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.     

Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.     

Adsorption of Human Recombinant Erythropoietin on Dialysis Membranes In Vitro

Abstract: The adsorptive characteristics of 5 dialysis membranes for recombinant human erythropoietin (EPO) were studied in vitro in a closed circuit system. For 120 min, EPO added with bovine serum was significantly adsorbed by polymethylmetacrylate (PMMA) and polyacry–lonitrile (PAN) membranes but not by Cuprophan, ethylene vinyl alcohol (EVAL), or polysulfone (PS) membranes. In addition the EPO adsorptive rate, as well as that of β₂–microglobulin (β₂–MG), was greater with a PMMA membrane than with a PAN membrane. EPO was not detected in the ultrafiltrate at 15 min with 5 membranes. These results indicate that EPO was eliminated by membrane adsorption only with some dialysis membranes.     

Mass Protection Program of Perinatal Hepatitis B Virus Infection in Japan and Impact of an Optional Booster Vaccination on Its Efficacy

We assessed the efficacy of a government-sponsored mass protection program in Osaka, Japan, for perinatal HBV infection in infants born to HBeAg positive HBV carrier mothers. We also evaluated the impact of optional follow-up procedures in such infants, including an evaluation of anti-HBs response and a booster dose of HBV vaccine for poor responders. The results demonstrated that this mass protection program protected 94.4% of the infants from perinatal HBV infection in the Osaka area. However, the proportion of infants with an unprotective level of anti-HBs was higher in the standard group than in the follow-up group both at 1.0 and 1.5 years of age, which was also the case for HBV events. Furthermore, the present study showed that a booster dose of vaccine in poor responders was very effective in promoting an anti-HBs response. In conclusion, we recommend that a follow-up blood test to confirm a response of anti-HBs to HBV vaccine should be performed at 4–8 weeks after the third injection of HBV vaccine in infants born to HBeAg positive HBV carrier mothers. We also recommend that a booster injection of HBV vaccine should be immediately given to poor responding infants who otherwise are at a considerable risk of developing HBV infection in late infancy.     

Diagnosis and classification of mandibular osteomyelitis.

To establish a unified classification system for mandibular osteomyelitis, various diagnostic terms were critically assessed and clinicopathologic findings of the lesions were carefully reviewed. We recommend classifying mandibular osteomyelitis into bacterial osteomyelitis and osteomyelitis associated with the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Other diagnostic terms were excluded because they were not appropriate for classification. Diagnostic criteria for bacterial osteomyelitis are suppuration and osteolytic change. The lesions are easily cured by antibiotic treatments. Mandibular osteomyelitis in SAPHO syndrome is characterized by nonsuppuration and a mixed pattern on radiography, with solid type periosteal reaction, external bone resorption, and bone enlargement. The presence of osteomyelitis in other bones, arthritis, or skin diseases (palmoplantar pustulosis, pustular psoriasis, and acne) strongly suggests this syndrome. Antibiotic therapy is usually ineffective and the symptoms of SAPHO syndrome are often persistent.     

Protective effect of nimodipine against quinolinic acid-induced damage of rat hippocampus in vitro.

The study was undertaken to examine the effect of nimodipine, calcium channels blocker, on the morphological alterations induced by quinolinic acid (QUIN). The experiment was performed on 21-day-old organotypic rat hippocampal cultures. Nimodipine was applied to the nutrient medium simultaneously with QUIN (both at 100 microM). Ultrastructural changes were evaluated 24 h, 5 and 7 days after the exposure to tested agent. It was shown that nimodipine induced distinct cytoprotective effect, especially considering the development of late neurotoxic injury produced by QUIN. However, the protection was not complete, indicating the participation of the other factors in the pathomechanism underlying structural damage produced by QUIN.     

Interstitial hyperthermia of malignant brain tumors using implant heating system (IHS)

We have developed an implant heating system (IHS) for interstitial hyperthermia of brain tumors. IHS consists of three compartments: ferromagnetic implant with low Curie point, induction coil and generator to produce high frequency magnetic field. The device works as follows: It is heated up to a Curie temperature (Tc) by Eddy current under the magnetic field. Heat generated in the implant is conducted to the tumor tissue into which it has been implanted. To evaluate the effect of this hyperthermia, a brain tumor model was produced by innoculation of VX2 tumor cells and treated either by hyperthermia with IHS alone, chemotherapy with ACNU alone, or with a combination of both. The longest survival was obtained by the combined treatment, and significant prolongation of survival was found in the single treatment groups. In the Phase I clinical trial, one or several implants (1.8 mm X 15 mm, Tc = 68 degrees C) made of Fe-Pt alloy were placed in the tumor by CT guided stereotactic procedure, or manually during craniotomy. Hyperthermia of above 42 degrees C for 30 to 60 minutes twice a week was brought about in ten cases of malignant brain tumor. CT evaluation was made in nine cases treated for more than ten times in this way. Five out of the nine cases responded to this hyperthermia with irradiation. In conclusion, a safe, repeated and longterm treatment was possible without significant side effects. The hyperthermia with IHS may also be applicable to benign intracranial tumors and neoplasms in other part of body as well.     

Differential modulation of the short- and long-latency somatosensory evoked potentials in a forewarned reaction time task.

OBJECTIVE: We investigated modulation of the short- and long-latency somatosensory evoked potentials (SEPs) in a forewarned reaction time task. METHODS: A pair of warning (auditory) and imperative stimuli (somatosensory) was presented with a 2 s interstimulus interval. In movement condition, subjects responded by grip movement with the ipsilateral hand to the somatosensory stimulation when the imperative stimulus was presented. In counting condition, they silently counted the number of imperative stimuli. The SEPs in response to the imperative stimuli were recorded. RESULTS: Frontal N30 and central N60 amplitudes were significantly smaller in the movement than in the counting or rest conditions. None of the short-latency components differed between the counting and rest conditions. In contrast to the short-latency components, P80 was significantly larger in the counting than in the rest condition, and showed a further increase from the counting to the movement condition. The N140 amplitude was significantly larger in the movement than the rest condition, but was not changed between the counting and the rest conditions. CONCLUSIONS: The attenuation of the frontal N30 and central N60, and the enhancement of the P80 and possibly the N140 resulted from the centrifugal mechanism. The present findings may show the different effects of voluntary movement on the early and subsequent cortical processing of the relevant somatosensory information requiring a behavioral response. SIGNIFICANCE: The present study demonstrated the differential modulation of short- and long-latency components of SEPs in a forewarned reaction time task.