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.     

Spontaneous Uterine Venous Rupture During Labour: A Case Report With Postoperative Ultrasonographic Findings

EDITORIAL COMMENT: We accepted this case for publication to remind readers that although uterine rupture during labour in a primigravida is extremely uncommon it does occur, or at any rate nulliparas can develop abdominal pain and shock in labour with a haemoperitoneum resulting from a tear in a vein in the lower posterior uterine wall. When one sees the hugely dilated uterine and ovarian venous plexuses at Caesarean section it is easy to believe that bleeding from such a vessel during labour could be prodigious. This case suggests that a dilated vein with blood flow derangements may be the cause. Nonetheless, as the authors warn us, the necessary response is not a precise diagnosis, but rapid laparotomy. See also Editorial Comment to Chin MMS, Harvey JA, Duffy BL. Uterine rupture during labour in a primigravida. Aust NZ J Obstet Gynaecol 1996; 36: 210.     

Four primary malignant tumors, including malignant melanoma and malignant lymphoma, in the same adult patient

We report an 80-year-old Japanese male with four primary malignant tumors: malignant melanoma, prostatic cancer, malignant lymphoma, and renal cell carcinoma, which occurred in that respective order. The combination of malignant melanoma and malignant lymphoma is rare. The patient was treated with BCG after an operation for malignant melanoma. He was also treated with cobalt 60 irradiation after an operation for prostatic cancer. We also discuss other reports of multiple malignant tumors and suggest some possible causes of this patient's primary malignant tumors.     

Big mitogen-activated protein kinase 1 (BMK1)/extracellular signal regulated kinase 5 (ERK5) is involved in platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration

Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1-SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5alpha, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1-SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.     

Characterization of peptide components in the venom of the scorpion Liocheles australasiae (Hemiscorpiidae).

Scorpion venoms are composed of a number of neurotoxic peptides. A variety of toxins have been isolated from the venoms of scorpions of the family Buthidae, however, little interest has been paid to non-Buthidae scorpions. In this study, we examined the toxicity of the venom of Liocheles australasiae (Hemiscorpiidae) to mice and crickets, and characterized the peptide components by HPLC and mass spectrometry. Over 200 components were detected in the L. australasiae venom by LC/MS analysis, with components of molecular masses ranging from 500 to 5000 Da being particularly abundant. A number of peptides contained two to four disulfide bridges, which was estimated based on the mass difference after derivatization of Cys residues. A peptide having a monoisotopic molecular mass of 7781.6 Da and four disulfide bridges was isolated from the venom. The peptide has a primary structure similar in terms of the position of eight Cys residues to those observed in several peptides found from scorpions, ticks and insects, although biological roles of these peptides are unknown.     

POSSIBLE PARTICIPATION OF NMDA AND GLYCINE RECEPTORS BUT NOT GABAA RECEPTORS IN ENFLURANE-INDUCED OPISTHOTONUS IN MICE

1. We previously reported that volatile anaesthetics produce incidences of a transient opisthotonus in mice, a sign of CNS stimulation. This study was performed to investigate mechanisms by which enflurane-induced opisthotonus (EIO) occurs. 2. The effects of pretreatment of N-methyl-d-aspartate (NMDA) antagonists dizocilpine (MK-801; DIZ) and ketamine (KET), GABA_A antagonists picrotoxin (PIC), pentylenetetrazol (PTZ) and glycine antagonist strychnine (STR) on the incidence of EIO were determined. Prior to exposure to 2.0% enflurane in air, male ddN mice were given intraperitoneal injections of 0.2 mL saline (control), 0.5–5.0 mg/kg DIZ, 20–80 mg/kg KET, 2.9 mg/kg PIC, 40.0 mg/kg PTZ and 0.75 mg/kg STR. After the injection, the behavioural state of the mice was observed for 20 min (the pre-enflurane period). During the exposure to enflurane the time for immobilization, that is, anaesthetic induction time (IT), and the incidence of EIO were measured. 3. Dizocilpine (1.0–5.0 mg/kg) and KET (80 mg/kg) significantly (P<0.01) reduced both the incidence of EIO and IT in a dose-dependent manner. During the pre-enflurane period DIZ produced incidences (5–40%) of transient seizures in a dose-dependent manner, while KET did not induce them at all. The two GABA_a antagonists had no detectable effect on the EIO. Strychnine significantly enhanced the EIO. These CNS stimulants resulted in a 3–10% incidence of transient seizure and/or opisthotonus during the pre-enflurane period, but there was no correlation between DIZ-induced seizure and EIO. 4. These results suggest that the EIO is mediated by the NMDA and the STR-sensitive glycine receptors, but not the GABA_A receptor. We speculate that DIZ acts on the NMDA-receptor and/or disrupts the balance between the inhibitory and the excitatory systems.     

Promoting effect of 12-O-tetradecanoylphorbol-13-acetate on the in vitro malignant transformation of fetal rat brain cells exposed in utero to ethylnitrosourea

In order to investigate the possibility that the theory of two-stage carcinogenesis can be applied to neurogenic carcinogenesis, we analyzed the promoting effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the in vitro malignant transformation of fetal rat brain cells exposed in utero to ethylnitrosourea (ENU). Rat brain cells were transferred to a cultured system at 72 h after a single pulse of ENU (50 mg/kg body weight) to pregnant SD-JCL rats on the 18th day of gestation. The positive findings of glial fibrillary acidic protein and S-100 protein in primary cultured cells by the analysis of immunohistochemistry revealed the neuroglial origin of transformed cells. These cells were divided into 12 groups and were treated twice per week with or without TPA at concentrations from 0.1 to 50.0 ng/ml. From the results of cellular morphology, Concanavalin A agglutinability, colony forming capacity in semisolid soft agar, and tumorigenicity in vivo, malignant transformation of fetal rat brain cells appeared earlier in the ENU group treated with TPA than in the untreated ENU group. On the basis of these observations, it is suggested that TPA might be effective as a tumor promoter on ENU-induced neurogenic carcinogenesis.