Japan Patent Office

Graphene and graphene oxide have attracted tremendous interest over the past decade due to their unique and excellent electronic, optical, mechanical, and chemical properties. This review focuses on the functional modification of graphene and graphene oxide. First, the basic structure, preparation methods and properties of graphene and graphene oxide are briefly described. Subsequently, the methods for the reduction of graphene oxide are introduced. Next, the functionalization of graphene and graphene oxide is mainly divided into covalent binding modification, non-covalent binding modification and elemental doping. Then, the properties and application prospects of the modified products are summarized. Finally, the current challenges and future research directions are presented in terms of surface functional modification for graphene and graphene oxide.

Among various studies reporting the outcome of surgical repairs of rotator cuff tears, comparisons are very difficult because of the absence of a classification system. A proposed classification system takes into account the extent of the tear, its topography in the sagittal and frontal planes, the trophic quality of the muscle, and the integrity of the long head of the biceps. The new classification system exploits the advances in diagnostic imaging and is useful in the assessment of nonoperatively treated patients.

Inflammatory processes are now recognized to play a central role in the pathogenesis of atherosclerosis and its complications. Plasma levels of several markers of inflammation have been found to be associated with future cardiovascular risk in a variety of clinical settings. These markers include cell adhesion molecules, cytokines, pro-atherogenic enzymes and C-reactive protein (CRP). Initially thought of as an inactive downstream marker of the inflammatory cascade, emerging evidence suggests that CRP may be directly involved in atherogenesis, and that arterial plaque can produce CRP, independent of traditional hepatic pathways. In addition to being a strong predictor of future cardiovascular risk amongst patients presenting with acute coronary syndromes, numerous studies have found that baseline levels of CRP are associated with risk of future myocardial infarction, stroke, peripheral vascular disease and cardiovascular death amongst apparently healthy populations. The combination of measurement of a marker of inflammation with lipid testing may improve upon risk stratification based on lipid testing alone, and intensification of programmes for exercise, weight loss, and smoking cessation is recommended for those with elevated CRP levels. Further trials are needed to confirm the potential benefits of statins amongst individuals with elevated CRP levels.

BACKGROUND: Central venous catheters are a principal source of nosocomial bloodstream infections, which are difficult to control. OBJECTIVE: To determine the efficacy of catheters coated with minocycline and rifampin in preventing catheter-related colonization and bloodstream infections. DESIGN: Multicenter, randomized clinical trial. SETTING: Five university-based medical centers. PATIENTS: 281 hospitalized patients who required 298 triple-lumen, polyurethane venous catheters. INTERVENTION: 147 catheters were pretreated with tridodecylmethyl-ammonium chloride and coated with minocycline and rifampin. Untreated, uncoated catheters (n = 151) were used as controls. MEASUREMENTS: Quantitative catheter cultures, blood cultures, and molecular typing of organisms to determine catheter-related colonization and bloodstream infections. RESULTS: The group with coated catheters and the group with uncoated catheters were similar with respect to age, sex, underlying diseases, degree of immunosuppression, therapeutic interventions, and risk factors for catheter infections. Colonization occurred in 36 (26%) uncoated catheters and 11 (8%) coated catheters (P < 0.001). Catheter-related bloodstream infection developed in 7 patients (5%) with uncoated catheters and no patients with coated catheters (P < 0.01). Multivariate logistic regression analysis showed that coating catheters with minocycline and rifampin was an independent protective factor against catheter-related colonization (P < 0.05). No adverse effects related to the coated catheters or antimicrobial resistance were seen. An estimate showed that the use of coated catheters could save costs. CONCLUSIONS: Central venous catheters coated with minocycline and rifampin can significantly reduce the risk for catheter-related colonization and bloodstream infections. The use of these catheters may save costs.

Empirical work on the causes and effects of inventive activity has had difficulty in finding measures that can indicate when and where changes in either inventive inputs or inventive output have occurred. The recent computerization of the U.S. Patent Office's data base may prove helpful in this context, but there is the problem that a priori we do not know the relationships between patent applications and economically meaningful measures of these inputs and outputs. To help solve this problem, this paper investigates the dynamic relationships among the number of successful patent applications of firms, a measure of the firm's investment in inventive activity (its R &amp; D expenditures),\tand an indicator of its inventive output (the stock market value of the firm).

Abstract The oxidation of olefins to carbonyl compounds with palladium compounds, especially the oxidation of ethylene to acetaldehyde, is at present carried out on a technical scale. The reaction takes place via a palladium‐olefin complex, the formation of which is inhibited by halide ions. Hydrolysis to the carbonyl compound is inhibited by hydrogen ions. The knowledge gained by studying the reaction of olefins with pure solutions of palladium salts allows important conclusions to be drawn concerning the action of technical catalyst solutions containing copper and palladium chloride.

Bariatric surgery is recognized as the most clinically and cost-effective treatment for people with severe and complex obesity. Many people presenting for surgery have pre-existing low vitamin and mineral concentrations. The incidence of these may increase after bariatric surgery as all procedures potentially cause clinically significant micronutrient deficiencies. Therefore, preparation for surgery and long-term nutritional monitoring and follow-up are essential components of bariatric surgical care. These guidelines update the 2014 British Obesity and Metabolic Surgery Society nutritional guidelines. Since the 2014 guidelines, the working group has been expanded to include healthcare professionals working in specialist and non-specialist care as well as patient representatives. In addition, in these updated guidelines, the current evidence has been systematically reviewed for adults and adolescents undergoing the following procedures: adjustable gastric band, sleeve gastrectomy, Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch. Using methods based on Scottish Intercollegiate Guidelines Network methodology, the levels of evidence and recommendations have been graded. These guidelines are comprehensive, encompassing preoperative and postoperative biochemical monitoring, vitamin and mineral supplementation and correction of nutrition deficiencies before, and following bariatric surgery, and make recommendations for safe clinical practice in the U.K. setting.

Recent technologic advancements have enabled the creation of portable, low-cost, and unobtrusive sensors with tremendous potential to alter the clinical practice of rehabilitation. The application of wearable sensors to track movement has emerged as a promising paradigm to enhance the care provided to patients with neurologic or musculoskeletal conditions. These sensors enable quantification of motor behavior across disparate patient populations and emerging research shows their potential for identifying motor biomarkers, differentiating between restitution and compensation motor recovery mechanisms, remote monitoring, telerehabilitation, and robotics. Moreover, the big data recorded across these applications serve as a pathway to personalized and precision medicine. This article presents state-of-the-art and next-generation wearable movement sensors, ranging from inertial measurement units to soft sensors. An overview of clinical applications is presented across a wide spectrum of conditions that have potential to benefit from wearable sensors, including stroke, movement disorders, knee osteoarthritis, and running injuries. Complementary applications enabled by next-generation sensors that will enable point-of-care monitoring of neural activity and muscle dynamics during movement also are discussed.

BACKGROUND: Our objectives were to compare the effects of subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD) on cerebral blood flow (CBF), and then to analyze the relationship between CBF and subcortical vascular disease, measured as volume of white-matter lesions (WMLs). METHODS: Eight mildly demented patients with SIVD (mean +/- SD; aged 77 +/- 8 years; Mini-Mental State Examination score 26 +/- 3 years) and 14 patients with AD were compared with 18 cognitively normal elderly subjects. All subjects had CBF measured using arterial spin-labeling magnetic resonance imaging, and brain volumes were assessed using structural magnetic resonance imaging. RESULTS: AD and SIVD showed marked CBF reductions in the frontal (P = 0.001) and parietal (P = 0.001) cortices. In SIVD, increased subcortical WMLs were associated with reduced CBF in the frontal cortex (P = 0.04), in addition to cortical atrophy (frontal, P = 0.05; parietal, P = 0.03). CONCLUSIONS: Subcortical vascular disease is associated with reduced CBF in the cortex, irrespective of brain atrophy.

A mechanistic hypothesis for the origin of the three domains of life is proposed. A population of evolving pre-cells is suggested to have had a membrane of a racemate of chiral lipids that continuously underwent spontaneous symmetry breaking by spatial phase segregation into two enantiomerically enriched membrane domains. By frequent pre-cell fusions and fissions these membrane domains became partitioned between two pre-cell subpopulations having predominantly one lipid enantiomer or the other. The origin of the Bacteria and Archaea is explained by divergence of first a population of proto-bacteria and later a population of proto-archaea from the evolving pre-cells, each by the emergence of an enantio-selective lipid biosynthesis within the corresponding pre-cell subtype. The origin of the Eukarya is explained by symbiosis between a population of Bacteria and a subpopulation of pre-cells with a predominance of the bacteria-type lipid enantiomers.

OBJECTIVES: To test the feasibility of a randomised trial in muscle-invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy. PATIENTS AND METHODS: SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2-3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non-responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non-inferiority of SBP in terms of overall survival (OS) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient-reported quality of life, clinician assessed toxicity, loco-regional recurrence-free survival, and rate of salvage RC after SBP. RESULTS: Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC; 20 SBP). Non-compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT. Long-term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups. CONCLUSIONS: Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn.

OBJECTIVE: The pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium. METHODS: Age-matched knee SF samples from 10 control subjects, 10 patients with early-stage OA, and 10 patients with late-stage OA were compared using 2-dimensional difference-in-gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles. RESULTS: Sixty-six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome. CONCLUSION: Proteins involved in the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted.

Abstract Thraustochytrids, marine protists whose dominant genera are Thraustochytrium and Schizochytrium , belong to the kingdom Chromista and are known as an industrial source of DHA. We describe here that thraustochytrid strain KH105, isolated as a DHA producer, also accumulates significant levels of β‐carotene and xanthophylls including canthaxanthin and astaxanthin. A4‐d cultivation using a medium composed of 10% glucose and less than 0.3% of nitrogen sources in a half‐concentration of seawater gave an astaxanthin production up to 6.1 mg/L, and canthaxanthin content reached more than 10 mg/L under conditions where a higher concentration of nitrogen sources (6%) was employed. It might be advantageous in mass production systems for these carotenoids to be extracted readily by simply suspending the cells with organic solvents such as acetone and chloroform. Analyses on the morphological and life history features of the KH105 strain revealed that it belongs to the genus Schizochytrium . This particular species of thraustochytrids is thus considered to be a promising source of xanthophylls as well as DHA for use in the food industry.

The eye is on the one hand dependent on visible light energy and on the other hand can be damaged by these and the contiguous ultraviolet (UV) and infrared wavelengths. Diseases of the eye in which sunlight has been implicated have been termed the ophthalmohelioses, and these conditions pose a significant problem to the eye health of many communities. The ophthalmohelioses have a tremendous impact on patients' quality of life and have significant implications on the cost of health care. Although cataract is not entirely caused by insolation, it now seems certain that sunlight plays a contributory role-cataract extraction is one of the, if not the most, commonly performed surgical procedures in many societies. Pterygium, typically afflicting a younger population, adds a tremendous burden, both human and financial, in many countries. We review evidence that peripheral light focusing by the anterior eye to the sites of usual locations of pterygium and cataract plays a role in the pathogenesis of these conditions. Recognition of the light pathways involved with foci at stem cell niches has directed our investigations into inflammatory and matrix metalloproteinase-related pathophysiologic mechanisms. An understanding of the intracellular mechanisms involved has provided some insight into how medical treatments have been developed for the effective management of ocular surface squamous neoplasia. The concept of peripheral light focusing has also provided direction in the prevention of these diseases. This has resulted in improved sunglass design and the further development of UV-blocking contact lenses. With the development of ocular UV fluorescence photographic techniques, we have been able to demonstrate preclinical ocular surface evidence of solar damage. Evidence that diet may play a role in the development of certain conditions is reviewed. The conundrum of the public health message about solar exposure is also reviewed, and in this context, the potential role of vitamin D deficiency is summarized. The eye may play a role in the development of individualized assessment techniques of solar damage, perhaps allowing us to provide better advice to both individuals and populations.

OBJECTIVE: To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α-enolase is mediated by Porphyromonas gingivalis enolase in the context of DR4 alleles. METHODS: Recombinant human α-enolase and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4-IE-transgenic mice and control mice (class II major histocompatibility complex-deficient [class II MHC(-/-)] and C57BL/6 wild-type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α-enolase and citrullinated α-enolase was assayed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α-enolase (CEP-1) and its arginine-bearing control peptide, REP-1, were also assessed by ELISA. RESULTS: Significant hind-ankle swelling (≥0.3 mm) occurred in DR4-IE-transgenic mice immunized with citrullinated human α-enolase (9 of 12 mice), uncitrullinated human α-enolase (9 of 12 mice), citrullinated P gingivalis enolase (6 of 6 mice), and uncitrullinated P gingivalis enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α-enolase, both citrullinated and unmodified, and to CEP-1 and REP-1 were detectable in all immunized mice except the class II MHC(-/-) control mice. CONCLUSION: This is the first animal model that links an immune response to P gingivalis enolase to an important subset of RA, defined by antibodies to citrullinated α-enolase in the context of DR4. The fact that arthritis and anti-CEP-1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α-enolase may be important in initiating the corresponding subset of human RA.

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall.

BACKGROUND: Data suggest that vitamin D plays a role in the treatment and prevention of prostate cancer. The combination of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) plus dexamethasone was studied based on evidence that dexamethasone potentiates the antitumor effects of calcitriol and ameliorates hypercalcemia. METHODS: Oral calcitriol was administered weekly, Monday, Tuesday, and Wednesday (MTW), at a dose of 8 microg, for 1 month, at a dose of 10 microg every MTW for 1 month, and at a dose of 12 microg every MTW thereafter. Dexamethasone at a dose of 4 mg was administered each Sunday, and MTW weekly. Calcium and creatinine were determined weekly and radiographs of the urinary tract were performed every 3 months. All patients were considered evaluable for toxicity. RESULTS: Forty-three men with androgen-independent prostate cancer were entered; 37 received at least 1 month of calcitriol given at a dose of 12 microg every day x 3 per week. The majority of patients had bone metastases and rising prostate-specific antigen (PSA) levels. All had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eight patients (19%) experienced partial responses by PSA criterion (PSA decline of > or =50%, persisting for > or = 28 days). Subjective clinical improvement occurred in some patients. Toxicity was minimal: urinary tract stones in 2 patients; and a readily reversible, CTC (v.3.0) Grade <2 creatinine increase in 4 patients. Throughout the study only 4 patients ever had a serum calcium level >11.0 mg/dL and no patient had a calcium level >12.0 mg/dL. CONCLUSIONS: The response rate reported in the current study (19%) was not found to be clearly higher than expected with dexamethasone alone. High-dose intermittent calcitriol plus dexamethasone appears to be safe, feasible, and has antitumor activity.

BACKGROUND: The authors developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. The strategy was evaluated initially to provide localized and sustained delivery of the radiosensitizer 5-fluorouracil (5-FU) after patients underwent surgical resection of malignant glioma. In this study, the microspheres were implanted by stereotaxy into deeply situated and inoperable brain tumors. METHODS: Ten patients with newly diagnosed, inoperable, malignant gliomas were included in the study, and 1 dose of 5-FU was studied (132 mg). After histologic confirmation, a suspension of poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres was implanted by stereotaxy into the tumor in one or several trajectories with one to seven deposits per trajectory. External beam radiation (59.4 grays) was started before postoperative Day 7. Patients were followed by clinical examination, computed tomography scanning, magnetic resonance imaging, and 5-FU assays in blood and cerebrospinal fluid (CSF). RESULTS: The number of trajectories was adapted to the size and shape of the tumor. Microsphere implantation was tolerated well, except in four patients who received a single trajectory and experienced a transitory worsening of preexisting neurologic symptoms. There were no episodes of edema or hematologic complications. 5-FU was detected in CSF and blood in some patients at very low concentrations. The median overall survival was 40 weeks, with 2 patients who had longer survival (71 weeks and 89 weeks, respectively). CONCLUSIONS: In this study, the authors demonstrated that biodegradable microspheres could be implanted by stereotaxy and were efficient systems for drug delivery into brain tumors. This method may have future applications in the treatment of patients other malignancies.

Microseisms are a continuous source of seismic signal which mainly consist of Rayleigh waves but are known to contain some other types of seismic waves. We developed a simple processing procedure for single-station three-component seismic data which allows us to select Rayleigh-wave dominated portions. Application of this procedure to data from Southern California led us to confirm that excitation of the secondary-peak microseisms (the predominant energy at about 0.15 Hz) occurs in coastal regions; the source directions, viewed at each station, do not change very much throughout the year. We also discovered that the ratio of the horizontal to vertical amplitudes in Rayleigh waves, termed H/Z in this paper, is shown to have seasonal variations. The H/Z estimates typically reach their maximum in winter and their minimum in summer. Seasonal variations are observed at most stations but peak-to-peak amplitudes of seasonal variations vary greatly from station to station, ranging between 0 and 40 per cent. Two hypotheses were examined to explain this phenomenon; the first hypothesis is that it is caused by seasonal changes in seismic velocities in a layer between the surface and the groundwater level. The second hypothesis is that it is caused by seasonal changes in relative excitation of higher modes compared to dominant fundamental-mode Rayleigh waves. The first hypothesis is not likely, because predicted amplitudes of seasonal variations in H/Z are too small to explain observed variations. The second hypothesis seems quite plausible if source regions move seasonally among regions with different ocean depths. The technique developed in this paper, however, is not sufficient to answer this question conclusively.

Melatonin is a natural substance ubiquitous in distribution and present in almost all species ranging from unicellular organisms to humans. In mammals, melatonin is synthesized not only in the pineal gland but also in many other parts of the body, including the eyes, bone marrow, gastrointestinal tract, skin and lymphocytes. Melatonin influences almost every cell and can be traced in membrane, cytoplasmic, mitochondrial and nuclear compartments of the cell. The decline in the production of melatonin with age has been suggested as one of the major contributors to immunosenescence and development of neoplastic diseases. Melatonin is a natural antioxidant with immunoenhancing properties. T-helper cells play an important role for protection against malignancy and melatonin has been shown to enhance T-helper cell response by releasing interleukin-2, interleukin-10 and interferon-γ. Melatonin is effective in suppressing neoplastic growth in a variety of tumors like melanoma, breast and prostate cancer, and ovarian and colorectal cancer. As an adjuvant therapy, melatonin can be beneficial in treating patients suffering from breast cancer, hepatocellular carcinoma or melanoma. In this paper, a brief review of recent patents on melatonin and cancer has also been presented.