Summary In order to investigate the effects of collagen peptide ingestion on fibroblasts and the extracellular matrix in the dermis, collagen peptide was administered orally to pigs at 0.2 g/kg body weight/d for 62 d, and its effects were compared with those of lactalbumin and water controls. Fibroblast density, and diameter and density of collagen fibrils were significantly larger in the collagen peptide group than in the lactalbumin and water control groups. The two major components of dermal glycosaminoglycans, hyaluronic acid and dermatan sulfate, which are present in the inter-fibrillar space, did not differ significantly among the three groups. However, the ratio of dermatan sulfate, which is derived from fibrilbound decorin, was largest in the collagen peptide group. These results suggest that ingestion of collagen peptide induces increased fibroblast density and enhances formation of collagen fibrils in the dermis in a protein-specific manner. Key Words collagen peptide, dermis, collagen fibril, glycosaminoglycan, electron microscopyThe skin is the largest organ in the human body and protects the body from various external insults. Skin comprises two layers, the epidermis and the dermis, consisting of stratified squamous epithelium and connective tissues, respectively. The dermis contains large amounts of extracellular matrix (ECM) components, such as collagen and glycosaminoglycans (GAG), mainly produced by fibroblasts ( 1 ). Collagen is the most abundant protein in the vertebrate body, comprising approximately 30% of the total protein. To date, over 20 types of collagen genes have been identified, and these are divided into three groups: fibrous collagen, fibrilassociated collagen and basement membrane collagen ( 2 ). In the dermis, type I collagen forms collagen fibrils that are further organized into collagen fibers in association with other types of fibrous or fibril-associated collagen ( 3 ). The size of collagen fibrils is an important factor that determines the physical nature of tissue, as collagen fibrils/fibers form the framework of the vertebrate body ( 4 ). The size of collagen fibrils varies depending on tissue type and physiological conditions ( 5 ). Their diameters are reportedly regulated, for example, by the content of collagen types III or V or other types of non-fibrous collagen. Rates of synthesis and degradation of collagen also probably determine the size of collagen fibrils ( 6 , 7 ).GAG consists of repeating two-sugar units and, with the exception of hyarulonic acid (HA), exists in tissue as proteoglycans that form covalent bonds with core proteins ( 8 ). The dermatan sulfate (DS) proteoglycan decorin is located on the surface of collagen fibrils and regulates their size ( 9 ). On the other hand, HA is highly hydrophilic and forms a gel with large amounts of water, playing a role in resisting external mechanical stresses ( 8 , 10 ). The change in the ratio of HA affects the diameter of the collagen fibrils ( 11 ). Thus, the size of collagen fibrils and the amount of GAG, such as ...

This article describes an advanced learning technology used to investigate hypotheses about learning by teaching. The proposed technology is an instance of a teachable agent, called SimStudent, that learns skills (e.g., for solving linear equations) from examples and from feedback on performance. SimStudent has been integrated into an online, gamelike environment in which students act as “tutors” and can interactively teach SimStudent by providing it with examples and feedback. We conducted 3 classroom “in vivo” studies to better understand how and when students learn (or fail to learn) by teaching. One of the strengths of interactive technologies is their ability to collect detailed process data on the nature and timing of student activities. The primary purpose of this article is to provide an in-depth analysis across 3 studies to understand the underlying cognitive and social factors that contribute to tutor learning by making connections between outcome and process data. The results show several key cognitive and social factors that are correlated with tutor learning. The accuracy of students’ responses (i.e., feedback and hints), the quality of students’ explanations during tutoring, and the appropriateness of tutoring strategy (i.e., problem selection) all positively affected SimStudent’s learning, which further positively affected students’ learning. The results suggest that implementing adaptive help for students on how to tutor and solve problems is a crucial component for successful learning by teaching.

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11-0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

Background: Several clinical studies have indicated the efficacy of cilostazol, a selective inhibitor of phosphodiesterase 3, in preventing cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). They were not double-blinded trial resulting in disunited results on assessment of end points among the studies. The randomized, double-blind, placebo-controlled study was performed to assess the effectiveness of cilostazol on cerebral vasospasm. Methods: Patients with aneurysmal SAH admitted within 24 h after the ictus who met the following criteria were enrolled in this study: SAH on CT scan was diffuse thick, diffuse thin, or local thick, Hunt and Hess score was less than 4, administration of cilostazol or placebo could be started within 48 h of SAH. Patients were randomly allocated to placebo or cilostazol after repair of a ruptured saccular aneurysm by aneurysmal neck clipping or endovascular coiling, and the administration of cilostazol or placebo was continued up to 14 days after initiation of treatment. The primary end point was the occurrence of symptomatic vasospasm (sVS), and secondary end points were angiographic vasospasm (aVS) evaluated on digital subtraction angiography, vasospasm-related new cerebral infarction evaluated on CT scan or MRI, and clinical outcome at 3 months of SAH as assessed by Glasgow Outcome Scale, in which poor outcome was defined as severe disability, vegetative state, and death. All end points were evaluated with blinded assessment. Results: One hundred forty eight patients were randomly allocated to the cilostazol group (n = 74) or the control group (n = 74). The occurrence of sVS was significantly lower in the cilostazol group than in the control group (10.8 vs. 24.3%, p = 0.031), and multiple logistic analysis showed that cilostazol use was an independent factor reducing sVS (OR 0.293, 95% CI 0.099-0.568, p = 0.027). The incidence of aVS and vasospasm-related cerebral infarction were not significantly different between the groups. Poor outcome was significantly lower in the cilostazol group than in the control group (5.4 vs. 17.6%, p = 0.011), and multiple logistic analyses demonstrated that cilostazol use was an independent factor that reduced the incidence of poor outcome (OR 0.221, 95% CI 0.054-0.903, p = 0.035). Severe adverse events due to cilostazol administration did not occur during the study period. Conclusions: Cilostazol administration is effective in preventing sVS and improving outcomes without severe adverse events. A larger-scale study including more cases was necessary to confirm this efficacy of cilostazol.

SimStudent is a machine-learning agent initially developed to help novice authors to create cognitive tutors without heavy programming. Integrated into an existing suite of software tools called Cognitive Tutor Authoring Tools (CTAT), SimStudent helps authors to create an expert model for a cognitive tutor by tutoring SimStudent on how to solve problems. There are two different ways to author an expert model with SimStudent. In the context of Authoring by Tutoring, the author interactively tutors SimStudent by posing problems to SimStudent, providing feedback on the steps performed by SimStudent, and also demonstrating steps as a response to SimStudent's hint requests when SimStudent cannot perform steps correctly. In the context of Authoring by Demonstration, the author demonstrates solution steps, and SimStudent attempts to induce underlying domain principles by generalizing those worked-out examples. We conducted evaluation studies to investigate which authoring strategy better facilitates authoring and found two key results. First, the expert model generated with Authoring by Tutoring is better and has higher accuracy while maintaining the same level of completeness than the one generated with Authoring by Demonstration. The reason for this better accuracy is that the expert model generated by tutoring benefits from negative feedback provided for SimStudent's incorrect production applications. Second, authoring by Tutoring requires less time than Authoring by Demonstration. This enhanced authoring efficiency is partially because (a) when Authoring by Demonstration, the author needs to test the quality of the expert model, whereas the formative assessment of the expert model is done naturally by