Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare missense/frameshift mutations.

Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n = 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese.     

Obstinate cough as a sole presenting symptom of non-metastatic renal cell carcinoma

Renal cell carcinoma (RCC) causes many kinds of symptoms such as hypercalcemia, hypertension, polycythemia and fever. Here we describe a rare case of RCC presenting with a persistent cough. After radical nephrectomy, the obstinate cough disappeared. When the tumor recurred locally, the cough also recurred. Furthermore, the cough disappeared completely again after the removal of the recurrent tumor. Although all the clinical findings suggested that the RCC caused the cough, we could not identify a specific humoral substance responsible for the cough.     

Association of sixty-one non-synonymous polymorphisms in forty-one hypertension candidate genes with blood pressure variation and hypertension.

We previously selected a group of hypertension candidate genes by a key word search using the OMIM database of NCBI and validated 525 coding single nucleotide polymorphisms (SNPs) in 179 hypertension candidate genes by DNA sequencing in a Japanese population. In the present study, we examined the association between 61 non-synonymous SNPs and blood pressure variations and hypertension. We used DNA samples taken from 1,880 subjects in the Suita study, a population-based study using randomly selected subjects. Analyses of covariance adjusting for age, body mass index, hyperlipidemia, diabetes, smoking, drinking, and antihypertensive medication revealed that 17 polymorphisms in 16 genes (APOB, CAST, CLCNKB, CTNS, GHR, GYS1, HF1, IKBKAP, KCNJ11, LIPC, LPL, P2RY2, PON2, SLC4A1, TRH, VWF) were significantly associated with blood pressure variations. Multivariate logistic regression analysis with adjustment for the same factors revealed that 11 polymorphisms in 11 genes (CAST, CTLA4, F5, GC, GHR, LIPC, PLA2G7, SLC4A1, SLCI8A1, TRH, VWF) showed significant associations with hypertension. Five polymorphisms in five genes, CAST(calpastatin), LIPC (hepatic lipase), SLC4A1 (band 3 anion transporter), TRH (thyrotropin-releasing hormone), and VWF (von Willebrand factor), were significantly associated with both blood pressure variation and hypertension. Thus, our study suggests that these five genes were susceptibility genes for essential hypertension in this Japanese population.     

Clinical statistics on inpatients admitted to the Department of Urology, Hyogo Prefectural Hospital Nishinomiya during 20 years from 1972 to 1991]

A statistic analysis was carried out on the 4,956 inpatients admitted to our Department of Urology from April 1972 to December 1991. The patients included 3,399 males and 1,557 females. A total of 4,105 operations including 255 renal allotransplantations were performed on 3,590 patients. Open surgery for upper urinary tract stones has been replaced by extracorporeal shock-wave lithotripsy (ESWL) in the last three years.     

A case of mixed connective tissue disease successfully treated for hemophagocytic syndrome with intermittent intravenous injection of cyclophosphamide]

A 52 year-old woman noticed general fatigue, polyarthralgia, and muscle weakness of lower extremities in October 2001. In December, she felt difficulty in walking due to muscle weakness. In January 2002, she admitted another hospital because of dyspnea on exertion and edema of lower extremities. Laboratory test revealed leukocytopenia, the elevation of creatine kinase and positive anti-U1-RNP antibodies. Her chest computed tomography (CT) showed severe interstitial pneumonia. Cardiac echogram revealed that she had pericardial effusion and pulmonary hypertension. Then she was transferred to Keio University Hospital and she was diagnosed as having mixed connective tissue disease (MCTD) manifestating myositis, interstitial pneumonia, pulmonary hypertension and pericarditis. Prednisolone (PSL) 60mg daily following to methylprednisolone (mPSL) pulse therapy was begun and her symptoms were gradually improved. In middle of February, she complained of high fever over 39.0 degrees C. Bacterial culture tests were negative and laboratory data indicated pancytopenia and a high level of serum ferritin. Bone marrow aspiration revealed hemophagocytosis in bone marrow specimens and she was diagnosed as having hemophagocytic syndrome associated with MCTD. mPSL pulse therapy was not effective and intermittent cyclophosphamide pulse therapy (IV-CY) was performed resulting in improvement of the symptoms. This case suggested the effectiveness of IV-CY therapy in patients with corticosteroid-resistant HPS associated with connective tissue diseases.     

Alveolar hydatid disease of the liver: computed tomography and transabdominal ultrasound with histopathological correlation.

The appearances of alveolar hydatid disease of the liver (AHDL) on computed tomography (CT) and ultrasound (US) were retrospectively compared with histopathological appearances in 67 patients with 100 separate lesions. The radiological features were correlated directly with the pathological specimens obtained from each patient. We conclude that the CT appearances are more specific, but that US has a role to play in mass screening in endemic areas, and intraoperatively.     

Cystic thyroid masses: ultrasonographic and pathologic correlation

Forty-nine patients with 63 cystic thyroid masses who had undergone preoperative sonography were retrospectively reviewed. 52 lesions (83%) were benign and others (17%) were malignant. Among various sonographic findings of cystic thyroid masses, oval cystic lesions with polyp or dome like solid component projecting into the lumen were all diagnosed adenomatous goiter. Irregular cystic structures with more than 2 cm finger like pedunculated mass extended into and/or out of the lumen were all diagnosed papillary carcinoma. Small oval cysts (less than or equal to 1 cm) with strong echo were all diagnosed colloid goiter. The other sonographic type of cystic thyroid masses had somewhat malignancy (12-30%), not having characteristics which differentiate benign from malignant lesions. Pathologic findings of malignant lesions showed that cancer cells existed rather in pericystic portion than in cyst wall except for finger like solid component projecting into the lumen which was papillary carcinoma itself. Ultrasonically guided needle biopsy should be performed to get samples of above portions.     

INTRA- AND INTERINDIVIDUAL VARIATION IN THE PHARMACOKINETICS OF TACROLIMUS (FK506) IN KIDNEY TRANSPLANT RECIPIENTS—IMPORTANCE OF TROUGH LEVEL AS A PRACTICAL INDICATOR

Background: Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests. Methods: The blood concentration-time curve was studied in 10 kidney transplant recipients on 26 Occasions after oral dosage of 2 to 18 mg every 12 hours. Whole blood concentration was measured by two-step irnmunoabsorption assay. Methylprednisolone was used as a concomitant immuno-suppressive drug. Results: The blood concentration-time curves showed remarkable interindividual variation. lntraindividual variation was also found, but the degree of variation was slight compared with interindividual variation. On 17 occasions of measurement in one patient, the dose was significantly correlated with trough (r = 0.684). C_max (r = 0.838) and AUC_0–12 (r = 0.817). In nine patients on nine occasions, however, the dose was not significantly correlated with trough (r = 0.351), C_max (r = 0.270) or AUC_0–12 (r = 0.355). t_max ranged from one to four hours (mean + SD; 2.8 + 1.3) and fluctuated in both intra- and interindividual measurements. In spite of a wide variation in the blood concentration-time-curve patterns, a highly significant linear relationship between trough and C_max or AUC_0–12 was observed in both intraindividual (C_max, r = 0.876; AUC_0–12, r = 0.926) and interindividual (C_max, f = 0.943; AUC_0–12, r = 984) measurements. Concluslons: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration.