Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: a randomized, double-blind, multicenter study.

This phase III study assessed the efficacy and safety of sacubitril/valsartan compared with those of olmesartan in Japanese patients with essential hypertension. Patients (n = 1161, aged ≥20 years) with mild to moderate hypertension (mean sitting systolic blood pressure [msSBP] ≥150 to <180 mmHg) were randomized to receive sacubitril/valsartan 200 mg (n = 387), sacubitril/valsartan 400 mg (n = 385), or olmesartan 20 mg (n = 389) once daily for 8 weeks. The primary assessment was a reduction in msSBP from baseline with sacubitril/valsartan 200 mg vs. olmesartan 20 mg at Week 8. Secondary assessments included msSBP reduction with sacubitril/valsartan 400 mg vs. olmesartan at Week 8 and reductions in mean sitting diastolic blood pressure (msDBP), mean sitting pulse pressure (msPP), and overall blood pressure (BP) control rate for all treatment groups at Week 8. Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP from baseline than olmesartan at Week 8 (between-treatment difference: -5.01 mmHg [95% confidence interval: -6.95 to -3.06 mmHg, P < 0.001 for noninferiority and superiority]). Greater reductions in msSBP with sacubitril/valsartan 400 mg vs. olmesartan, as well as in msDBP and msPP with both doses of sacubitril/valsartan vs. olmesartan (P < 0.05 for all), were also observed. Patients treated with sacubitril/valsartan achieved an overall higher BP control rate. The safety and tolerability profiles of sacubitril/valsartan were generally comparable to those of olmesartan. The adverse event rate with sacubitril/valsartan was not dose-dependent. Treatment with sacubitril/valsartan was effective and provided superior BP reduction, with a higher proportion of patients achieving target BP goals than treatment with olmesartan in Japanese patients with mild to moderate essential hypertension.

Assessment of serum biomarkers in patients with plaque psoriasis on secukinumab.

The molecular basis of interleukin (IL)-17A in driving psoriasis pathogenesis is not fully elucidated yet. To investigate the underlying mechanisms and biomarkers associated with IL-17A and the role in psoriasis pathogenesis, over 30 serum proteins were evaluated in a study assessing the effectiveness and safety of secukinumab, where treatment was directly switched from cyclosporin A to secukinumab. Serum ß-defensin 2 (BD-2) levels rapidly and robustly reduced following secukinumab treatment. BD-2 levels were well-correlated with Psoriasis Area and Severity Index (PASI) score; changes in BD-2 levels preceded change in PASI score. Serum BD-2, an easily measurable protein, can possibly be used as a suitable surrogate biomarker to monitor responses to IL-17A-targeted therapies for psoriasis in clinical practice.

Long-term efficacy and safety of secukinumab in Japanese patients with moderate to severe plaque psoriasis: 3-year results of a double-blind extension study.

Secukinumab, a fully human monoclonal antibody neutralizing interleukin-17A, has been shown to have significant efficacy in the treatment of moderate to severe psoriasis. Long-term (3-year) efficacy and safety of secukinumab in Japanese patients with moderate to severe psoriasis were evaluated in an extension study of a large phase 3 global study (SCULPTURE). In the core study, 52 Japanese patients with 75% improvement of Psoriasis Area and Severity Index (PASI-75) response at week 12 were re-randomized to a fixed interval (FI; every 4 weeks) schedule and retreatment as needed (RAN), in which patients received placebo until start of relapse, at which time secukinumab was reinitiated. Fifty Japanese patients completed the 52-week core study, and 47 patients entered the extension study with the same double-blind regimens up to week 152. All patients in the secukinumab 300 mg FI and seven patients in 150 mg FI groups completed 3 years of treatment. PASI-90 and -100 at the end of year 3 were achieved in 69.2% and 53.8%, respectively, in 300 mg FI and 42.9% and 42.9%, respectively, in 150 mg FI, indicating high sustained response in 300 mg FI. Mean absolute PASI was continually low in 300 mg FI and numerically higher in 150 mg FI. Dermatology Life Quality Index of 0/1 was maintained by approximately two-thirds of 300 mg FI patients, and all EuroQoL 5-Dimension Health Questionnaire domain measures were also improved. FI dosing was consistently more efficacious than RAN. The safety profile of secukinumab remained favorable, with no new safety concerns identified.

Secukinumab improves psoriasis symptoms in patients with inadequate response to cyclosporine A: A prospective study to evaluate direct switch.

There are limited data on the safety and efficacy of switching to secukinumab from cyclosporine A (CyA) in patients with psoriasis. The purpose of the present study was to assess the efficacy and safety of secukinumab for 16 weeks after direct switching from CyA in patients with moderate-to-severe psoriasis. In this multicenter, open-label, phase IV study, 34 patients with moderate-to-severe psoriasis and inadequate response to CyA received secukinumab 300 mg s.c. at baseline and weeks 1, 2, 3, 4, 8 and 12. The primary end-point was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. The efficacy of secukinumab treatment was evaluated up to week 16, and adverse events (AE) were monitored during the study. The primary end-point of the PASI 75 response at week 16 was achieved by 82.4% (n = 28) of patients receiving secukinumab. Early improvements were observed with secukinumab, with PASI 50 response of 41.2% at week 2 and PASI 75 response of 44.1% at week 4. AE were observed in 70.6% (n = 24) of patients, and there were no serious AE or deaths reported in the entire study period. Secukinumab showed a favorable safety profile consistent with previous data with no new or unexpected safety signals. The results of the present study show that secukinumab is effective in patients with psoriasis enabling a smooth and safe direct switch from CyA to biological therapy.

Is renoprotection by angiotensin receptor blocker dependent on blood pressure?: the Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) study.

To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30-300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.

[A study of the factors that affect parental acceptance of children's disabilities--a literature review].

The process of parental acceptance of a child's disability is complex and involves a myriad of factors, including the nature of the child's disability, factors related to the parents and societal factors. Despite the type of disability and the severity of that disability often being the most significant factors related to the process of acceptance, the majority of previous studies have combined multiple disabilities into a single category. For example, the point at which parent and child begin to live together with a disability marks a "beginning." The nature and timing of this beginning differs depending on the disability and thus has a large impact on the process of acceptance. Moreover, despite acceptance patterns diverging between sexes, the majority of previous studies have sampled only mothers and not fathers. Future research needs to use a more detailed analysis of disability type and its severity, and examine the modality of telling a patient and his or her family of a disability. Further studies also need to sample both mother and father, and consider the familial and social aspects of the process of parental acceptance.

[Process of parental acceptance of a child's disability: literature review].

This study used a literature review to examine the process of parental acceptance regarding disability in a child. Our results identify two main theoretical concepts, stages of grief and chronic sorrow, which describe the emotional responses that parents express following the diagnosis of a child's disability. Stages of grief involve a long-term process through which parents struggle to accept their child's condition, eventually leading to acceptance of their child's disability. Alternately, chronic sorrow describes parental life-long sadness throughout their child's lifetime, periodically repeating at critical times in their child's development. Researchers in Japan have developed a disability acceptance model that combines both concepts. This study found that analysis and interpretation of the parental acceptance process varied with each researcher. It is essential for health care professionals who provide support to children with disabilities to understand the process which parents as primary caregivers undergo to accept the conditions of their child's disability. Knowledge of the main theoretical concepts will give them a broader perspective of the parental acceptance experience. Additional systematic studies are recommended to further understand this issue.

In vivo expression of UDP-N-acetylglucosamine: Alpha-3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I (GnT-1) in Aspergillus oryzae and effects on the sugar chain of alpha-amylase.

UDP-N-Acetylglucosamine: alpha-3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I (GnT-I) is an essential enzyme in the conversion of high mannose type oligosaccharide to the hybrid or complex type. The full length of the rat GnT-I gene was expressed in the filamentous fungus Aspergillus oryzae. A microsomal preparation from a recombinant fungus (strain NG) showed GnT-I activity that transferred N-acetylglucosamine residue to acceptor heptaose, Man(5)GlcNAc(2). The N-linked sugar chain of alpha-amylase secreted by the strain showed a peak of novel retention on high performance liquid chromatography that was same as a reaction product of in vitro GnT-1 assay. The peak of oligosaccharide disappeared on HPLC after beta-N-acetylglucosaminidase treatment. Mass analysis supported the presence of GlcNAcMan(5)GlcNAc(2) as a sugar chain of alpha-amylase from strain NG. Chimera of GnT-I with green fluorescent protein (GFP) showed a dotted pattern of fluorescence in the mycelia, suggesting localization at Golgi vesicles. We concluded that GnT-1 was functionally expressed in A. oryzae cells and that N-acetylglucosamine residue was transferred to N-glycan of alpha-amylase in vivo. A. oryzae is expected to be a potential host for the production of glycoprotein with a genetically altered sugar chain.

Cloning and expression of 1,2-alpha-mannosidase gene (fmanIB) from filamentous fungus Aspergillus oryzae: in vivo visualization of the FmanIBp-GFP fusion protein.

1,2-alpha-Mannosidase catalyzes the specific cleavage of 1,2-alpha-mannose residues from protein-linked N-glycan. In this study, a novel DNA sequence homologous to the authentic 1,2-alpha-mannosidase was cloned from a cDNA library prepared from solid-state cultured Aspergillus oryzae. The fmanIB cDNA consisted of 1530 nucleotides and encoded a protein of 510 amino acids in which all consensus motifs of the class I alpha-mannosidase were conserved. Expression of the full length of 1,2-alpha-mannosidase cDNA by the Aspergillus host, though it has rarely been done with other filamentous-fungal mannosidase, was successful with fmanIB and caused an increase in both intracellular and extracellular mannosidase activity. The expressed protein (FmanIBp) specifically hydrolyzed 1,2-alpha-mannobiose with maximal activity at a pH of 5.5 and a temperature of 45 degrees C. With Man(9)GlcNAc(2) as the substrate, Man(5)GlcNAc(2) finally accumulated while hydrolysis of the 1,2-alpha-mannose residue of the middle branch was rate-limiting. To examine the intracellular localization of the enzyme, a chimeric protein of FmanIBp with green fluorescent protein was constructed. It showed a dotted fluorescence pattern in the mycelia of Aspergillus, indicative of the localization in intracellular vesicles. Based on these enzymatic and microscopic results, we estimated that FmanIBp is a fungal substitute for the mammalian Golgi 1,2-alpha-mannosidase isozyme IB. This and our previous report on the presence of another ER-type mannosidase in A. oryzae (Yoshida et al., 2000) support the notion that the filamentous fungus has similar steps of N-linked glycochain trimming to those in mammalian cells.

Current hair mercury levels in Japanese: survey in five districts.

To understand the current Japanese hair mercury levels, we planned a survey of hair mercury among the general populations of different regions in Japan. The present paper, as the first report of the survey, summarized the results obtained in five districts, Minamata, Kumamoto, Tottori, Wakayama and Chiba. Hair samples were collected at beauty salons, barbershops and primary schools in each district with questionnaires on age, sex, amount and species of fish usually consumed, hair-dyed and artificial hair waving "permanent wave." The total mercury levels of 3686 hair samples collected were analyzed by an oxygen combustion-gold amalgamation method. The geometric mean of the total mercury concentration was significantly higher in males than in females, i.e., 2.55 microg/g and 1.43 microg/g, respectively. The sex difference was also observed on hair samples without artificial waving, i.e., 2.64 microg/g and 1.64 microg/g, respectively. The geometric mean in each district varied from 2.23 to 4.79 microg/g for males and from 1.23 to 2.50 microg/g for females. The average hair mercury levels were highest in Chiba among the five districts both in males and females. A multiple regression analysis revealed a significant correlation of the mercury level with age, sex, amount of daily fish consumption, tuna and bonito as usually consumed fish, artificial waving and Chiba as a residential area. In the laboratory experiment, we found that the treatment of hair samples with a lotion for artificial waving caused a 30%-reduction in the mercury content. Furthermore, longitudinal hair analysis showed a marked difference in the concentration between the hair root and the tip of the hair taken from artificially waved females; higher values were observed at the hair root. These results suggested that artificial waving significantly removes hair mercury and that hair analysis at the hair root should be necessary to estimate an accurate methylmercury exposure for waved persons.