs, the pharmacokinetic constants for the intravenous constant infusion and intramuscular injection were similar to each other, and the serum levels after the intravenous constant infusion for 1 hr were similar to those after the intramuscular injection except the peak time. 2) In both rabbits and dogs, Vd increased with the dose and a linear correlation was noted between log Vd and log (dose). 3) The tissue concentrations of dibekacin decreased with the decrease in the serum concentration. 4) A correlation equation, log T 1/2 = 0.194 . log B + 1.128, was obtained, where T 1/2 and B represent the biological half-life of dibekacin and the body weight of animals, respectively. It was suggested that the pharmacokinetic behaviors of dibekacin in human beings can be predicted from the results of the animal experiments.

This paper reports a case of liver cirrhosis associated with hepatocellular carcinoma (HCC) of a woman who was converted from hepatitis B surface antigen (HBs-Ag) positive to antibody against HBs-Ag (anti-HBs) positive in the serum through an immunoregulatory steroid rebound phenomenon. The histology of the biopsy specimen taken before the seroconversion showed an early stage of liver cirrhosis with moderate infiltration of mononuclear cells. At autopsy about 3 years after the seroconversion, the liver tissue free of the tumor was in an early stage of liver cirrhosis. Fibrosis did not advance as compared with the biopsy specimen. In addition, mononuclear cell infiltration decreased remarkably and piecemeal necrosis disappeared after the seroconversion. The immunohistologic examination of hepatocytes demonstrated that positive stainings for HBs-Ag and for hepatitis B core antigen (HBc-Ag) in the biopsy specimen turned to be negative in the autopsy specimen. These facts indicate that the steroid rebound phenomenon eliminated free hepatitis B virus (HBV) in the hepatocytes in the absence of massive necrosis of hepatocytes. HBV-DNA integration was proved in the genome of HCC by molecular hybridization method.

A physiologically based model for drug reabsorption in renal tubules was applied to sulfanilamide reabsorption kinetics in rats, rabbits and dogs. The reabsorption percent of sulfanilamide decreased with an increase of urine flow rate in the three animal species examined. Furthermore, the reabsorption percent increased with the decrease of the glomerular filtration rate (GFR), even though the urine flow rate normalized by GFR was the same. The power law formula was obtained between AR (l) X Pe and the animal body weight. The power was 0.721, which was less than unity. In contrast, sigma was not dependent on animal body weight. The reabsorption percent of sulfanilamide in man was calculated using AR (l) X Pe and sigma obtained from animal data. The value thus calculated was 50-60%, which was comparable to the reported value (52%) in healthy human subjects. Therefore, the reabsorption percent of sulfanilamide in man was successfully predicted by the extrapolation of animal data.

The renal accumulation of dibekacin, one of the aminoglycoside antibiotics, was pharmacokinetically analyzed and the mechanism of the renal accumulation of these antibiotics was investigated. The remaining amounts of dibekacin in the kidneys were adequately expressed by the bi-exponential equation. There was no possibility of a covalent bond between dibekacin and the renal tissue components. The renal accumulation of the aminoglycoside antibiotics was explained in terms of the two successive processes, renal tubular reabsorption and electrostatic interaction between these antibiotics and the tissue components. In other words, these antibiotics were reabsorbed at the renal tubules and transported into renal tubular epithelial cells and bound to the tissue components by electrostatic force. The electrostatic interaction also played an important role in increasing the acute toxicities of aminoglycoside antibiotics.

We studied the mechanism on protective effect of fosfomycin against experimental nephrotoxicity induced by dibekacin. In order to simplify an experimental model, the dehydrated Wistar rats were used, because a single injection of dibekacin at 30 mg/kg induced acute renal failure in the dehydrated rats, characterized by alteration of urinalytic parameters and BUN values, and retarded elimination of dibekacin from blood. When the rats were administered simultaneously with fosfomycin at 120 mg/kg, the rate of elimination was restored almost to normal, accompanied with improvement of the nephrotoxic parameters. However, markedly accelerated elimination over normal one was not observed, indicating that the improved elimination was not the reason of protection but a result of normal kidney function. On the other hand, fosfomycin protected the proximal tubular lysosomes from the injury of aminoglycoside, as evidenced a) in vivo by suppression of myeloid body formation and protection of lysosomal membrane integrity of the rats treated with dibekacin, and b) in vitro by dose-dependent protection of the lysosomal membrane integrity of the kidney cells. A study of structure-protective activity relation revealed that phosphonate anion possessing an epoxy function was important for protection, and that the mechanism of protection differed from the antibacterial mechanism.

A novel method was proposed to predict the elimination half-lives of cephalosporins from plasma protein binding (unbound fraction, f) and fraction of the dose excreted into urine (f*) on the basis of the following four assumptions. 1) The drug is only distributed to the extracellular fluid, 2) the bound fraction of the drug in plasma is independent of the plasma drug concentration, 3) the binding protein of the drug is albumin, 4) the unbound drug in plasma is excreted by the glomerular filtration and the contribution of active secretion and reabsorption is negligible. The VSS's and t1/2 beta's of MT-141, one of cephalosporins, in rabbits, dogs and healthy human subjects were well predicted, whereas in rats, the prediction of the both values was failed. The t1/2 beta's of various cephalosporins in healthy subjects were calculated from f and f*, in reasonably good agreement with the observed ones, except for some cephalosporins which have been reported to be secreted actively in the renal tubules. Thus, the comparison of the calculated t1/2 beta's with the observed ones makes it possible to presume the renal excretion mechanism. Moreover, this method will be applicable to other drugs which satisfy the above four assumptions.