Distribution of human herpesvirus 6 and varicella-zoster virus in organs of a fatal case with exanthem subitum and varicella

The distribution of human herpesvirus 6 (HHV-6) and varicella-zoster virus (VZV) was examined in autopsy samples from a fatal case with both virus infections. A 9-month-old boy developed convulsive seizures followed by macular skin rashes, rapidly progressed to brain death, and died 15 days after the onset, when signs of varicella were noted. An isolation of HHV-6 from blood and evaluation of antibody activities to various viral agents including HHV-6 were performed before his death. Postmortem examinations included: (i) isolation of HHV-6 and VZV from tissues or organs; (ii) detection of both virus antigens in tissues or organs by an indirect immunofluorescent assay using monoclonal antibodies to both viruses; (iii) amplification of both viruses and human herpesvirus 7 DNA sequences by a nested polymerase chain reaction assay; and (iv) endonuclease digestion of amplified products of HHV-6 DNA for differentation of variants A and B. Human herpesvirus 6 DNA was detected in peripheral blood mononuclear cells (PBMC) and plasma obtained at the eruptive stage but present only in PBMC 15 days after, indicating the primary infection with HHV-6, although the virus was not isolated from the same blood sample and a significant rise in the antibody titers to HHV-6 was not observed. Both virus antigens and DNA were detected in various tissues or organs obtained at autopsy, but only VZV was isolated from these samples, suggesting disseminated infection with both viruses in an infant. All the amplified products of HHV-6 DNA were variant B. Among the findings for the distribution of virus antigens, it was noteworthy that HHV-6 antigen was demonstrated in the endothelial cells of small vessels in the frontal lobe of the brain. There was no evidence of HHV-7 infection. These data indicate that the primary HHV-6 infection closely followed by the primary VZV infection had the potential hazard of an unexpected and apparently life-threatening event, in which disseminated infections with both viruses were noted in multiple tissues or organs including the brain.     

Vardenafil 20-mg demonstrated superior efficacy to 10-mg in Japanese men with diabetes mellitus suffering from erectile dysfunction

AIM: Vardenafil is a highly selective and potent phosphodiesterase type-5 inhibitor for the treatment of erectile dysfunction (ED). The efficacy of vardenafil has been demonstrated in a broad range of ED populations, but has not yet been assessed in Japanese patients with diabetes mellitus (DM), although DM is frequently associated with difficult-to-treat ED. This is the first study to investigate whether high-dose vardenafil (20 mg) can demonstrate superior efficacy to the usual dose (10 mg) in this subpopulation in Japan. METHODS: The study was a randomized, placebo-controlled, double-blind, multi-centre, parallel group comparison 12-week study. Following 4 weeks observation period, 778 patients aged 26-64 years old with ED and DM (HbA1c >12% at screening was excluded) both of more than 3 years duration were randomly allocated to one of the three groups, vardenafil 10 mg, 20 mg, or placebo (randomization ratio 3:3:1). Erectile function (EF) domain score of the International Index of Erectile Function was estimated as the primary efficacy parameter. RESULTS: Vardenafil 10 and 20 mg both significantly improved the EF domain score from 13.6 and 13.9 at baseline to 21.8 and 22.9 at last observation carried forward (LOCF), respectively, compared to placebo (13.7 at baseline to 16.3 at LOCF; p<0.0001). In addition, vardenafil 20 mg demonstrated superior efficacy to 10 mg (p<0.05), and the difference was more evident in severe ED patients (baseline EF domain score <11). The safety profile was comparable between these two doses (drug-related adverse events: 6.6, 22.0 and 24.2% in placebo, vardenafil 10 mg, and 20 mg arms, respectively). The most common adverse events were hot flush, headache and nasal congestion, which were mild in intensity and transient, and are known to be common to PDE5 inhibitors. CONCLUSION: In Japanese men with DM and ED, vardenafil 10 mg and 20 mg were effective in improving erectile function with comparable safety profiles. Vardenafil 20 mg demonstrated superior efficacy compared with 10 mg, suggesting incremental clinical benefit in using the higher dose in this difficult-to-treat population.     

Safety and efficacy of vardenafil in patients with erectile dysfunction: Result of a bridging study in Japan

AIM: Vardenafil is a selective and highly potent phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), with improved selectivity for PDE5 and demonstrated efficacy for improving sexual function in men with ED. The current study investigated the safety and efficacy of this new PDE5 inhibitor in Japanese men with ED. METHODS: This was a prospective, double blind, randomized clinical trial designed to evaluate the efficacy and safety of vardenafil. Following a 4-week treatment-free observation period, 283 eligible patients were randomized to 12 weeks treatment with vardenafil 5 mg, 10 mg, 20 mg, or placebo. Primary efficacy responses were assessed using the scores of Q3 and Q4 of the international index of erectile function (IIEF). RESULTS: All three vardenafil doses showed significantly better improvement than the placebo group in Q3 and Q4 scores of the IIEF questionnaire, either at 12 weeks or at the 'last observation carried forward' (LOCF, P < 0.0001). Q3 scores were improved to 4.06 with vardenafil 5 mg, 4.53 with vardenafil 10 mg, and 4.64 with vardenafil 20 mg, versus 3.17 with placebo. Comparable scores for Q4 were 3.47, 4.15 and 4.31 versus 2.31 for placebo. Up to 86% of patients achieved improved erections as assessed by the global assessment question (GAQ). Reported adverse event rates were 35.3%, 45.3% and 54.5% with vardenafil 5 mg, 10 mg and 20 mg, respectively, versus 21.1% in the placebo group. No serious adverse drug reactions were reported. The most common treatment-emergent adverse events were transient headache, flushing and rhinitis, which were mostly mild. CONCLUSION: Vardenafil is an effective and well-tolerated treatment for ED and provides improvement in key indices of erectile function among Japanese men with ED. The results of our trial show that up to nearly 90% of patients achieve improved erections with the administration of vardenafil.     

HYDROGEN-TRITIUM EXCHANGE TITRATION OF THE HISTIDINE RESIDUES IN BOVINE HEART CYTOCHROME C AND ANALYSIS OF THEIR MICROENVIRONMENT

Microenvironments of the three histidine residues located at the positions 18, 26, and 33 from the amino terminus in bovine heart cytochrome c were analysed in solution by the hydrogen-tritium exchange titration method, which has been developed in this laboratory. Histidine-18, which is liganded to the heme iron, and histidine-26 did not incorporate tritium in native state, indicating that the two are located in solvent inaccessible hydrophobic regions. Histidine-33 was labeled with tritium to an appreciable extent and seemed to be partially buried in the molecule. The pKa value estimated for histidine-33 was 6.1 at 37° by the tritium exchange titration, suggesting that the residue interacts very weakly with a neighboring cationic group. These results seem to be compatible with the tertiary structure of the protein deduced from the X-ray crystallographic analysis.     

Suppression of active Arthus reaction by colchicine

An effect of colchicine on the active Arthus reaction in rabbits was investigated in vivo with simultaneous evaluation of in vitro chemotactic activity of polymorphonuclear leukocytes. Arthus reactions were induced by intracutaneous injection of ovalbumin into rabbits preimmunized with ovalbumin. Colchicine, 1 mg/kg or 2 mg/kg, injected intraperitoneally one hour prior to the induction of the Arthus reaction, suppressed erythema and induration at 12 h, when histology showed decreased numbers of C3, suggestive of the presence of immune complexes, persisted to 24 h. In vitro chemotaxis of polymorphonuclear leukocytes using Boyden chamber techniques revealed suppression of the activity in the colchicine-treated animals at 6 and 12 h. These findings suggest that colchicine inhibits vascular injury by interfering with directional chemotaxis of polymorphonuclear leukocytes to the lesional sites.     

Clinical Application of Left Ventricular Assist Devices

In Japan, 32 patients have had application of monoventricular and biventricular assist devices during the past three years. Five of the 32 patients treated by the Fall of 1986 have successfully achieved long-term survival. In this paper we describe our experience with the Tomasu and Pierce VAD in a total of four and two patients, respectively. Four of the six patients could be successfully weaned from the VAD and two of them were long-term survivors. Nonsynchronizing pumping of the VADs was effective, as well as synchronizing pumping. Anticoagulant therapy is highly recommended during the use of the VAD although there was no significant incidence of thromboembolism or thrombus in the devices in this clinical series.     

THYROID FUNCTION IN PATIENTS WITH MYOTONIC DYSTROPHY

In order to investigate endocrine disturbances in patients with myotonic dystrophy (MD), 12 patients and 20 normal controls were studied. All patients were clinically euthyroid and there were no significant differences between circulating levels (mean +/- SD) of T4 (114.7 +/- 26.8 vs 129.9 +/- 28.3 nmol/l), FT4 (16.6 +/- 4.5 vs 18.4 +/- 3.8 pmol/l), T3 (1.61 +/- 0.29 vs 1.86 +/- 0.33 pmol/l), TSH (2.7 +/- 1.3 vs 2.4 +/- 1.4 mU/l), TBG (26.7 +/- 5.5 vs 27.6 +/- 4.9 mg/l), T4/T3 (84.3 +/- 18.4 vs 82.1 +/- 15.3), and FT4/FT3 (0.28 +/- 0.05 vs 0.33 +/- 0.08). Serum FT3 (4.3 +/- 1.4 pmol/l) in patients were significantly lower than those (5.3 +/- 0.9 pmol/l) in normal controls (P less than 0.02). Thyroidal 131I-uptakes (8.7 +/- 4.3%) in patients were significantly lower than those (25.8 +/- 7.4%) in controls (P less than 0.01). The mean maximal TSH responses following TRH stimulation were significantly less in patients with MD (11.4 +/- 4.5 vs 17.0 +/- 6.2 mU/l; P less than 0.02). Neither circulating thyroid microsomal nor thyroglobulin antibodies were detectable in the 11 patients tested. Serum thyroglobulin concentrations were within the normal range in all patients but one. In conclusion, it is suggested that normal levels of serum T4, T3, FT4, TSH, TBG, T4/T3 and FT4/FT3, slight but significant decrease of serum FT3, reduced TSH response to TRH and a decrease of thyroidal radioiodine uptake might be due to a slight functional failure of TSH secretion in patients with myotonic dystrophy.     

Studies on the Mechanism of Hypoproteinemia in Gastric Cancer: 1. Albumin Leakage into the Stomach in Gastric Cancer Patients

The leakage of serum albumin into the gastric juice was measuredusing ¹³¹I-RISA as a tracer in 30 cases with — and eightcases without — gastric carcinoma. A marked increase ofalbumin leakage was noticed in six cases with gastric cancer.Apparent correlation was not found between the degree of leakageof serum albumin and any such factors as age, sex, gastric acidity,PAS stainability, Borrmann's type, histological type and sizeof crater. Edema of mucosa and submucosal tissue and severe lymphatic invasionof cancer cells were found in the cases with high leakage. Thesefindings, therefore, suggested that stasis of lymph in the tumorand the surrounding normal tissue of the stomach was one ofthe causes of albumin leakage into the lumen of the stomach. ^*This work was supported by a grant from the Ministry of Healthand Welfare.