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.     

Clinical experience of local thermotherapy in the treatment of benign prostatic hyperplasia]

Thirty-five patients with benign prostatic hyperplasia (age range: 45-88 years; average: 67.5 years) underwent local thermotherapy with prostathermer. Clinical therapeutic effect was evaluated in 30 of the 35 patients: 2 patients interrupting from therapy and 3 receiving pretherapeutic indwelling catheters were not included. A total of 6 treatments (2 per week) were performed, each lasting for 60 minutes. As for subjective improvement, improvement of nocturia was noted in 70.0% of all patients and sense of residual urine in 70.7%. Post-therapeutic nocturnal and daytime decreases in urination frequency were statistically significant (p less than 0.01). Objective improvement in residual urine volume occurred in 19 of the 30 cases, and elevation in uroflowmetric maximal flow rate following therapy was statistically significant (p less than 0.05). Among complications ascribable to catheter insertion were urethral bleeding (3 cases), epididymitis (1 case) and pyuria (1 case). Therapeutic result based primarily on subjective symptoms and partly on objective findings was fairly good in 17 cases (about 57%), and slightly good in 25 cases (about 83%). In conclusion, this therapy seems to be useful in the treatment of benign prostatic hyperplasia.     

Experimental models of reflex contractile activity in the rabbit bladder

We were able to produce two highly reproducible experimental models (in the rabbit) that demonstrated a high degree of reflex bladder contractile activity. In one model, a somatovesical reflex was induced by touching or pinching the perineal area. This reflex may be organized through a neurogenic reflex at the spinal level. In another model, rhythmic bladder contractions were produced by distal urethral constriction in the absence of bladder distension. These rhythmic contractions were thought to be due to a supraspinal reflex. In both types of contractile reflexes, intravenous administration of hexamethonium inhibited the reflex contractile activity virtually completely, intravenous atropine inhibited over 90% of the induced contractile activity, thus suggesting that these contractions were mediated reflexly through cholinergic stimulation. These two models of reflex bladder contractions should be useful for the study of hyperreflexic bladders.     

A case of multiple cranial neuropathy after Campylobacter jejuni infection]

We report a patient who developed overlapping symptoms of ophthalmoplegia and oropharyngeal palsy after Campylobacter jejuni infection. A 15-year-old man had diarrhea and fever, and developed dysarthria, diplopia and ptosis two weeks later. He did not show ataxia, weakness or abnormal tendon reflexes in the extremities during the clinical course. In the acute phase of the disease, we found significant elevation of anti-GQlb and anti-GTla IgG antibodies in the serum, and high-dose intravenous immunoglobulin therapy remarkably ameliorated the symptoms. Our patient was atypical of Fisher syndrome or pharyngeal-cervical-brachial (PCB) weakness, and this is the first case of multiple cranial neuropathy associated with C. jejuni infection.     

Immunohistochemical Detection of Porcine Teschovirus Antigen in the Formalin‐fixed Paraffin‐embedded Specimens from Pigs Experimentally Infected with Porcine Teschovirus

Porcine teschovirus (PTV) antigens were detected by a streptavidin‐biotin complex method in formalin‐fixed paraffin‐embedded tissues of 3‐week‐old pigs that had been inoculated intravenously with PTV Talfan strain. PTV antigens were detected in cytoplasm of nerve cells, glial cells and endothelial cells in the cerebellar nuclei, the grey matter of the midbrain, pons and medulla oblongata and the ventral horn of the spinal cord and of ganglion cells in the spinal ganglion corresponding to those lesions characterized as non‐suppurative encephalomyelitis and ganglionitis. The results of this study suggest that nerve cells of the brain stem and spinal cord and ganglion cells of the spinal ganglion permit PTV replication and represent the main target cell population of PTV. This is the first study to demonstrate PTV antigen by immunohistochemistry in formalin‐fixed paraffin‐embedded tissue specimens from pigs infected with PTV.     

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

To investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G(–273)C (P=0.0074), C(–297)T (P=0.0195), and IMS-JST071749 (P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G(–273)C genotype was influential in another set of subjects (P=0.0310, n=743). However, the distribution of the ABCA1 G(–273)C genotype in subjects with MI (n=598) was not different from that in the control population (n=801). These results indicate that ABCA1 G(–273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.     

Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin-angiotensin-aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls (p<0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p<0.01; odds ratio=5.26, 95% confidence interval: 1.69-16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.     

Membrane currents of the tunicate egg under the voltage-clamp condition.

1. Ionic currents of the egg membrane of a certain tunicate. Halocynthia roretzi Drashe, were studied by the voltage-clamp technique. 2. The membrane depolarization beyond -55mV in standard artificial sea water induced mainly transient inward current and slight outward currents, when the holding potential was kept at -99 mV. 3. The transient inward current was composed of two components; the major one showed a faster time course, a more negative critical level of about -55 mV, and a reversal potential around +60 mV and the minor one showed a slower time course, a less negative critical level o -10 mV, and no definite reversal potential. 4. The major component became maximum at about -25 mV with the peak time of 6-9 msec at 15 degrees C, and the maximum currents ranged from 0-5 to 1-5 X 10(-5) A/cm2. 5. The major component of the inward current was abolished by the replacement of Na with choline or Tris or Cs ions, while it was almost unaltered by the replacement with Li. The minor component was independent of Na concentration in the external solution. 6. The major component showed the activation and inactivation identical with those of Na current of other excitable membranes. A conditioning depolarization over -90 mV inactivated the Na current and the half inactivation of the major inward current was obtained by a conditioning pulse to -56 mV, when the pulse duration was 400 msec and the temperature was at 15 degrees C. 7. The time course of the Na current was formulated with m and h parameters in the following equations: (see article). 8. The kinetic parameters taum and tauh of egg Na current were calculated and compared with those of the squid axon. The potential dependence of taum and tauh was almost identical with that of the axon, but the absolute values of both taum and tauh were ten- to twentyfold larger than those of the axon in any range of the membrane potential. 9. The temperature depdence of the kinetic parameters taum, tauh and of the chord conductance gNa was studied. The Q10's for taum and tauh were both 4-0, while the Q10 for gNa was 2-0 in the temperature range from 5 to 20 degrees C. 10. The outward and inward rectifying conductances of egg membrane were remarkably activated at the potential level above +100 mV and below -70 mV respectively in standard artificial sea water. Both increased currents were subsequently subject to inactivation. 11. It was suggested that Na, Ca, K inward rectifying and K outward rectifying conductances all exist separately in the egg cell membrane and the Na current was essentially identical with that through the Na channel in other excitable membranes.