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.     

Preliminary results of intermittent retrograde cerebral perfusion during proximal aortic arch surgery.

OBJECTIVE: Continuous retrograde cerebral perfusion during aortic arch surgery is associated with cerebral edema. In this report, we describe the clinical use of a new type of intermittent retrograde cerebral perfusion. SUBJECTS AND METHODS: Fourteen patients with a Stanford type A dissection were included in this study. With the usual method of retrograde cerebral perfusion, about 2,500 mL venous blood is drained from bicaval cannulae into a hard-shell reservoir, and oxygenated blood is perfused through the superior vena caval cannula. The flow rate is 300 mL/min. After about 15 min, retrograde perfusion is discontinued, and drainage from the bicaval cannulae is restarted. When a bloodless field is necessary, perfusion also is discontinued. RESULTS: Two to seven cycles of intermittent retrograde cerebral perfusion were administered (average, 3.1+/-0.4, mean+/-SD). The total retrograde perfusion time was 36.0+/-1.9 min which was equivalent to 74.8% of the circulatory arrest time. No patient developed edema of the upper body. The time to wake-up was 3 to 14 h (average, 6.5+/-1.0 h). No patient suffered any neurologic complications even though the time of circulatory arrest was greater than 60 min in four cases. Head magnetic resonance imaging or computed tomography was performed in 12 cases, and no evidence of hypoxic brain injury was detected. CONCLUSIONS: Our clinical experience using a moderate amount of intermittent retrograde cerebral perfusion is superior to continuous retrograde cerebral perfusion for protecting the brain during aortic arch surgery.     

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.     

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.     

Regulation of macrophage phagocytosis of syngeneic erythrocytes by T-cell subsets from NZB mice: differential effects of T cells from young and old mice.

The regulation of syngeneic erythrophagocytosis (EP) by macrophages (M phi) harvested from young and old NZB mice was examined by spectrophotometric assay and morphological observation. Peritoneal exudate M phi from young NZB mice weakly ingested syngeneic red blood cells (RBC). T cells derived from old NZB mice accelerated ingestion of RBC by young M phi. On the contrary, T cells from young NZB mice suppressed EP by young T cells appeared clearly when they were added to M phi derived from old mice, which ingested syngeneic RBC actively without help by old NZB T cells. Namely, such an active EP by old M phi was completely suppressed when they were incubated with young T cells. Simultaneous addition of both young and old T cells to either young or old NZB M phi with RBC suppressed the EP. Pretreatment of young T cells with anti-Lyt 1.2 antibody and complement (C) made the suppressive activity prominent, and preincubation with anti-Lyt 2.2 and C eliminated the suppressive activity, but gave rise to the enhancing activity. Young T-cell homogenates added to younger or old M phi together with RBC did not reveal suppressive activity for EP, and on the contrary facilitating activity appeared predominantly. Young and old T-cell homogenates added together to young M phi did not suppress EP. The largest of T-cell-factor accelerating EP was M phi, but not RBC. M phi with active EP belong to Ia-bearing subpopulations.     

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.     

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.     

Effect of subthreshold voltage-dependent conductances on the transfer function of branched excitable cells and the conduction of synaptic potentials

1. Impulse response functions were determined from complex point impedance and transfer functions from cultured NG-108 cells to simulate the propagation of a synaptic potential in response to the release of transmitter. In general, the flow of synaptic current has a much shorter duration than the normal membrane time constant, thereby making the use of impulse response functions useful approximations to synaptic events. 2. The resonance observed during the activation of the potassium conductance was reflected in the impulse response function as a pronounced damped oscillation. A comparison of the impulse response functions calculated from point impedance and transfer functions showed similar results for current injections in the growth cone. 3. In addition to the resonance effects of the voltage-dependent conductances on transfer and impulse response functions due principally to the activation of conductances for outward currents, transfer functions were measured during the activation of a steady-state negative conductance. Under these conditions the phase function approaches 180 degrees, indicating that the voltage response is out of phase with the current. 4. In the steady state, the effect of a negative conductance is to algebraically add to the positive conductances and generally decrease the absolute conductance unless there is a net negative current. The decreased conductance enhances the impulse response and the DC space constant, thus leading to a better propagation of slow potentials. This effect can be seen as a decrease in the electrotonic length, L, with intermediate depolarizations. At large depolarizations the steady-state activation of the K conductance generally dominates and leads to a greatly increased electrotonic length. 5. Both the net conductances and the associated kinetics play a role in shaping the potential changes during a synaptic current. This is especially critical if there is a net negative steady-state conductance. Under these conditions there is a surprising reduction in the impulse response function. 6. Thus, during a subthreshold activation of the voltage-dependent negative conductances, the observable synaptic potentials would be either large potential responses due to an apparent increase in the impedance (algebraic summation of positive and negative conductances with a net positive conductance) or a minimal response because of the phasic cancellation due to a net negative conductance. The latter condition could exist near the synaptic reversal potential due to a large synaptic drive and would appear experimentally as a form of inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)