The Effectiveness of the Semi-quantitative Assessment of Microalbuminuria Using Routine Urine Dipstick Screening in Patients with Diabetes.

Objective The early diagnosis and treatment of microalbuminuria is important for preventing the progression of diabetic kidney disease in patients with diabetes. In this study, we assessed the accuracy of the semi-quantitative measurement of microalbuminuria by urine dipstick screening in patients with diabetes. Methods The semi-quantitative urinary albumin-to-creatinine ratio (QUACR) was used for microalbuminuria screening. A total of 291 diabetes patients with normoalbuminuria [urine albumin-to-creatinine ratio (UACR) <30 mg/g・Cre; n=205] or microalbuminuria (UACR 30-299 mg/g・Cre; n=86) were enrolled as study participants. Both the qualitative test of albumin (QUA) and the QUACR of early-morning or spot urine samples were performed at the same time. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic utility of the QUACR to that of the QUA in the detection of microalbuminuria. Results The sensitivity and specificity values of the QUACR were 84.9% and 76.6%, respectively. Those of the QUA were 53.5% and 84.4%, respectively. In the ROC analysis, the area under the curve values of the QUACR and QUA for the diagnosis of microalbuminuria were 0.807 (95% confidence interval: 0.752-0.863) and 0.689 (0.618-0.760), respectively. Conclusion These results suggest that the QUACR is a simple and efficient test-with high levels of sensitivity and specificity-for the detection of microalbuminuria in patients with diabetes.

A Patient with an Extra-adrenal Pheochromocytoma and Germ-line SDHB Mutation Accompanied by an Atypical Meningioma.

The gene succinate dehydrogenase subunit B (SDHB) encodes a protein comprising part of the mitochondrial complex II, which links the Krebs cycle and the electron-transport chain. Heterozygous germ-line SDHB mutations causes familial pheochromocytoma-paraganglioma syndrome and has also been linked to gastrointestinal stromal tumors, as well as renal cell carcinomas. We herein report a patient with a germ-line SDHB mutation who presented with an atypical meningioma that was identified as originating from a somatic SDHB mutation. The 41-year-old man, who had a surgical history of extra-adrenal pheochromocytoma at 23 years of age, recently developed gait disorder and hypertension. At the radiological examination, a tumor was detected in the cervical spinal cord at the C6-7 intervertebral level. The pathological findings of the isolated tumor were atypical meningioma assessed as grade II according to the World Health Organization criteria. Inherited neoplasia syndrome was suspected because of the patient's history of early-onset extra-adrenal pheochromocytoma and the development of meningioma. We therefore performed molecular genetic analyses. A direct sequence analysis revealed a heterozygous germ-line frameshift mutation in SDHB, specifically an 11-nucleotide deletion, c.305-315delCAATGAACATC, in exon 4, resulting in a frameshift p.A102EfsX12. Additionally, the sequence analysis of the tumor DNA revealed only a mutated allele with a frameshift mutation in the germ-line SDHB. Our findings suggest that SDHB plays an important role in the pathogenesis of meningiomas as well as pheochromocytomas. Therefore, a differential diagnosis for metastatic pheochromocytoma and other new onset tumors, including meningioma, particularly in patients with germ-line SDHB mutations and a previous history of pheochromocytoma should be carefully made.

Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression.

Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography-computed tomography (PET-CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA-like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) - euchromatic histone-lysine N-methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes.

Impact of aldosterone-producing adenoma on cardiac structures in echocardiography.

BACKGROUND: Primary aldosteronism (PA) is a most common cause of secondary hypertension. In PA, left ventricular hypertrophy (LVH) is more progressive than in any other cause of hypertension. Aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are major subtypes of PA. However there is little information concerned with differences of cardiac structures between these two subtypes. METHODS: We reviewed echocardiographic findings in 46 patients with PA. All patients had a positive screen test and subtypes of PA were confirmed by adrenal vein sampling. Subjects consisted of 20 patients with APA (APA group, 52.4 ± 10.8 years) and 26 patients with IHA (IHA group, 56.2 ± 9.5 years). We investigated differences of cardiac structures and functions in the left atrium and ventricle between the APA group and IHA group. RESULTS: In terms of clinical characteristics, the height and duration of hypertension were greater and serum potassium concentration and BMI were lower in the APA group than in the IHA group. Plasma aldosterone concentration (PAC) and PAC to plasma renin activity ratio were higher in the APA group than in the IHA group. In echocardiographic assessment, the left atrial volume, left ventricular end-diastolic and end-systolic diameters, left ventricular mass (LVM), and prevalence of LVH were greater in the APA group than in the IHA group. Multiple linear regression analysis revealed that the diagnosis of APA independently correlated with left atrial volume, left ventricular end-diastolic diameter, and LVM. CONCLUSIONS: We demonstrated that differences of cardiac structures between the APA group and IHA group existed. In APA, left atrial enlargement and LVH were more prominent than in IHA.

Significantly high level of late-night free cortisol to creatinine ratio in urine specimen in patients with subclinical Cushing's syndrome.

OBJECTIVE: Absence of a late-night cortisol nadir is a consistent biochemical abnormality in patients with cortisol-producing adenoma. We evaluated the abnormality of late-night urinary free cortisol to creatinine ratio (late-night UFCCR) in patients with subclinical Cushing's syndrome (SCS). METHODS: Fifty-eight patients with incidentally detected adrenocortical adenomas [SCS: 9; nonfunctioning adenoma (NF): 49] were enrolled as subjects. Values measured in all patients were urinary free cortisol accumulated between 9:00 p.m. and 11:00 p.m. (late-night UFCCR), serum cortisol at 11:00 p.m. (midnight serum cortisol: MSC), serum cortisol after 1-mg overnight dexamethasone suppression test (1 mg-DST) and 24-h urinary free cortisol (UFC). RESULTS: Median late-night UFCCR value in SCS was significantly higher than that in NF (P < 0·001). Significant correlations were observed between late-night UFCCR and each of serum cortisol after 1 mg-DST and MSC (r = 0·537, P < 0·001 and r = 0·556, P < 0·001, respectively). There was no significant correlation between serum cortisol after 1 mg-DST and 24-h UFC (r = 0·211, P = 0·112). In receiver operating characteristic analysis for diagnosis of SCS, the areas under the curves of late-night UFCCR and 24-h UFC were 0·937 (95% confidence interval 0·865-1·008) and 0·726 (0·874-0·999), respectively. Late-night UFCCR cut-off value of 4·9 nmol/µmol Cre showed a sensitivity of 100% and a specificity of 76·6%. CONCLUSION: Patients with SCS showed higher late-night UFCCR values than those with NF. Late-night UFCCR was significantly correlated with autonomous cortisol production findings. Diagnostic performance of late-night UFCCR was superior to 24-h UFC. These results suggest that late-night UFCCR might represent one of the simple and reliable tests for SCS diagnosis.

Treatment of patients with hypothalamic-pituitary lesions as adult-onset Langerhans cell histiocytosis.

We report four cases of adult-onset Langerhans cell histiocytosis (LCH) with central nervous system (CNS) lesions in the hypothalamic-pituitary region. The first clinical symptoms were diabetes insipidus (two patients), hypothyroidism (one patient), and decreased libido/erectile dysfunction (one patient). Diagnosis was delayed as the CNS lesion was not initially suspected to be secondary to LCH, with a median time from symptom onset to treatment of 3.0 (range <1-5.3) years. In three patients, the tumor mass was effectively reduced by chemotherapy; however, all patients continue to exhibit hypopituitarism. Early diagnosis and initiation of treatment are required to improve the outcome of CNS-LCH in adult patients.

Resistance to thyroid hormone accompanied by Graves' disease.

Resistance to thyroid hormone (RTH) is characterized by elevated serum levels of thyroid hormones and normal or slightly increased serum thyrotropin (TSH) levels. Recently it has been suggested that chronic TSH stimulation in RTH activates intrathyroidal lymphocytes, leading to thyroid damage and autoimmune thyroid disease (AITD). Therefore, individuals with RTH have an increased likelihood of AITD compared to unaffected relatives. We here report a 33-year-old woman in whom we diagnosed Graves' disease and treated her with thiamazole (MMI). For two years, her TSH levels were suppressed when thyroid hormones were elevated and conversely they were increased when thyroid hormones levels were decreased. These findings were common for a clinical course during treatment for Graves' disease with anti-thyroid drug. However, three years after the initiation of MMI therapy, she had a normal or gradually elevated serum TSH level even though the level of thyroid hormones never decreased, indicating inappropriate secretion of TSH. We concluded she had RTH clinically, and we demonstrated by direct sequence analysis a mutation of the TRß gene, causing replacement of a glycine (G) with arginine (R) at codon 251. The finding of an elevated TSH level without decreased thyroid hormones should suggest the presence of RTH during therapy of Graves' disease.

Perospirone, a novel antipsychotic agent, hyperpolarizes rat dorsal raphe neurons via 5-HT1A receptor.

To investigate the effect of cis-N-[4-[4-(1,2-benz-isozole-3-yl)-1-piperazinyl]butyl] cyclohexane-1,2-dicarboximide hydrochloride (perospirone), a novel antipsychotic agent with high affinities for D(2)/5-HT(2) receptors, on the rat dorsal raphe (DR) neurons, an electrophysiological study was performed using the tight-seal whole-cell patch-clamp technique. Applications of perospirone at the concentration between 10(-)(9) and 10(-)(5) M hyperpolarized the membrane potential and inhibited spontaneous action potentials of the DR neurons in a concentration-dependent manner. This effect of perospirone on DR neurons is similar to that of typical 5HT(1A)-receptor agonists, including 8-OH-DPAT or tandospirone. In addition, WAY100635, a 5-HT(1A)-receptor antagonist, inhibited this perospirone-induced hyperpolarization of DR neurons, suggesting that perospirone physiologically acts on DR neurons as a 5HT(1A)-receptor agonist. These results provide new profiles of perospirone as an antipsychotic drug.