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.     

Stochastic resonance with differential code in feedforward network with intra-layer random connections.

We examined stochastic resonance with a differential coding scheme using a multilayer feedforward neural network which is composed of intra-layer connections. We show that the network, with random synaptic connections in each layer, encodes an input signal into a spike coherence that represents temporal differences among the inputs. We also demonstrate that both internal and external noise enhance the detection of weak signals. Finally, we discuss how the feedforward network with intra-layer random connections is similar to a membrane in its sensitivity to and amplification of a change in stimulus and suggest that the intensity of internal noise may be tuned in a real brain.     

Genetic linkage analysis of pulmonary fibrotic response to silica in mice.

Inter-individual variations in the development of silicosis, even within the same environments, have been reported, which suggest the contribution of genetic factors in silicosis aetiology. The aim of the present study was to determine whether there is any significant genetic influence on the development of silicosis. Furthermore, which genetic loci are responsible for the pulmonary response to silica exposure? Eight strains of inbred mice were used to examine the genetic influence on the lung fibrotic response to silica exposure. After intercross-breeding between the most susceptible and most resistant strains, a genome-wide linkage analysis of quantitative trait loci (QTL) was performed. Hydroxyproline was applied as an index, and genotypes of 167 marker genes were analysed by fragment analysis using a capillary-type sequencer. There was significant inter-strain difference in the mean concentration of hydroxyproline contents among the eight strains of mice. Breeding studies were conducted between the most susceptible, C57BL/6J, and the most resistant strain, CBA/J. A genome-wide linkage analysis of silica-exposed intercrossed cohorts identified significant QTL on chromosome 4 and suggestive QTL on chromosomes 3 and 18. The present study demonstrates that genetic factors may play a significant role in fibrotic-lung responses to silica; one significant and two suggestive quantitative trait loci were identified.     

Zinc, calcium, and magnesium metabolism: effects on plasmacytomas in Balb/c mice

The effects of different amounts of dietary zinc on the Zn absorption rate and on Zn, calcium and magnesium concentrations in tissues of MOPC 104E tumor-bearing Balb/c mice were determined. The Zn absorption rate was inversely related to the amounts of Zn in their diets and was lower than that of nontumor-bearing control mice fed a laboratory mice chow. Zn concentrations of tumor-bearing mice were also low compared with control mice but tumor Zn concentrations, regardless of the concentrations of Zn in the diets, were higher than those of normal tissues of the host other than the pancreas. Ca concentrations in tumor and tissues of tumor-bearing mice were higher than in control animals but Mg concentrations in tissues of tumor-bearing mice appeared to be similar to those of control mice. Results suggest that tumor-bearing mice have a lower intestinal Zn absorption capacity and a higher Zn uptake rate causing other tissues to become hypozincemic and hypercalcemic.     

Biochemical activities of lysosomal acid hydrolases in leukemic cells

The biochemical activities of 8 lysosomal acid hydrolases in leukemic cells from 48 patients were examined. Characteristic alterations were found in α-mannosidase, β-galactosidase and N-acetyl-β-glucosaminidase activities of leukemic cells. The level of α-mannosidase activity was much higher in myelo(mono)genous leukemias (AML, AMoL, AMMoL, CML and CMMoL) than in lymphogenous ones (ALL, T-cell leukemia, hairy cell leukemia and CLL) without exception. The β-galactosidase activity also differed as a result of α-mannosidase, except in T-cell leukemia. In T-cell leukemia it was within the range of normal lymphocytes, but in the other lymphogenous leukemias it was significantly below normal. N-acetyl-β-glucosaminidase activity in myelo(mono)genous leukemic cells was above the range of normal granulocytes. The changes in these enzyme levels were consistent. The lymphocytic or myelocytic nature of three cases of acute undifferentiated leukemia could be determined by enzyme studies. In two cases it was lymphocytic and in one it was myelocytic. The enzymatic abnormalities were also found in morphologically mature neutrophils from patients with not only chronic types (CML, CMMoL) but also acute types (AMoL, AMMoL) of leukemias, and were similar to those of their respective leukemic cells. Analysis of lysosomal enzymes (at least three of those mentioned above), can elucidate one of the biochemical properties of leukemic cells and may be valuable in the differentiation of leukemias.     

Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion.

From January 1986 to December 1988, a prospective trial of transcatheter arterial treatment was carried out for hepatocellular carcinoma (HCC). Two hundred seventy-five patients were included. Okuda's staging system was employed. Patients with Stage I and II HCC were treated by transcatheter arterial embolization (TAE) with a gelatin sponge containing an anti-cancer agent (protocol 1a); a gelatin sponge and iodized oil mixed with an anti-cancer agent (protocol 1b); or iodized oil mixed with an anti-cancer agent (protocol 2). Patients with Stage III HCC were treated with iodized oil with anti-cancer agent (protocol 2). As an exception, patients with an unsuccessful superselective catheterization into the proper hepatic artery by Seldinger technique or obstruction of the main trunk of the portal vein were treated with percutaneous transcatheter arterial infusion into the common hepatic artery regardless of stage (protocol 3). Tumor type and extension, area of tumor involvement, portal vein involvement, method of treatment, and presence of ascites and icterus were found to be the significant factors for an initial response to therapy. Treatment method was the most important factor. Respective survival rates at 1 and 2 years were 70.9% and 55.3% for protocol 1a; 62.3% and 43.8% for protocol 1b; 37.8% and 18.3% for protocol 2; and 16.5% and 0% for protocol 3. Many factors proved to significantly influenced prognosis; however, tumor type had the most important prognostic significance followed by AFP value, ascites, treatment protocol, and area of tumor involvement.     

A case of transient bioprosthetic valve regurgitation and hemolysis devoloping early after surgery using Carpentier-Edwards valve.

The Carpentier-Edwards pericardial bioprosthesis has been markedly improved in the long-term results and valve-related complications including valve dysfunction, compared to the previous generation bioprosthesis. We report a patient in whom transient prosthetic valve regurgitation and hemolysis occurred early after mitral valve replacement using a Carpentier-Edwards pericardial bioprosthesis and were resolved by preservative therapy. The patient was a 77-year-old female diagnosed with severe mitral valve stenosis and insufficiency. She underwent mitral valve replacement with a Carpentier-Edwards pericardial bioprosthesis. Opening and closing of the three leaflets looked good on intraoperative transesophageal echocardiography (TEE). The only prosthetic valve regurgitation was evident at the central region where the leaflets form coaptation, and no abnormal findings were seen. Serum lactate dehydrogenase (LDH) was decreased to 405 U/l after surgery. However, LDH again began to increase on the 3rd day after surgery and it increased to 1,830 U/l on the 14th day after surgery. Hemolytic urine was detected on 10th day after surgery. PVL was not detected, but moderate abnormal regurgitation from the outside of the stent pocket was detected on TEE. Revision of valve replacement was considered, but LDH thereafter to 393 U/l on 41st day after surgery. The TEE was repeated, and only a trace of central jet was detected without abnormal regurgitation, unlike the previous examination. The patient did not develop any complications thereafter and was discharged on 47th day after surgery. LDH was nearly normal at the time of discharge.