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.     

Comparison of immunohistochemical staining of a mitochondrial protein, lipoamide dehydrogenase, with Fab'-peroxidase conjugates prepared by maleimide or periodate

IgG-maleimide peroxidase, Fab'-maleimide peroxidase, polymer and monomer types of Fab'-periodate peroxidase were prepared from an antibody against rat lipoamide dehydrogenase, a component of the pyruvate dehydrogenase complex which is located in mitochondria. They were examined for immunohistochemical staining of the rat kidney. Fab'-maleimide peroxidase was the best for staining mitochondrial protein. IgG-maleimide peroxidase and the monomer type of Fab'-periodate peroxidase had the same intensity of staining. The polymer type of Fab'-periodate peroxidase could not stain the lipoamide dehydrogenase.     

A case of pheochromocytoma with severe paralytic ileus

We report herein a rare case of a 26 year old woman with pheochromocytoma complicated by paralytic ileus. She presented with remarkable abdominal distension and respiratory difficulty but was effectively treated by surgical removal of the tumor with preoperative and operative management using alpha and beta adrenergic blocking agents. An excessive and persistent catecholamine production from large tumors or massive metastases characterizes this rare complication, and a review of the English and Japanese literature is given following this report.     

Accumulation of cyanide and thiocyanate in haemodialysis patients.

BACKGROUND: Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. METHODS: We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. RESULTS: Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. CONCLUSIONS: The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.     

UFT for head and neck cancers: its tissue concentrations and effects on lymphocyte subpopulations

Summary UFT, a combination of the masked compound of 5-fluorouracil (FT-207) and uracil, was given to head and neck cancer patients for 1 week preoperatively and for 8 weeks postoperatively. Drug concentrations were examined in the surgically removed tissues. The concentrations of FT-207, 5-fluorouracil, and uracil were higher in tumor tissues than in normal tissues. The lymphocyte subpopulations were assessed by cytofluorometry with monoclonal antibodies. There was no evidence that adjuvant chemotherapy with UFT specifically suppresses immunocompetent cells. We therefore conclude that further clinical evaluation of adjuvant chemotherapy with UFT would be worthwhile.     

Clinical studies on a newly devised amino acid solution for neonates

In 97 neonates receiving total parenteral nutrition in the postoperative period, clinical assessment was made for a newly devised amino acid solution (PF-I-III) from the standpoint of plasma amino acid profile and nutritional effect. These amino acid solutions prepared are characterized by the high concentration of branched-chain amino acids up to 40%, increased arginine and decreased glycine, phenylalanine and methionine as compared with commercially available solutions. In the PF group, each amino acid was kept within the range of standard value. Correlation between plasma amino acid profiles and the dose of each amino acid administered was obtained, from which minimum, standard, and maximum doses for each amino acid was determined. Based on these values, we proposed new formula for neonates which elicits no abnormal plasma amino acid pattern even when amino acids are administered at the dosage level of 1.5-2.5 g/kg/day.     

Affinity of neuroleptics for D1 receptor of human brain striatum.

We determined the inhibition-dissociation constant (Ki) of a number of neuroleptics for D1 receptors of normal human brain tissue using [3H]SCH23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3[benzazepine-7- ol]. SCH23390 had the highest affinity with a Ki of 0.76 nM. Among clinically used drugs, propericiazine showed the highest affinity with a Ki of 10 nM. When neuroleptics were classified according to chemical structures, the Ki values were as follows. Phenothiazines ranged from 10 nM to 250 nM. Butyrophenones ranged from 45 nM to 250 nM. Thioxanthenes ranged from 12 nM to 340 nM. Orthopramines were more than 10,000 nM. The Ki values for the binding site of this study were significantly correlated with those reported in studies using animal brain. The possible relationship between D1 receptors and negative symptoms is discussed.