Evaluation of myopathy risk for HMG-CoA reductase inhibitors by urethane infusion method

Purpose of the present study was to evaluate the myopathy risk using a urethane infusion method following oral administration of five kinds of commercial HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (HCRIs), (pravastatin (PV), simvastatin (SV), cerivastatin (CeV), atorvastatin (AV), and fluvastatin (FV)) alone or with coadministration of bezafibrate (BF). The solubility of HCRIs in various solvents was determined as a criterion of the physicochemical property. The plasma creatine phosphokinase (CPK) level as a marker of myopathy in normal rats was screened under urethane infusion after oral administration of HCRI alone or with BF coadministration. Also, renal tissue specimens were prepared and the myoglobin remaining in the tissue was visualized by the labeled avidin-biotin technique. The plasma CPK level in normal rats under urethane infusion following oral administration of five kinds of HCRI increased as the dose of HCRI increased, and coadministration of BF further increased the CPK level for each drug. The risk of myopathy evaluated from the CPK level was ranked as follows: CeV>FV>AV>SV>PV. Myoglobin deposition was observed in the cast of proximal tubules, cytoplasm of distal tubules and collecting ducts of rat kidney extracted from rats treated with HCRIs under urethane infusion. Histopathological findings showed that the extent of myoglobin deposition increased on coadministration of BF with each drug. The correlation was found for myopathy risk evaluated by CPK level using the urethane infusion method and drug lipophilicity, ie., the water/n-octanol partition coefficient except for the case of SV. Histopathological findings for the kidney following HCRI treatment also reflected the CPK level in rats under urethane infusion.     

Behavior tests and immunohistochemical retinal response analyses in RCS rats with subretinal implantation of Okayama-University-type retinal prosthesis

We have developed a photoelectric dye-coupled polyethylene film as a prototype of retinal prosthesis, which we named Okayama University-type retinal prosthesis. The purposes of this study are to conduct behavior tests to assess vision in Royal College of Surgeons (RCS) rats that underwent subretinal implantation of the dye-coupled film and to reveal retinal response to the dye-coupled film by immunohistochemistry. Polyethylene films were made of polyethylene powder at refined purity, and photoelectric dyes were coupled to the film surface at higher density compared with the prototype. Either dye-coupled film or dye-uncoupled plain film used as a control was implanted subretinally from a scleral incision in both eyes of an RCS rat at 6 weeks of the age. Behavior tests 2, 4, 6, and 8 weeks after implantation were conducted by observing head turning or body turning in the direction consistent with clockwise or counterclockwise rotation of a black-and-white-striped drum around a transparent cage housed with the rat. After the behavior tests at 8 weeks, rats’ eyes were enucleated to confirm subretinal implantation of the films and processed for immunohistochemistry. In the behavior tests, the number of head turnings consistent with the direction of the drum rotation was significantly larger in RCS rats with dye-coupled- compared with plain-film implantation [P < 0.05, repeated-measure analysis of variance (ANOVA), n = 7]. The number of apoptotic neurons was significantly smaller in eyes with dye-coupled- compared with plain-film implantation (P < 0.05, Mann–Whitney U test, n = 6). In conclusion, subretinal implantation of photoelectric dye-coupled films restored vision in RCS rats and prevented the remaining retinal neurons from apoptosis.     

Preface

Among clinically isolated β-hemolytic streptococci, Streptococcus pyogenes and S. agalactiae were considered the main pathogens in humans until recently. In 1996, S. dysgalactiae subsp. equisimilis (SDSE) was proposed as a novel taxon among human-derived streptococcal isolates. SDSE has Lancefield group C or G antigens, exhibits strong β-hemolysis, and exerts streptokinase activity upon human plasminogen and proteolytic activity upon human fibrin. Similarly to group A streptococci, SDSE possesses virulence factors including M protein, streptolysin O, streptolysin S, streptokinase, hyaluronidase, C5a peptidase, and others. SDSE may exist among the normal flora of the skin, oropharynx, and gastrointestinal and genitourinary tracts. In the twenty-first century, invasive SDSE infection (i.e., cellulitis, urosepsis, and pneumonia) leading to various disseminated diseases is being diagnosed increasingly in Japan, elsewhere in Asia, in Europe, and in America. Particularly, among elderly patients, these invasive diseases are encountered increasingly in Japanese hospital emergency departments. Analysis of the part of the emm gene encoding the amino acid sequence at the N-terminal end of the M protein is used to determine the molecular epidemiology of SDSE. The distribution of emm types from patients with invasive or noninvasive infections differs between surveillance results from different countries. In this review, we summarize the characteristics of phenotypes and virulence factors in SDSE strains; the review also focuses on emerging SDSE infectious disease and future vaccination research.     

Atypical pemphigus with immunoglobulin G autoantibodies against desmoglein 3 and desmocollin 3

In patients with pemphigus vulgaris (PV), pathogenic immunoglobulin (Ig)G antibodies are most commonly directed against desmoglein 3 (Dsg3). It has recently been reported, however, that IgG anti‐desmocollin 3 (Dsc3) antibodies are detected in some cases of pemphigus with or without IgG anti‐Dsg3 antibodies. We present a case of pemphigus with IgG antibodies against Dsg3 and Dsc3. Subsequent studies showed that the cell surface distribution pattern of Dsc3 but not Dsg3 was altered, suggesting that suprabasal acantholytic blisters were induced by IgG anti‐Dsc3 antibodies rather than IgG anti‐Dsg3 antibodies. Our case suggests that anti‐Dsc3 antibodies may be pathogenic in cases positive for the dual cadherin autoantibodies.     

Isolation and characterization of microsatellite loci in the intertidal snail Batillaria multiformis (Mollusca Gastropoda)

Intertidal snails of the genus Batillaria are a common group in tidelands throughout Japan. Recently, population sizes of Batillaria multiformis have been reduced due to coastal area reclamation. Using next generation sequencing, we developed 11 microsatellite markers to reveal the genetic diversity and gene flow among populations and combined them into a single multiplex panel. Evaluating polymorphisms in two populations showed that the numbers of alleles per locus ranged from 2 to 17 and 2 to 15, and the expected heterozygosity ranged from 0.274 to 0.936 and 0.455 to 0.934 in Mangokuura estuary and Kasari Bay, respectively.     

Homeostasis model assessment of insulin resistance,quantitative insulin sensitivity check index,and oral glucose insulin sensitivity index in nonobese,nondiabetic subjects with high-normal blood pressure

To investigate the relationships between high-normal blood pressure (BP) and insulin resistance, we examined insulin sensitivity in 306 nonobese and nondiabetic Japanese subjects with various BP categories (optimal BP, normal BP, high-normal BP, and hypertension). Insulin sensitivity was measured from fasting plasma glucose and insulin values and those during a 75-g oral glucose tolerance test by five formulas: the homeostasis model assessment of insulin resistance (HOMA-R), the quantitative insulin sensitivity check index (QUICKI), the oral glucose insulin sensitivity (OGIS) index, and two insulin sensitivity indexes (ISI-composite and ISI-stumvoll). The HOMA-R was significantly higher, and the QUICKI was significantly lower in subjects with hypertension than in subjects with optimal BP. Both HOMA-R and QUICKI values showed that high-normal BP patients had a higher (but not significant) degree of insulin resistance than optimal BP patients. The OGIS index was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The ISI-composite was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP, and it was also significantly lower in subjects with hypertension than in subjects with normal BP. The ISI-stumvoll was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The OGIS index, ISI-composite, and ISI-stumvoll significantly decreased with increasing severity of BP status among the normotensive groups (optimal BP, normal BP, and high-normal BP). These findings indicate that insulin resistance is present even in the high-normal BP categories of nonobese and nondiabetic Japanese individuals.