Local outbreak of Streptococcus pneumoniae serotype 12F caused high morbidity and mortality among children and adults.

Pneumococcal serotype replacement is an important issue after the introduction of pneumococcal conjugate vaccine (PCV) in children. After the introduction of 13-valent PCV, the incidence of invasive pneumococcal diseases (IPD) caused by Streptococcus pneumoniae serotype 12F (Sp12F) have increased in some countries; however, an outbreak of Sp12F has not reported in the post-13-valent PCV era. We experienced a local outbreak of Sp12F during March through May 2016 in Tsuruoka city, Japan after the introduction of 13-valent PCV in 2013. The IPD patients were two children and seven adults, three of whom died with a rapid disease progress. Although the clear transmission route was not determined, eight of the nine patients (89%) had close contact with children, which suggests that transmitted colonisation of Sp12F among children and adults might be the source of transmission. Continuous monitoring of IPDs, along with the determination of pneumococcal serotypes, is warranted in the post-13-valent PCV era. New IPD control strategies may be needed if this fatal outbreak continues to occur.

Effects of SA7060, a novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, on deoxycorticosterone acetate-salt-induced hypertension in rats.

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl) propionic acid, prevents deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related organ damage, such as cardiovascular hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with candoxatril and enalapril, which are a selective NEP and ACE inhibitor, respectively. During DOCA-salt treatment for 4 weeks, the rats were given SA7060, candoxatril, enalapril or vehicle, once daily by gavage. The 4-weeks treatment with DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and increases in urinary excretion of protein and blood urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of atrial natriuretic peptide and cyclic GMP in SA7060- or candoxatril-treated animals. Histopathological examination of the kidney in DOCA-salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or candoxatril. When the vascular hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with the sham rats. The development of vascular hypertrophy was suppressed by the treatment with SA7060, candoxatril or enalapril. Our findings indicate that SA7060 efficiently prevents DOCA-salt-induced hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both renin-dependent and renin-independent hypertensive subjects, although further studies examining efficiency in a renin-dependent hypertensive model are needed.

Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice.

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra-deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1beta, IL-6, and tumor necrosis factor alpha were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.

Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 5). Effects of repeated doses of flutamide for 2 and 4 weeks.

Flutamide, a nonsteroidal antiandrogen, was administered orally to 8-week (for the 2 week study) and 6-week-old (for the 4 week study) male Crj:CD(SD) rats at dose levels of 0 mg/kg, 60 mg/kg and 200 mg/kg daily for 2 weeks or 4 weeks in order to determine whether a 2 week treatment period is sufficient for detection of drug effects on the male reproductive system. Flutamide treatment for 4 weeks resulted in decreased organ weights of the epididymides and prostate, decreased sperm counts and Leydig cell proliferation in the testes at 60 mg/kg and 200 mg/kg. Decreased sperm motility and histological lesions in the seminiferous tubules were observed at 200 mg/kg. Flutamide treatment for 2 weeks decreased organ weight of epididymides and prostate and caused Leydig cell proliferation in the testes at 60 mg/kg and 200 mg/kg. Decreased sperm counts and sperm motility, and histological lesions in seminiferous tubules were observed at 200 mg/kg. The results of this study showed that 2 weeks treatment with flutamide causes histological lesions of testes and disorders of sperm parameters similar to those observed with 4 weeks treatment, indicating that 2 weeks treatment is sufficient for detection of effects of flutamide on the male reproductive system.

Beta adrenergic antagonist permeation across cultured rabbit corneal epithelial cells grown on permeable supports.

PURPOSE: To determine whether cultured rabbit corneal epithelial cells (RCEC), grown on permeable supports, provide a suitable in vivo model for characterizing transcellular drug permeation and metabolism. METHODS: Primary rabbit corneal epithelial cells grown in DMEM-F12 were seeded on Transwell-COL inserts coated with fibronectin. The epithelial barrier integrity was evaluated, based on measurements of 14C-mannitol and 3H-PEG900, and their transepithelial electrical resistance (TEER). Ultrastructure evaluation was based on scanning electron microscopy and transmission electron microscopy, which were performed 8 days after seeding. Measurements of beta adrenergic antagonist permeability were performed to assess transcellular permeability. RESULTS: Eight days after seeding, the TEER reached a peak of 144 omega.cm2 and the 14C-mannitol and 3H-PEG900 permeabilities were 6.8 x 10(-6) and 2.9 x 10(-6) cm/sec, respectively. Ultrastructural analysis revealed a multilayered structure with numerous microplicae and typical cytoplasmic organelles along with desmosomes. The relationship between permeation of beta-blockers and lipophilicity resembled the intact isolated cornea. CONCLUSIONS: This is the first description of cultured RCEC grown on permeable support. Many of its properties mimic those described in the intact corneal epithelium. Even though its electrical tightness is less than that of the intact cornea, the transcellular permeability to lipophilic beta-antagonists is comparable to the isolated preparation. Therefore, this model will facilitate characterization of ocular permeation mechanisms of hydrophobic drugs whose route of permeation is transcellular.

The effects of betamethasone derivatives on endotoxin-induced uveitis in guinea pigs.

OBJECTIVE AND DESIGN: We reported previously that the betamethasone derivative betamethasone dipropionate behaves as an anti-glucocorticoid in rat endotoxin-induced uveitis (EIU). In the present study, we produced EIU in guinea pigs and investigated the effects of betamethasone dipropionate on the EIU. MATERIAL: Male Hartley guinea pigs were used. TREATMENT: Glucocorticoids were instilled into the eye. METHOD: To elicit EIU, lipopolysaccharide (LPS) was injected into the anterior chamber of the eye. Cell numbers in the aqueous humor after LPS injection were determined by flow cytometry. Prostaglandin E2 (PGE2) production after LPS injection into the anterior chamber was also examined. RESULTS: Intracameral injection of LPS (1 microgram/eye) induced cell infiltration into the anterior chamber and PGE2 production. Betamethasone dipropionate inhibited cell infiltration and PGE2 production more strongly than betamethasone. These results suggest that betamethasone dipropionate is a potent glucocorticoid in guinea pigs. CONCLUSIONS: Structure-activity relationships of glucocorticoids in the guinea pig EIL model may differ from those in the rat EIU model.

Toxicity study of the angiotensin converting enzyme inhibitor rentiapril in rats.

A three-months toxicity study of an angiotensin converting enzyme (ACE) inhibitor, rentiapril (CAS 80830-42-8), was performed in Sprague-Dawley rats by oral administration. The dose levels of 0, 30, 125, 500 and 1000 mg/kg were tested in both sexes, in which each experimental group comprised 10 rats. Another ACE inhibitor, captopril, was used as a reference compound. Rentiapril at the highest dose of 1000 mg/kg caused low food consumption and death of some animals with signs of bloody feces and anemia. In males and females receiving 500 and 1000 mg/kg, there were low body weight gain, increases in water intake, urine volume and serum BUN level, and decreases in levels of various erythrocytic parameters. Kidney weight was increased dose-dependently in both sexes. Histopathologically, renal changes in the 500 and 1000 mg/kg groups consisted of proximal tubular degeneration, juxtaglomerular cell hyperplasia and interstitial cell infiltration. Similar, but mild, changes in proximal tubules were present in the female 125 mg/kg group. Dead animals from the highest dose groups further showed gastrointestinal hemorrhagic erosion and/or ulcer, decreased bone marrow erythropoiesis and hepatocytic vacuolar degeneration. There was no pathological alteration in rats from other rentiapril-treated groups, as well as in controls. These results indicate that the no-effect dose of rentiapril in rats by three months oral administration is 30 mg/kg in female and 125 mg/kg in male, and suggest that, like other ACE-inhibitors, this compound also has a toxic potential to affect renal tissues.

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats.

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)