Sanae Midorikawa

The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection.

OBJECTIVE Several recent studies have indicated that patients with adrenal incidentaloma often have disturbed glucose tolerance or/and hypertension. It is unclear whether these metabolic conditions could be caused by adrenal incidentaloma. We investigated the prevalence of disturbed glucose tolerance, hypertension and insulin resistance in the patients with non‐functioning adrenal incidentaloma and evaluated the changes of the parameters such as glucose tolerance, blood pressure and insulin sensitivity after adrenalectomy.

Nuclear disasters and health: lessons learned, challenges, and proposals

Past nuclear disasters, such as the atomic bombings in 1945 and major accidents at nuclear power plants, have highlighted similarities in potential public health effects of radiation in both circumstances, including health issues unrelated to radiation exposure. Although the rarity of nuclear disasters limits opportunities to undertake rigorous research of evidence-based interventions and strategies, identification of lessons learned and development of an effective plan to protect the public, minimise negative effects, and protect emergency workers from exposure to high-dose radiation is important. Additionally, research is needed to help decision makers to avoid premature deaths among patients already in hospitals and other vulnerable groups during evacuation. Since nuclear disasters can affect hundreds of thousands of people, a substantial number of people are at risk of physical and mental harm in each disaster. During the recovery period after a nuclear disaster, physicians might need to screen for psychological burdens and provide general physical and mental health care for many affected residents who might experience long-term displacement. Reliable communication of personalised risks has emerged as a challenge for health-care professionals beyond the need to explain radiation protection. To overcome difficulties of risk communication and provide decision aids to protect workers, vulnerable people, and residents after a nuclear disaster, physicians should receive training in nuclear disaster response. This training should include evidence-based interventions, support decisions to balance potential harms and benefits, and take account of scientific uncertainty in provision of community health care. An open and joint learning process is essential to prepare for, and minimise the effects of, future nuclear disasters.

Amelioration of Genetic Hypertension by Suppression of Renal G Protein-Coupled Receptor Kinase Type 4 Expression

Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein–coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar–Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were ≈90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.

Thyroid ultrasound findings in children from three Japanese prefectures: Aomori, Yamanashi and Nagasaki.

Due to the likelihood of physical and mental health impacts following the unprecedented accident at the Fukushima Dai-ichi Nuclear Power Plant, the Fukushima prefectural government decided to conduct the Fukushima Health Management Survey to assist in the long-term health management of residents. This included thyroid ultrasound examination for all children in Fukushima. For appropriate evaluation of ultrasound screening of the thyroid, it is important to understand its reference data of thyroid findings in children in general. In order to analyze the frequencies of specific thyroid findings, we conducted ultrasound screening of the thyroid by the same procedures as used in Fukushima in 4,365 children, aged 3 to 18 years, from three Japanese prefectures. Overall, thyroid cysts were identified in 56.88% and thyroid nodules in 1.65% of the participants. Thyroid cysts and nodules with a maximum diameter of more than 5 mm were identified in 4.58% and 1.01%, respectively, and age-adjusted prevalences were 3.82% and 0.99%, respectively. Although the prevalence of cysts and nodules varied among the examination areas, no significant differences were observed among the three examination areas in the prevalence of cysts and nodules with a maximum diameter of more than 5 mm. Also, the prevalence of thyroid cysts and nodules, especially those with a maximum diameter of more than 5 mm, significantly increased with age, and showed a female predominance. We also identified ectopic thymus (1.95%), diffuse goiter (1.40%), ultimobranchial body (0.73%), lymph node swelling (0.21%) and thyroid agenesis (0.05%). This is the first ultrasound description of the age-adjusted prevalence of thyroid cysts and nodules, or of the prevalence of abnormalities other than cysts and nodules, such as ectopic thymus, in relation to age, in the general Japanese child population. We contend that this can provide relevant information for the Fukushima Health Management Survey and future population studies.

Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus.

This study evaluated abnormal fibrinolysis in diabetic patients in terms of the pathophysiological significance and reversibility by oral hypoglycemic agents. Forty-seven patients with type 2 diabetes mellitus were randomly treated for 4 weeks with glibenclamide (n = 23) or troglitazone (n = 24). Before and after treatment, glycemic control, steady-state plasma glucose and insulin (SSPG and SSPI, respectively), and markers of fibrinolysis (tissue plasminogen activator [tPA] and plasminogen activator inhibitor-1 [PAI-1]) were analyzed in each patient. Pretreatment plasma PAI-1 in diabetic patients, but not tPA, was well correlated with the severity of retinopathy assessed by the fluorescence technique. Four weeks of treatment with troglitazone significantly decreased hemoglobin A1c (HbA1c), SSPG, and PAI-1 without an alteration of tPA. The troglitazone-induced decrease in plasma PAI-1 (50.3 v28.8 micromol/L; P < .05) was correlated with HbA1c (8.80% v7.21%, r = .539, P < .01) and SSPG (16.2 v 8.97 mmol/L, r = .562, P < .01) but not with SSPI. In contrast, treatment with glibenclamide for 4 weeks also reduced the HbA1c titer to almost the same extent as troglitazone (1.38% v 1.59%), but did not change the plasma PAI-1 or SSPG titer. These results suggest that an abnormal fibrinolytic state, especially overproduction of PAI-1, may be a pathogenic factor in the development of diabetic complications such as retinopathy, which may be improved by correction of the insulin resistance with troglitazone.

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN–treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.

Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma

Pheochromocytoma (PCC) and paraganglioma (PGL) are genetically and phenotypically heterogeneous catecholamine-producing neoplasms. They can occur sporadically or as a part of hereditary disease. Approximately 30% of PCC/PGL are believed to be caused by germline mutations (Welander et al. 2011). Of these, succinate dehydrogenase subunit B (SDHB) gene mutation is considered a high-risk factor for malignancy. Loss of heterozygosity at the SDHB locus (1p36)wasobserved inall tumorswithSDHBmutation, and Gimenez-Roqueplo et al. (2003) strongly suggested that SDHB is a tumor suppressorgene. Subsequently, loss of SDHB protein immunoreactivity in SDHB-mutated PCC/PGL (SDHB–PCC/PGL) was reported with 100% sensitivity and 84% specificity (van Nederveen et al. 2009). Thus, SDHB immunohistochemistry can be used to screen SDHB– PCC/PGL using paraffin-embedded pathological materials. SDHB mutation is the only established factor that indicates future metastasis. Therefore, it is important to analyze the histological characteristics of SDHB–PCC/PGL. It is generally accepted that it is difficult to distinguish histological differences between benign and malignant PCC/PGL. The current consensus is that a long-term follow-up is required after the surgery to screen for recurrence or metastasis in all PCC/PGL patients, regardless whether hereditary or sporadic in origin. Kimura et al. (2014) proposed a histological grading system called the Grading of Adrenal PCC and PGL (GAPP) classification for predicting metastasis. GAPP is composed of six factors: histological pattern, cellularity, presence or absence of comedo-type necrosis, vascular or capsular invasion, Ki67labeling index (%), and elevated catecholamine type. Each factor was assigned a point and the number of points was summated. Tumor scores of 0–2, 3–6, and 7–10 were classified into well differentiated (WD), moderately

Plasma vascular endothelial growth factor in Japanese Type 2 diabetic patients with and without nephropathy

AIM To determine whether plasma vascular endothelial growth factor (VEGF) level is elevated in Type 2 diabetic patients with an early stage of diabetic nephropathy. METHODS We studied 71 Japanese Type 2 diabetic patients with normal serum creatinine level (<100 micromol/l) (age 63.0 [60.3-65.6] years old, diabetes duration 15.6 [14.0-17.3] years, HbA1c 7.36% [7.06-7.66%], mean [95% confidence interval, CI]): normoalbuminuric patients (n=36); microalbuminuric patients (n=21); and proteinuric patients (n=14). Plasma VEGF concentration was measured by a quantitative sandwich enzyme immunoassay technique. RESULTS Plasma VEGF concentration was not related to the degree of albuminuria: normoalbuminuric patients (25 [13-95] ng/l, median [25th-75th percentile]); microalbuminuric patients (33 [15-120] ng/l); and proteinuric patients (54 [17-107] ng/l). Plasma VEGF level in patients with retinopathy (25 [15-95] ng/l, n=30) was not elevated as compared to those without retinopathy (53 [14-126] ng/l, n=34). Plasma VEGF tended to correlated negatively with diabetes duration (Rs=-.217, P=.0690) and HbA1c (Rs=-.221, P=.0647), whereas there was no correlation between plasma VEGF level and age, serum creatinine or urinary albumin to creatinine ratio (ACR) of the patients, respectively. Plasma VEGF level in the group of patients with HbA1c equal to or below the median (<7.2%) was significantly higher than that in the group of patients with HbA1c above the median (>7.2%) (P<.05). CONCLUSIONS The results suggested that Type 2 diabetic patients with microalbuminuria and those with retinopathy are not necessarily associated with an elevation of circulating plasma VEGF concentration. Plausible association between plasma VEGF level and glycemic control remains to be seen.

Elevation of Serum Soluble E-and P-Selectin in Patients with Hypertension Is Reversed by Benidipine, a Long-Acting Calcium Channel Blocker

Hypertension is a major risk factor for atherosclerotic cardiovascular disease. Selectins, cell-surface adhesion molecules involved in leukocyte rolling and attachment to the vascular endothelium, play a role in the initiation of atherosclerosis. We investigated whether or not serum levels of soluble adhesion molecules are elevated in patients with essential hypertension (EH) and examined whether antihypertensive therapy lowers such levels. Twenty-one patients who had untreated mild to moderate EH without diabetes mellitus, hyperlipidemia, or obesity were recruited at a clinic for hypertensive patients. Blood pressure was measured, and the serum levels of soluble E-selectin, P-selectin, L-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular-cell adhesion molecule 1 (VCAM-1) were determined by enzyme-linked immunosorbent assays before and after 12, 24, and 53 weeks of antihypertensive treatment with benidipine, a long-acting calcium channel blocker, given at a dose of 6 mg/day for 53 weeks. As a control, 21 age- and sex-matched patients without hypertension were studied. Serum E- and P-selectin levels were significantly higher in the subjects with EH than in the controls (p<0.01). There were no differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 levels between the patients with EH and the controls. Treatment with benidipine decreased the elevated blood pressure over a 53-week study period (mean blood pressure: 119.8±6.5 mmHg at baseline, 101.0±5.9 mmHg at 12 weeks, 98.6±7.3 mmHg at 24 weeks, and 93.9±5.5 mmHg at 53 weeks). Serum levels of soluble E- and P-selectin decreased after the initiation of benidipine treatment and correlated with diastolic blood pressure. Serum levels of soluble L-selectin, VCAM-1, and ICAM-1 did not change significantly during the period of benidipine treatment. Benidipine treatment reduced the content of P-selectin in the platelets from patients with EH, as determined by Western blot analysis. In conclusion, decreased blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both. Benidipine may be protective against vascular damage in people with hypertension, not only by lowering blood pressure, but also by inhibiting the expression of selectins.

The protocol and preliminary baseline survey results of the thyroid ultrasound examination in Fukushima [Rapid Communication]

UNLABELLED After the Fukushima nuclear power plant accident on March 11, 2011, the public of Japan became particularly concerned about the possibility of an increased risk of childhood thyroid cancer, similar to what was observed after the Chernobyls accident. Due to serious public health perception, there was an urgency to evaluate the baseline levels of childhood thyroid status in Fukushima prefecture. Therefore we have commenced a thyroid ultrasound examination (TUE) survey of the approximately 360,000 pediatric inhabitants (0 to 18 years of age) who lived in Fukushima at the time of the accident in October 2011. The subjects were divided into three categories according to the standardized diagnostic criteria of ultrasound findings. Category A contained the subjects whose TUE findings were intact or benign. Category B were recommended a confirmatory TUE. Category C was recommended an immediate confirmatory TUE. RESULTS The survey of 40,302 subjects in the first year was completed in March, 2013. There were 40,097 (99.5%), 205 (0.50%) and 0 subjects in categories A, B and C, respectively. Of the 82 category B subjects who underwent fine needle aspiration cytology (FNAC), 12 were diagnosed with a malignant tumor or were suspected to have malignancy. The 12 subjects received thyroid surgery and 11 thyroid cancers and one benign nodule were confirmed histologically after surgery. This is the first large-scaled TUE survey to employ sophisticated ultrasound screening and aim to evaluate the baseline frequency of childhood thyroid nodules and cysts. The results will become the golden standard of future comparative TUE in Fukushima, Japan.