Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 g/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 ؎ 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 ؎ 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRPcontaining neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach. Diabetes 50:2438 -2443, 2001 E nergy intake and expenditure are tightly regulated in mammals (1). Several neuronal populations, particularly in the hypothalamic arcuate nucleus (ARC), are involved in the regulation of energy homeostasis and have been implicated as possible targets of orexigenic peptides (1). These include neuropeptide Y (NPY)/agouti-related protein (AGRP) coexpressing neurons, pro-opiomelanocortin (POMC) neurons, and growth hormone-releasing hormone (GHRH) neurons, which are known to be stimulated (NPY and AGRP) or suppressed (POMC and GHRH) by starvation (2-10). However, central administration of NPY, AGRP, and GHRH increased food intake in rats, whereas ␣-melanocyte-stimulating hormone (␣-MSH), an end product of POMC processing, decreased food intake when injected centrally (11-13).The growth hormone secretagogues (GHSs) are synthetic peptide and nonpeptide compounds that stimulate the pulsatile release of growth hormone (GH) after intravenous administration (14). Central administration of GHSs also stimulates feeding behavior (15). GHS receptor (GHS-R) mRNA is expressed in the pituitary gland and in several areas of the brain, including the hypothalamus (16). In the hypothalamus, GHS-R mRNA is expressed in NPY/AGRP-, POMC-, and GHRH-containing neurons (17)(18)(19). Ghrelin, an end...

For many antibodies, each antigen-binding site binds to only one antigen molecule during the antibody's lifetime in plasma. To increase the number of cycles of antigen binding and lysosomal degradation, we engineered tocilizumab (Actemra), an antibody against the IL-6 receptor (IL-6R), to rapidly dissociate from IL-6R within the acidic environment of the endosome (pH 6.0) while maintaining its binding affinity to IL-6R in plasma (pH 7.4). Studies using normal mice and mice expressing human IL-6R suggested that this pH-dependent IL-6R dissociation within the acidic environment of the endosome resulted in lysosomal degradation of the previously bound IL-6R while releasing the free antibody back to the plasma to bind another IL-6R molecule. In cynomolgus monkeys, an antibody with pH-dependent antigen binding, but not an affinity-matured variant, significantly improved the pharmacokinetics and duration of C-reactive protein inhibition. Engineering pH dependency into the interactions of therapeutic antibodies with their targets may enable them to be delivered less frequently or at lower doses.

Aim:To develop a simple screening test to identify older adults at high risk for sarcopenia. Methods:We studied 1971 functionally independent, community-dwelling adults aged 65 years or older randomly selected from the resident register of Kashiwa city, Chiba, Japan. Data collection was carried out between September and November 2012. Sarcopenia was defined based on low muscle mass measured by bioimpedance analysis and either low muscle strength characterized by handgrip or low physical performance characterized by slow gait speed. Results:The prevalence of sarcopenia was 14.2% in men and 22.1% in women. After the variable selection procedure, the final model to estimate the probability of sarcopenia included three variables: age, grip strength and calf circumference. The area under the receiver operating characteristic curve, a measure of discrimination, of the final model was 0.939 with 95% confidence interval (CI) of 0.918-0.958 for men, and 0.909 with 95% CI of 0.887-0.931 for women. We created a score chart for each sex based on the final model. When the sum of sensitivity and specificity was maximized, sensitivity, specificity, and positive and negative predictive values for sarcopenia were 84.9%, 88.2%, 54.4%, and 97.2% for men, 75.5%, 92.0%, 72.8%, and 93.0% for women, respectively. Conclusions:The presence of sarcopenia could be detected using three easily obtainable variables with high accuracy. The screening test we developed could help identify functionally independent older adults with sarcopenia who are good candidates for intervention. Geriatr Gerontol Int 2014; 14 (Suppl. 1): 93-101.

New lists of potentially inappropriate medications and potential prescribing omissions called "Screening Tool for Older Person's Appropriate Prescriptions for Japanese" were constructed. We anticipate that future studies will highlight more evidence regarding the safety of high-quality drugs, further improving the provision of appropriate medical care for the elderly. Geriatr Gerontol Int 2016: 16: 983-1001.