The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study.

BACKGROUND: The cytokine interleukin-31 (IL-31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and efficacy of blocking the IL-31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL-31 receptor A (IL-31RA) monoclonal antibody, which binds to IL-31RA to inhibit subsequent IL-31 signalling. OBJECTIVES: To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD. METHODS: In this randomized, double-blind, placebo-controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy. RESULTS: No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose-dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about -50% at week 4 with CIM331 compared with -20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate. CONCLUSIONS: A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL-31.

Association between the neutrophil myeloperoxidase index and subsets of bacterial infections.

The mean myeloperoxidase index (MPXI) is calculated during the routine complete blood count performed using the autoanalyzer ADVIA120/2120. The pattern of changes in the neutrophil myeloperoxidase levels in patients with specific infectious diseases was analyzed by assessing the MPXI levels. In patients with bacterial sepsis, identified by positive blood-culture tests, with (n = 29) and without (n = 51) systemic inflammatory response syndrome, the mean MPXI significantly reduced to -3.18 and -2.06, respectively. In contrast, among patients with nontuberculous nonseptic bacterial infections (n = 40), the mean MPXI significantly elevated to 5.51, while tuberculosis patients (n = 37) and patients with viral infection (n = 60) showed an unchanged MPXI (mean values, -0.46 and -1.06, respectively). Among the parameters of inflammation, only the C-reactive protein values showed a weak correlation with the MPXI levels. [Conclusion] These results indicate that MPXI is correlated with some specific infectious states, i.e. MPXI is low in bacterial sepsis and high in nontuberculous nonseptic bacterial infections. MPXI appears to be an independent and useful biomarker for the diagnosis and follow-up of infectious diseases, especially when the MPXI values are obtained at regular intervals during the disease courses of the patients.

Successful treatment of retrograde ejaculation with amezinium.

The effect of amezinium, a new type of antihypotensive agent, on retrograde ejaculation was evaluated in 3 patients with retrograde ejaculation. The patients received 10 mg amezinium orally once a day. All patients achieved antegrade ejaculation. Semen analyses revealed 6-50 x 10(6)/mL (mean 28.7 x 10(6)/mL) sperm with a motility of 20-50% (mean 36.7%). The wives of 2 patients became pregnant within 6 months of the initial treatment. None of the patients had any side effects. It would appear that amezinium is a useful treatment for retrograde ejaculation.

Effect of testosterone replacement therapy on serum PSA in patients with Klinefelter syndrome.

The effect of testosterone replacement therapy on serum prostate-specific antigen (PSA) was investigated in 11 patients with Klinefelter syndrome. Significant increases in serum testosterone level and prostate volume were observed after testosterone replacement therapy. However, serum PSA level did not change after testosterone replacement therapy. It would appear that serum PSA is not influenced by exogenous testosterone in patients with Klinefelter syndrome.

The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans.

OBJECTIVE: Our objective was to evaluate the activity of cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO), and N-acetyltransferase 2 (NAT2) from early to late pregnancy and after delivery. METHODS: Twelve women were studied on three occasions during pregnancy (early, 8-16 weeks' gestation; middle, 20-28 weeks' gestation; and late, 32-39 weeks' gestation) and about 1 month after delivery. Caffeine was used as a metabolic probe. After the women ingested a can or a bottle of caffeine-containing soft drink, urine samples were collected for 12 hours. The caffeine metabolites measured were 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), 1-methyl-uric acid (1U), 1,7-dimethyl-uric acid (17U), and 1,7-dimethylxanthine (17X). The hepatic enzyme activities were estimated by the urinary caffeine metabolic ratios as follows: CYP1A2 = (AAMU + 1X + 1U)/17U; XO = 1U/(1X + 1U); NAT2 = AAMU/(AAMU + 1X + 1U). RESULTS: Statistically significant differences were found in CYP1A2 (P < .0001) and NAT2 (P < .01). The mean metabolic ratios for CYP1A2 during pregnancy (6.80, 5.18, and 4.97 for the early phase, middle phase, and late phase, respectively) were significantly lower than the ratio after delivery (10.39). The mean metabolic ratio for NAT2 in the early phase (0.57) was significantly lower than after delivery (0.66). There was no significant difference in metabolic ratios for XO during pregnancy and after delivery. CONCLUSION: The data demonstrate that pregnancy influences CYP1A2 and NAT2 activity. CYP1A2 activity decreases not only in late pregnancy but also in early and middle pregnancy.

Possible involvement of the membrane-bound form of peroxiredoxin 4 in acrosome formation during spermiogenesis of rats.

Peroxiredoxins are novel peroxidases that exhibit divergent biological functions. The fourth member, Prx4, is synthesized with a signal sequence and, after processing, secreted as a 27-kDa form in most tissues. A 31-kDa Prx4 which corresponds to the unprocessed, membrane-bound form is found only in testis. This study was undertaken in order to investigate the role of the membrane-bound Prx4 during spermiogenesis in rats. The Prx4 transcript was observed in testes at 14 days of age, the age before puberty, and its level increased only slightly during aging. Only the secretable form of Prx4 was present before 30 days of age, but the membrane-bound Prx4 became detectable in adult testes, although sum of the two forms appeared to be the same after 21 days old. While weak immunoreactivity to the Prx4 antibody was detected in spermatogenic cells for all ages, a strong immunoreactivity was observed in the elongating spermatid and residual body of adult testis. Prx4 was present in the lumen of the endoplasmic reticulum, Golgi bodies, and the perinuclear space in young rat testes. However, the localization of Prx4 was restricted to membranes of the acrosomal vesicle of the elongated spermatid and was not detected in spermatozoon. Once spermiogenesis is accomplished, vesicles containing the membrane-bound Prx4 were released into the residual body, along with residual membranous components. Thus the conversion of the soluble form to the membrane-bound form may have a role in the acrosome formation during vesicular reorganization during spermiogenesis.

Sutureless vasovasostomy using new vascular closure staples in rats.

To evaluate the efficacy of sutureless vasovasostomy using vascular closure staples, 20 male Sprague-Dawley rats were used for the study. In each rat, a sutureless vasovasostomy using vascular closure staples was performed on a randomly selected side, and a conventional end-to-end microsutured anastomosis was performed on the opposite side. Operation time was significantly shorter for sutureless vasovasostomy using vascular staples (p < .001). Four weeks after the surgery, however, patency rate and granuloma formation were not different for conventional end-to-end vasovasostomy vs. sutureless vasovasostomy. These findings suggest that sutureless vasovasostomy is simple to perform and requires fewer special technical skills. This procedure may provide an alternative to the conventional vasovasostomy.

Reevaluation of testicular biopsies of males with nonobstructive azoospermia in assisted reproductive technology.

Spermatogenesis was investigated in seminiferous tubules of 100 males with nonobstructive azoospermia. Forty-four (44%) cases had Sertoli-cell-only syndrome, 23 (23%) had spermatogonium in the tubules, 17 (17%) had primary spermatocyte in the tubules, and 16 (16%) had round or late spermatid in the tubules. No cases showed secondary spermatocyte present in the tubules. The mean serum follicle-stimulating hormone (FSH) in males with nonobstructive azoospermia was significantly higher than that in males with obstructive azoospermia (p < .001). The mean concentrations of serum FSH in cases with Sertoli-cell-only syndrome and spermatogonium in the tubules were significantly higher than those in cases with primary spermatocyte and spermatid in the tubules (p < .05-.001). The results indicate that the evaluation of testicular histology using the type of germ cells present in seminiferous tubules is available for assisted reproductive technology.

Adult mesoblastic nephroma with ciliated epithelium. A case report.

A case of renal pelvic tumors occurring in a 44-year-old man is reported. There were two polypoid renal pelvic tumors which consisted of glandular and stromal components. Some glands in the tumors had ciliated epithelium and were quite similar to the epididymal tubules. Other glands in the tumors resembled the collecting duct or the mesonephric remnant seen in female genitalia. Immunohistochemistry and electron microscopy revealed smooth muscle differentiation of the stromal cells of these tumors. Some psammoma bodies were seen in the glands of the tumors. We diagnosed these tumors as adult mesoblastic nephroma (MN). The patient has been followed up for 14 months, showing no evidence of recurrence. Differentiation of the tumors from angiomyolipoma, leiomyoma, and nephrogenic adenofibroma is discussed. Adult renal tumors that consist of epithelial and stromal components have been reported under various names. They constitute clinicopathologically different entities originating from pediatric MN. We suggest that these tumors should be termed "adult MN".

The use of ebastine, a mast cell blocker, for treatment of oligozoospermia.

The effect of mast cell blocker (ebastine) on semen quality was evaluated in 15 idiopathic oligozoospermic males. Ten milligrams/day of ebastine was administered orally for 3 months. Nine cases (66.7%) showed definite improvement in the semen quality. The wives of 3 patients (20%) became pregnant within 6 months of the initial treatment. It would appear that mast cell blocker (ebastine) significantly improves semen quality in men with idiopathic oligozoospermia.

Labeling conditions using a 2-aminobenzamide reagent for quantitative analysis of sialo-oligosaccharides.

During 2-aminobenzamide (2-AB)-labeling of sialo-oligosaccharides the authors encountered a significant loss of sialic acids under the reported conditions, at 65 degrees C for 2 h. By examination of the relationship between labeling temperature and recovery of tetra-sialylated oligosaccharides, 2-AB-labeling at 37 degrees C for 16 h resulted in a maximum yield with practically no loss of sialic acid. Under the newly optimized conditions, the reproducibility of 2-AB-labeling was examined in triplicate with three lots of recombinant human erythropoietin (r-HuEPO). The present conditions gave analytical data comparable to those obtained by the established NaB[3H]4 labeling procedure. The modified method has been applied to oligosaccharide structural analysis of sialoglycoprotein therapeutics.

Pharmacokinetic changes of theophylline and amikacin through the menstrual cycle in healthy women.

The objective of this open-label, single-dose study was to clarify the influence of the menstrual cycle on the pharmacokinetics of theophylline (n = 10) and amikacin (n = 8) in young healthy Japanese women with regular menstrual cycles. Each subject received an intravenous infusion of theophylline or amikacin sulfate at four different phases--mid-follicular (phase I), peri-ovulatory (phase II), mid-luteal (phase III), and premenstrual days (phase IV). In the theophylline study, there were no significant differences in the pharmacokinetic parameters among the four phases studied. In the amikacin study, CLtot was 15% higher in phase III than in phase I (p < 0.01). Vd beta was 35% higher in phase III than in phase I (p < 0.05). The other pharmacokinetic parameters of amikacin were not significantly altered during the menstrual cycle. Evidence suggests that the phase of the menstrual cycle may be a factor in determining the pharmacokinetics of amikacin.

[Ultrasonogram of carotid artery in endoarterectomy patients].

Ultrasonograms of the carotid artery were compared with the intraoperative finding of atheroma plaque in terms of stenosis, fragility, ulceration and calcification. Soft type, intermediate type and these mixed type plaques were fragile plaques in almost all cases. All hard type plaques were tough plaques. The detection of stenosis and calcification was satisfactory, however that of ulceration was not sufficient. The stenotic lesions frequently existed in bilateral carotid arteries and the intima was easy to become thick even after the endoarterectomy. The ultrasonogram was thought to be the essential study for the carotid artery lesions.

Seroprevalence and field isolation of bovine immunodeficiency virus.

A seroprevalence study of bovine lentivirus, known as bovine immunodeficiency virus (BIV), was conducted in 12 different dairy herds in Hokkaido, where some herds were a high prevalence of bovine leukemia virus (BLV) infection. Amongst 611 cattle, 28.6% of cattle were BLV-seropositive, and 11.7% of cattle were seropositive for BIV, while 4.2% of cattle were seropositive for both BIV and BLV. For the isolation of BIV, 19 samples of peripheral blood mononuclear cells (PBMC) and one sample of milk-derived leukocytes were prepared from BIV-seropositive cows. These PBMC and leukocyte preparations were then co-cultivated with cc81 cells, a cat cell line transformed by mouse sarcoma virus. BIV was isolated from 17 PBMC and one milk-derived leukocyte samples. The isolated viruses showed slow replication and syncytia formation. Major core antigen, p26 from these isolates were reacted with anti-BIV (American isolate R-29) serum. In addition, proviral DNA was detected in blood and milk samples by nested polymerase chain reaction and subsequent Southern blot hybridization. Nucleotide sequence analysis of the amplified pol gene products showed its 99.0 to 99.7% homology to that of BIV R-29. These results indicate that the Japanese BIV isolates appear to be antigenically and genetically similar to the American R-29. Since BIV was isolated from milk samples, BIV could possibly be transmitted through milk. This is the first report of BIV isolation in Japan.

Bone marrow transplantation in a Holstein heifer with bovine leucocyte adhesion deficiency.

Bone marrow transplantation (BMT) was performed in a 9-month-old heifer with bovine leucocyte adhesion deficiency (BLAD). Clinical and haematological findings, selected neutrophil function and CD18 expression of neutrophils in a B2 integrin-deficient heifer were examined. Twelve months after BMT, a small fluorescent region in the CD18-positive area of a flow cytometric profile was demonstrated and estimated to represent 0.3-0.5% of the CD18-positive neutrophils as measured by flow cytometric analysis following immunomagnetic separation. The animal's clinical condition appeared to improve and stabilize over our observation period of 28 months following BMT. Newly expressed CD18 seemed to play an important role in ameliorating the clinical signs of BLAD in this heifer.

Survival of transfused CD18-positive granulocytes and their chemiluminescent response in a heifer with leukocyte adhesion deficiency.

Granulocyte transfusion (GT) was performed in an 8-month-old heifer with leukocyte adhesion deficiency (BLAD) to monitor the changes in transfused CD18-positive neutrophils and associated neutrophil chemiluminescent (CL) response in beta 2-integrin-deficient host. The CD18-positive neutrophils were detected in blood from the BLAD heifer during the first 3 hr after 2.6 x 10(9) cells were infused by GT, and disappeared by 5 hr after GT. The CL response of neutrophils was increased 1.7 to 2.8-fold in the BLAD heifer during the first 3 hr after GT, thereafter CL response decreased gradually from 2 to 5 hr after GT.

Structure-activity relationships of penem antibiotics: crystallographic structures and implications for their antimicrobial activities.

Twelve closely related crystal structures of the penem derivatives revealed a characteristic short contact of the oxygen atom in the C2 side-chains with the S1 atom. The side-chain conformations of the crystal structures showed a good correlation with the antimicrobial activity. In particular, the penems which show high antimicrobial activity have similar torsion angles for S1-C2-C1'-C2', suggesting that the disposition of the C2' atom would be important for binding to penicillin-interacting enzymes. Two conformations of the C6 hydroxyethyl group were observed in the crystal structures. Of those two, the conformation with a larger torsion angle (delta = 179.2 degrees) is deduced to be the enzyme-bound conformation in the Michaelis complex.