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Objective Assess patient characteristics, real-world treatment patterns, and health care resource utilization (HCRU) among patients with psoriatic arthritis (PsA) in Japan. Methods Patients diagnosed with PsA from April 2009 through July 2017 were identified from the Medical Data Vision database. Patient characteristics, treatment patterns, and HCRU were evaluated for these patients. Results A total of 639 patients met inclusion criteria and were included in the analysis for patients with a PsA diagnosis. Over 12 months following diagnosis, patients received oral NSAIDs (61.7%), conventional synthetic disease-modifying antirheumatic drugs (DMARDs) (55.1%), corticosteroids (35.1%), topical NSAIDs (34.0%), adalimumab (14.7%), infliximab (9.7%), secukinumab (5.0%), ustekinumab (4.5%), ixekizumab (1.6%), and golimumab (1.6%). A total of 227 (35.5%) patients initiated biologic DMARDs (bDMARDs) over the median 25.2 months of study follow-up. Compared with the overall group of patients diagnosed with PsA, patients who initiated bDMARDs had higher median total per-patient health care costs ($27,772 vs. $11,316), lower median per-patient hospitalization costs ($31,164 vs. $39,359), and fewer median hospital days per admission (8.0 vs. 12.0 days). Conclusion This study presents knowledge of the current state of patient characteristics, treatment patterns, HCRU, and costs among patients with PsA in Japan. Considering the relatively recent guideline recommendations, the preliminary treatment patterns suggest physicians may be following treatment guidelines.

Chinese hamster ovary (CHO) cells have frequently been used in biotechnology as a mammalian host cell platform for expressing genes of interest. Previously, we constructed a detailed physical chromosomal map of the CHO DG44 cell line by fluorescence in situ hybridization (FISH) imaging using 303 bacterial artificial chromosome (BAC) clones as hybridization probes (BAC-FISH). BAC-FISH results revealed that the two longest chromosomes were completely paired. However, other chromosomes featured partial deletions or rearrangements. In this study, we determined the end sequences of 303 BAC clones (BAC end sequences), which were used for BAC-FISH probes. Among 606 BAC-end sequences (BESs) (forward and reverse ends), 558 could be determined. We performed a comparison between all determined BESs and mouse genome sequences using NCBI BLAST. Among these 558 BESs, 465 showed high homology to mouse chromosomal sequences. We analyzed the locations of these BACs in chromosomes of the CHO DG44 cell line using a physical chromosomal map. From the obtained results, we investigated the regional similarities among CHO chromosomes (A–T) and mouse chromosomes (1–19 and sex) about 217 BESs (46.7% of 465 high homologous BESs). Twenty-three specific narrow regions in 13 chromosomes of the CHO DG44 cell line showed high homology to mouse chromosomes, but most of other regions did not show significant correlations with the mouse genome. These results contribute to accurate alignments of chromosomes of Chinese hamster and its genome sequence, analysis of chromosomal instability in CHO cells, and the development of target locations for gene and/or genome editing techniques. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10616-018-0233-5) contains supplementary material, which is available to authorized users.

Objectives This study aimed to identify factors associated with initiation and adherence of osteoporosis medication from a patient perspective. Methods A web-based survey was developed based on health behavior theories. Descriptive analyses were conducted for all survey items. Analyses in a structural equation modeling framework were conducted to identify factors associated with treatment initiation and adherence. Results Five hundred forty-five women completed the questionnaire. A majority were currently receiving medications for osteoporosis (n = 376, 69.0%) and 25.0% of these patients (n = 94) were considered adherent to their treatment. Knowledge was strongly associated with osteoporosis treatment initiation (standard error [SE], 0.58). Greater knowledge of disease was associated with increased likelihood of initiating medication. Medication complexity (SE, 0.49) and perceived susceptibility to fracture and loss of independence (SE, −0.37) were also associated with initiation. Perceived barriers (SE, −0.85) such as inconvenience, lack of efficacy and financial burden were observed to be the greatest obstacle to adherence. The greater the perceived barriers, the less likely patients were to adhere to medication. Patients' perception of self-efficacy (SE, 0.37) also affected adherence. The greater the patient perception of ability to independently manage their medication, the more likely they were to adhere to the medication. Conclusions Different factors were found to be associated with initiation and adherence of osteoporosis medication. Patient knowledge of their disease and the perception of barriers were found to be the most influential. Empowering patients with the knowledge to better understand their disease and decreasing the perception of barriers through education initiatives may be effective in improving patient outcomes.

The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients.In routine clinical practice, Japanese patients initiated on teriparatide 20 μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected.Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6-12 months, 51.6% during 12-18 months, and 58.8% during 18-24 months (all p .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals.JFOS demonstrated effectiveness of teriparatide 20 μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

The Spontaneously Diabetic Torii (SDT) fatty rat, a model for obese type 2 diabetes, shows bone quantitative abnormalities, namely low bone mineral density (BMD). The objective of this study was to evaluate bone morphological changes, in particular identifying the bone qualitative abnormalities, in the SDT fatty rat. Male SDT fatty rats showed increases in total trabecular area and trabecular number and decreases in trabecular thickness in cancellous bones of the proximal tibia, indicating trabecular miniaturization. The SDT fatty rat is useful for investigation of pathophysiological changes in bone quality in diabetic osteoporosis.

The Spontaneously Diabetic ToriiLeprfa(SDT fatty) rat is a novel type 2 diabetic model wherein both male and female rats develop glucose and lipid abnormalities from a young age. In this study, we investigated gender differences in abnormalities and related complications in SDT fatty rats. Food intake was higher in males compared to female rats; however, body weight was not different between genders. Progression of diabetes, including increases in blood glucose and declines in blood insulin, was observed earlier in male rats than in females, and diabetic grade was more critical in male rats. Blood lipids tended to increase in female rats. Gonadal dysfunction was observed in both male and female rats with aging. Microangiopathies, such as nephropathy, retinopathy, neuropathy, and osteoporosis, were seen in both genders, and pathological grade and progression were more significant in males. Qualitative and quantitative changes were observed for metabolic disease gender differences in SDT fatty rats. The SDT fatty rat is a useful model for researching gender differences in metabolic disorders and related diseases in diabetes with obesity.

Spontaneously Diabetic ToriiLeprfa(SDT fatty) rat, established by introducing thefaallele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, in SDT fatty rats were seen at younger ages compared to those in the SDT rats. In this paper, we overview pathophysiological features in SDT fatty rats and also describe new insights regarding the hematology, blood pressure, renal complications, and sexual dysfunction. The SDT fatty rats showed an increase of leukocytes, especially the monocyte count, prominent hypertension associated with salt drinking, end-stage renal disease with aging, and hypogonadism. Unlike other diabetic models, the characteristic of SDT fatty rat is to present an incidence of diabetes in females, hypertension, and retinopathy. SDT fatty rat is a useful model for analysis of various metabolic disorders and the evaluation of drugs related to metabolic disease.

Chromosome identification using Chinese hamster ovary (CHO) genomic bacterial artificial chromosome (BAC) clones has the potential to contribute to the analysis and understanding of chromosomal instability of CHO cell lines and to improve our understanding of chromosome organization during the establishment of recombinant CHO cells. Fluorescence in situ hybridization imaging using BAC clones as probes (BAC-FISH) can provide valuable information for the identification of chromosomes. In this study, we identified chromosomes and analyzed the chromosome rearrangement in CHO cells using BAC-FISH methods.

Chinese hamster ovary (CHO) cells have frequently been used in biotechnology for many years as a mammalian host cell platform for cloning and expressing genes of interest. A detailed physical chromosomal map of the CHO DG44 cell line was constructed by fluorescence in situ hybridization (FISH) imaging using randomly selected 303 BAC clones as hybridization probes (BAC-FISH). The two longest chromosomes were completely paired chromosomes; other chromosomes were partly deleted or rearranged. The end sequences of 624 BAC clones, including 287 mapped BAC clones, were analyzed and 1,119 informative BAC end sequences were obtained. Among 303 mapped BAC clones, 185 clones were used for BAC-FISH analysis of CHO K1 chromosomes and 94 clones for primary Chinese hamster lung cells. Based on this constructed physical map and end sequences, the chromosome rearrangements between CHO DG44, CHO K1, and primary Chinese hamster cells were investigated. Among 20 CHO chromosomes, eight were conserved without large rearrangement in CHO DG44, CHO K1, and primary Chinese hamster cells. This result suggested that these chromosomes were stable and essential in CHO cells and supposedly conserved in other CHO cell lines.

Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.

A novel peptide antibiotic, K-582, which exhibited significant growth inhibition of Candida, viruses and ascites tumor in mice, was found in the culture medium of a strain of Metarhizium anisopliae by Kondo et al. (J. Antibiotics33, 535–542 (1980)]. K-582 consisted of two components, designated K-582 A and K-582 B. Threonine, tyrosine, ornithine, and an unusual amino acid were common in both peptides, but lysine was an extra component of K-582 A. The unusual amino acid was identified to be threo-γ-hydroxy-L-arginine (OHArg) by means of mass, nuclear magnetic resonance and infrared spectrometries of the derivatives and the related compounds. The threonine and the arginine were assigned to be L-configuration, and the ornithine and the tyrosine to be D-configuration in both K-582 A and K-582 B, and the lysine to be L-configuration by comparison of their optical rotatory dispersion spectra with those of standard amino acids. The elucidation of primary structure revealed that they were closely related heptapeptides with the following sequence: K-582 A:H-Arg-OHArg-Orn-Thr-Orn-Lys-Tyr-OH; K-582 B:H-Arg-OHArg-Orn-Thr-Orn-OHArg-Tyr-OH, and had the identical sequence in terms of the configuration of their constituents, namely L-L-D-L-D-L-D.

This review assesses the feasibility of using glycemic index (GI) as a predictor of appetite, hunger and satiety by surveying published human intervention studies. We also discuss the relationship between GI and two appetite/satiety control hormones, leptin and ghrelin. Ingestion of high-GI food increased hunger and lowered satiety in short-term human intervention studies. This effect may be attributed to the rapid decline in blood glucose level following a hyperinsulinemic response caused by a sharp and transient increase in blood glucose level that occurs after the ingestion of high-GI food, which is defined as the glucostatic theory. However, appetite, hunger and satiety after the ingestion of foods with varying GI were inconsistent among long-term human intervention studies. From the few relevant long-term studies available, we selected two recent well-designed examples for analysis, but they failed to elicit clear differences in glycemic and insulinemic responses between high- and low-GI meals (consisting of a combination of different foods or key carbohydrate-rich foods incorporated into habitual diets). One of the reasons that these studies could not predict glycemic response to mixed meals is presumably that the GI of each particular food was not reflected in that of the mixed meals as a whole. Thus, it is difficult to conclude that the GI values of foods or mixed meals are a valid long-term predictor for appetite, hunger and satiety. Both insulin and insulin-mediated glucose uptake and metabolism in adipose tissue affect blood leptin concentration and its diurnal pattern. Circulating ghrelin level is suppressed by carbohydrate-rich meals, presumably via glycemia and insulinemia. Accordingly, low-GI foods may not necessarily increase satiety or suppress appetite and/or hunger because of the lack of insulin-mediated leptin stimulation and ghrelin suppression. However, insulin-mediated leptin stimulation and ghrelin suppression per se is not consistent among studies; thus we were not able to identify a clear relationship among GI, satietogenic leptin, and appetitic ghrelin.

The surface of carbonyl iron powder or a mixture of carbonyl iron and ferrite was coated with polymethylmethacrylate (PMMA) microspheres by a hybridization method to make hybrid powders, and then electromagnetic wave absorption properties of the hybrid composites prepared with these hybrid powders have been investigated. As for the carbonyl iron/PMMA hybrid composite, the reflection loss less than −20 dB could be achieved in a frequency range of 1.7–5.0 GHz when the composite thickness was below 5.00 mm. In the case of the carbonyl iron-ferrite/PMMA hybrid composite, a similar reflection loss was observed in a frequency range of 4.3–13.0 GHz. Thus, the addition of ferrite was found to be useful for achieving a large absorption in a wide frequency range, especially for higher frequency values. Simulated values for the minimum reflection loss are well agreed with actually measured ones, because of homogeneous distribution of carbonyl iron and/or ferrite in these hybrid composites.

Polystyrene (PS)-based hybrid particles containing a large amount of Mg(OH)2powder treated with methylhydrogen polysiloxane (MHS) were fabricated by a bulk and subsequent suspension two-step polymerization method. All the particles fabricated showed spherical shape and their particle sizes were about 500 μm, irrespective of the additive amount of the Mg(OH)2powder modified with MHS (ST-1). The actual content of ST-1 powder incorporated inside each kind of hybrid particle was almost the same as that in the raw mixture, and agglomeration of ST-1 powder was hardly observed inside the hybrid particles. The compressive strength of the hybrid particles remained almost unchanged, even when the ST-1 powder content increased from 10 to 50 phr. Furthermore, a composite fabricated by employing the hybrid particles achieved homogenous distribution of ST-1 powder and showed a higher oxygen index than that of a composite fabricated by directly mixing of PS pellets and ST-1 powder.

Autoimmune hepatitis represents a ubiquitous human health problem and has a poor prognosis. Dihydroquercetin (DHQ), a well-known antioxidant, significantly inhibits fulminant hepatitis through anti-oxidant and anti-inflammation mechanisms. In this study, we show that administration of DHQ ameliorated concanavalin A (ConA)-induced mouse liver injury by increasing the survival rate, reducing the serum ALT and AST level, preventing histopathological injuries and decreasing pro-inflammatory cytokine mRNA expression in hepatic tissue. As macrophages/Kupffer cells in oxidative stress and pro-inflammatory mediators play an important role in the pathogenesis of immune-mediated hepatitis, we further exposed mouse RAW264 macrophage cell lines to ConA in vitro and found that DHQ significantly inhibited mRNA expression and secretion of IFN-γ and TNF-α in cell culture supernatant. In addition, DHQ significantly enhanced heme oxygenase-1 (HO-1) expression in a dose- and time-dependent manner via increased Nrf2 expression in cytoplasm and nuclear translocation. Furthermore, DHQ enhanced phosphorylation of three members of the mitogen-activated protein kinase (MAPK) family, and cell treatment with MEK/ERK (PD98059), p38 (SB203580) and JNK (SP600125) inhibitors reduced DHQ-induced HO-1 expression. These results indicate that DHQ possesses hepatoprotective properties against ConA-induced liver injury, which are attributed to its ability to scavenge oxidative stress and to inhibit the release of inflammatory mediators via upregulation of HO-1 activity through the MAPK/Nrf2 signaling pathway in macrophages/Kupffer cells.

哺乳類の骨格筋や脳に多く含まれ,食肉中の機能性成分として注目されているヒスチジン含有ペプチド(カルノシン,アンセリン)の加齢に伴う筋肉含有量の変化を把握する目的で,2,8,18,40,50,60週令のマウスを用いて検討を行った。また,カルノシンを経口投与した影響も検討した。本研究により,マウス骨格筋中カルノシン量は,8週令のマウスに比較し50週令まで増加を示し,60週令では減少する傾向が観察された。また,40週令マウスの骨格筋におけるカルノシン経口投与の影響は観察されなかった。今後さらに週令の高い動物での検討やカルノシン投与量の検討が必要である。, Carnosine is a β-alanyl-L-histidine dipeptide and is found in skeletal muscle and nervous tissue at concentrations ranging from 1 to 25mM. The muscle food that has been postulated to be a bioactive food component contains this dipeptide. Some anti-aging effects of carnosine have also been demonstrated at the whole animal level. There is evidence that carnosine concentrations may decline with age in rodents and humans and the carnosine concentration in the muscles of short-lived species appears to be much lower than that in long-lived species. While carnosine has been detected in mouse muscle, very little is known about the changes of carnosine concentration with, age in detail and after intake of carnosine. Therefore, we investigated the age-related change of carnosine concentration in mouse muscle and the effects of carnosine intake. In this study, carnosine concentration in muscle was increased after birth and carnosine concentration in 60-week-old mice was slightly decreased. While the effects after intake of carnosine was not observed. Further studies should be performed to investigate the changes of carnosine concentration in more aged-mice and the effects after intake of carnosine.

Iron deficiency is one of the major nutritional problems in developing countries. Food fortification is assumed to be an effective method for enhancing iron absorption. Sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), a metal chelate, is one of the iron fortificants. It is a flavorless and inert compound. However, it is possible that EDTA may bind to metals other than iron and influence their absorption because of its strong chelating property. In this study, we determined the effect of NaFeEDTA on the absorption of various trace elements in the presence and absence of inhibitor using a multitracer technique. The multitracer is a carrier-free and salt-free solution containing a large number of radioactive nuclides. This method allows the simultaneous evaluation of behavior for a number of trace elements under strictly identical experimental conditions. As a result, incorporating NaFeEDTA into the rat diet did not lead to a deficiency in essential metals such as Zn, Mn, and Se in the presence of tannic acid. Furthermore, the uptake of various elements in the NaFeEDTA-fed rats is not inhibited by tannic acid. Thus, NaFeEDTA may be a suitable fortificant for improving iron-deficiency status in developing countries. Our findings in this study demonstrated that the multitracer technique provides us with many findings in nutritional research.

In the present study, we characterized diacylglycerol (DAG) oil in terms of energy metabolism by comparing oxygen consumption and respiratory quotient (RQ), as well as blood parameters, in rats after administration of emulsions containing either DAG or triacylglycerol (TAG) with similar fatty acid composition. Twelve male Wistar rats (250–280 g) were acclimatized, and then catheterized into the stomach, and held individually in Bollman restraining cages. After 24 hours fasting, each emulsion containing either DAG or TAG (10 g/kg body weight) was infused. Oxygen consumption and fat oxidation in the DAG group gradually increased after administration of the DAG emulsion and became significantly higher than those of the TAG group. RQ in both groups dropped after administration of emulsion, but the values of the DAG group were significantly lower than that of the TAG group. The postprandial serum triglyceride level was significantly increased from 60 minutes after administration in the TAG group, and 240 minutes in the DAG group, compared to the preprandial level. The serum triglyceride level tended to be lower in the DAG group than in the TAG group at 60 minutes and thereafter, and the statistical difference between the TAG and DAG groups was significant at 300 minutes after administration. These results suggest that DAG oil infusion might lead to higher energy expenditure and lipids oxidation compared to TAG oil with a similar fatty acid composition.

内因性抗酸化物カルノシンの神経細胞保護効果を検討する目的で,7週令及び40週令マウスを用いて,脳内海馬CA1領域における病理組織及び免疫組織化学的解析を行った。その結果,7週令マウスに比較し40週令マウスの海馬CA1領域では,神経細胞の脱落が観察され,eNOSやCu/Zn-SOD免疫染色性の増加も確認された。これに対し,40週令マウスに2週間のカルノシソ(100mg/kg)を投与した群では,40週令コントロールマウスにみられた神経細胞の脱落が抑制されたことが確認された。また,カルノシソ投与によるGFAP陽性アストロサイトの活性増大とCu/Zn-SOD活性抑制傾向が観察された。カルノシンはアストロサイトの活性化とfree radical scavenging機能により,海馬領域の神経細胞を保護することが示唆されるが,その詳細なメカニズム解明にあたってはさらなる検討が必要である。, Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide and is found in brain and other long-lived tissues of humans at concentrations as high as 20mM. It is demonstrated that carnosine has several functions, such as anti-ischemic activity, anti-glication effect and membrane-protecting properties. In this study, we investigated the effect of L-carnosine on age-related histopathological and immunohistochemical alteration in glial fibrillary acidic protein (GFAP), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) protein of the hippocampal CAl sector in 7- and 40-week old mice. Histopathological observations showed that neuronal change or hippocampal CA1 neurons, which was observed in 40-week old mice, was preserved by carnosine treatment. Immunohistochemical stainings for GFAP and nNOS were unchanged in 40-week old mice. However, immunohistochemical stainings for eNOS and Cu/Zn-SOD increased in hippocampal cells of 40-weeks old mice compared with 7-week old mice. Additionally, GFAP immunopositive cells in carnosine treatment mice were increased compared with 7-week old mice. From these observations, we suggest that carnosine is effective on age-related neurodegeneration of hippocampal CA1 sector.

Reports have shown that soybeans are goitrogenic. In the present study, we investigated the effects of a high soybean diet in rats that were fed normal or iodine-deficient chow on the regulation of anterior pituitary hormone production. Iodine deficiency alone resulted in thyroid hyperplasia, reduced serum thyroxine levels, and a tendency towards an increase in serum thyroid stimulating hormone (TSH). The combination of a high soybean and low iodine diet (ID + DS) acted synergistically to induce thyroid hypertrophy, reduce serum thyroxine and tri-iodothyronine, and markedly increase serum TSH. Immunohistochemical analysis revealed that rats fed the ID + DS diet exhibited a marked increase in their number of pituitary TSH, prolactin (PRL), and growth hormone (GH) producing cells. Pituitary transcription factor-1 (Pit-1) which is involved in the expression of the TSH, PRL, and GH genes was also increased in ID + DS fed rats. These results suggest that a diet high in soybean products modulates anterior pituitary hormone production by regulating Pit-1 induction, in iodine-deficient animals.

The effects of particle gel (PG) on the rheological properties of gellan gum gels were investigated. Samples were 1.2% gellan gum gels with 5 mM CaCl 2 (MG-CaCl 2 ) or without CaCl 2 (MG), to which various amounts a particle gel of 1.2% gellan gum containing 5 mM CaCl 2 (PG-CaCl 2 ) was added. Breaking stress and storage Young's modulus of MG containing PG-CaCl 2 increased with increased PG-CaCl 2 content, while those of MG-CaCl 2 containing PG-CaCl 2 decreased. PG-CaCl 2 behaved as an active filler in MG and as an inactive filler in MG-CaCl 2 . Activation of PG-CaCl 2 may be the result of interaction between calcium ions in the particles and carboxyl groups in the gellan gum molecules of the matrix.

Carbohydrates are global foodstuffs and important energy sources. They also influence many physiologic functions, including brain function and physical performance and are ultimately related to human health. In 1998, ILSI Japan formed a team to conduct research on "The Medical and Nutritional Aspects of Sugars." The research included studies of several new aspects of the metabolic characteristics and physiologic effects of sugars. This paper presents some highlights of our research, including the background of the project, the metabolic characteristics of sugars, and the effect of sugars on glycemic response, memory, and appetite and food intake in humans, etc.

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a model of obese type 2 diabetes, shows obesity, hyperglycaemia and low bone mineral density (BMD). The objective of this study is to evaluate the effects of parathyroid hormone (1-34) [PTH(1-34)] on BMD and glucose metabolism in the SDT-fa/fa rat. SDT-fa/fa rats showed obesity with hyperglycaemia and decreased serum osteocalcin levels and the tibial BMD. A 4-week treatment of PTH(1-34) (20 µg/kg/day) increased the serum osteocalcin levels and the tibial BMD, and decreased the serum glucose levels without changing the serum insulin levels. These findings indicate that PTH(1-34) improved not only BMD but also glucose metabolism in SDT-fa/fa rats. This study suggests that PTH(1-34) is a novel agent for the treatment of diabetic osteoporosis.

Enterostatin, the N-terminal activation pentapeptide of procolipase that is produced by the pancreas, reduces food intake from high-fat diet when injected either peripherally or centrally to rats. We investigated uptake across the blood–brain barrier (BBB) and tissue distribution of enterostatin by giving radioactive-labeled enterostatin ( 3 H-VPDPR) intravenously. Low levels of 3 H-VPDPR were detected in many areas of the brain, with greatest radioactivity in the frontal cortex, hippocampus and cerebellum. Radioactivity was found in the plasma and all tissues, with the highest amount detected in the pancreas.

Functionally graded PMN-PT ceramics, which had a continuously varying graded composition from one surface toward the other of the specimen, were examined with respect to their dielectric property. Specimens were prepared by sintering superposed layers of green compacts of (1-x)PMN-xPT solid solutions with different values of x. The electric permittivity (e) of single-phase (1-x)PMN-xPT ceramics showed a peak at the Curie temperature, which shifted towards higher temperatures with increasing x. On the other hand, the profile of e vs temperature (T) for the graded PMN-PT ceramics experienced a linear characteristic. Furthermore, a flat profile was obtained by varying the volume of layers. The relative permittivity was 10000 ± 200 in the temperature range from room temperature to 120°C. In addition, the temperature coefficient of permittivity could be arbitrary adjusted by cutting the specimen diagonally.

The effects of brewer's yeast cell walls and two of its components, glucan and mannan, on the absorption of 59Fe by anemic rats were investigated. After administration of the label, the percentage of 59Fe taken up into the blood of group given glucan was generally similar to that of a group given yeast cell walls, both values were higher than in controls. The incorporation of 59Fe into the small intestines was higher in the group given glucan than in the controls or a group given a glucan-mannan mixture. Glucan is the main substance in yeast cell walls that increases iron absorption.

(1) Administration of resiniferatoxin (RTX; 50 μg/kg, s.c.) induced triphasic metabolic responses with immediate facilitation followed by transitory inhibition and subsequent long-lasting facilitation in urethan-anesthetized rats. The temperature of skin increased immediately after the RTX injection, suggesting cutaneous vasodilation and heat loss. The colonic temperature decreased initially and then increased above the baseline level. (2) Pretreatment with ruthenium red, a putative vanilloid receptor (VN 2 ) antagonist, attenuated the RTX-induced heat loss and inhibition of heat production. (3) Adrenal demedullation selectively attenuated the RTX-induced immediate thermogenesis, and the β -blocker propranolol prevented both phases of thermogenesis. Thus, the sympathetic nervous system and adrenaline contributed to the thermogenic responses.

We examined the properties of voltage-dependent Ca(2+) channels (VDCCs) mediating 1-methyl-4-phenylpyridinium (MPP(+))-evoked [3H]DA release from rat striatal slices. In some cases, the Ca(2+)-independent efflux of neurotransmitters is mediated by the high-affinity neurotransmitter-uptake systems. To determine whether such a mechanism might be involved in MPP(+)-evoked [3H]DA release. MPP(+) (1,10 and 100 microM) evoked the release of [3H]DA from rat striatal slices in a concentration-dependent manner. In the absence of Ca(2+), MPP(+) (10 and 100 microM)-evoked [3H]DA release was significantly decreased to approximately 50% of control (a physiological concentration of Ca(2+)). In the presence of Ca(2+), nomifensine (0.1,1 and 10 microM) dose-dependently and significantly inhibited the MPP(+)-evoked release of [3H]DA. Nomifensine (1 and 10 microM) also dose-dependently and significantly inhibited the MPP(+)-evoked release of [3H]DA under Ca(2+)-free conditions. MPP(+)-evoked [3H]DA release was partly inhibited by nicardipine (1 and 10 microM), an L-type Ca(2+) channel blocker. On the other hand, the N-type Ca(2+) channel blocker omega-conotoxin-GVIA (omega-CTx-GVIA) (1 and 3 microM) did not affect this release. omega-agatoxin-IVA (omega-Aga-IVA) at low concentrations (0.1 microM), which are sufficient to block P-type Ca(2+) channels alone, also had no effect. On the other hand, MPP(+)-evoked [3H]DA release was significantly decreased by high concentrations of omega-Aga-IVA (0.3 microM) that would inhibit Q-type Ca(2+) channels. In addition, application of the Q-type Ca(2+) channel blocker omega-conotoxin-MVIIC (omega-CTx-MVIIC) (0.3 and 1 microM) also significantly inhibited MPP(+)-evoked [3H]DA release. These results suggest that MPP(+)-evoked [3H]DA release from rat striatal slices is largely mediated by Q-type Ca(2+) channels, and the Ca(2+)-independent component is mediated by reversal of the DA transport system.

The specificity and dose dependence of the synergistic effects of soybean intake with iodine deficiency on the induction of thyroid proliferation were investigated in female F344 rats. In the first experiment, rats were divided into 6 groups, each consisting of 5 animals, and fed a basal diet containing 20% gluten, an iodine-deficient basal diet alone or an iodine-deficient diet containing 0.2%, 1.0%, 5.0% or 25% defatted soybean for 5 weeks. Soybean feeding synergistically induced thyroid hyperplasias with iodine deficiency only at the 25% dose. In the second experiment, rats were also divided into 6 groups, each consisting of 5 animals, and fed a basal diet, a diet containing 20% defatted soybean, 0.025% sulfadimethoxine (SDM), 20% defatted soybean + 0.025% SDM, 0.05% phenobarbital (PB) or 20% defatted soybean + 0.05% PB for 5 weeks. The SDM treatments significantly (P < 0.05 - 0.01) increased the thyroid weights, but this increase rate was less prominent in the SDM + soybean group than in the SDM alone group. The PB treatment was also associated with a tendency for increase in thyroid weight, but again this was smaller in the PB + soybean group than in the PB alone group. Although the SDM or PB treatments reduced the serum triiodothyronine and thyroxine levels and consequently increased the serum thyroid-stimulating hormone (TSH) levels, the soybean feeding did not affect or rather attenuated these changes. Our results clearly indicate that soybean feeding does not synergistically enhance the effects of SDM or PB on the rat thyroid. Thus it can be concluded that soybean intake specifically interacts with iodine deficiency in induction of thyroid proliferative lesions in rats, only at high doses.

Systemic administration of capsaicin elicits heat production, which can be observed in decerebrated preparations but is blocked by spinal transection. To identify the critical locus involved in the capsaicin-induced thermogenesis in the brainstem, we studied the effect of capsaicin on rats with bilateral electrolytic lesions in the premotor areas of sympathoadrenal preganglionic neurons. Lesions in the rostral ventrolateral medulla (RVLM), but not in other regions, largely attenuated the capsaicin-induced heat production. Unilateral microinjection of 30-100 nl capsaicin (0.5%, w/v) into the RVLM elicited a heat production response, whereas capsaicin injection in neighboring areas or vehicle injection into the RVLM did not affect heat production. These results suggest that the thermogenic effect of capsaicin is mediated, at least in part, by some capsaicin-sensitive structure in the RVLM.

Background Body temperature is usually regulated by opposing controls of heat production and heat loss. However, systemic administration of capsaicin, the pungent ingredient of hot peppers, facilitated heat production and heat loss simultaneously in rats. We recently found that the capsaicin-induced heat loss and heat production occur simultaneously and that the biphasic change in body temperature is a sum of transient heat loss and long-lasting heat production. Moreover, suppression of the heat loss response did not affect capsaicin-induced heat production and suppression of heat production did not affect capsaicin-induced heat loss. These observations suggest the independent peripheral mechanisms of capsaicin-induced thermal responses. Thus, the capsaicin-induced thermal responses apparently lack an integrated control. Methods Male Wistar rats were maintained at an ambient temperature of 24 +/- 1 degrees C on a 12 h on-off lighting schedule at least for two weeks before the experiments. They were anesthetized with urethane (1.5 g/kg, i.p.) and placed on a heating pad, which was kept between 29 and 30 degrees C. Skin temperature(Ts) was measured with a small thermistor, which was taped to the dorsal surface of the rat's tail, to assess vasoactive changes indirectly. Colonic temperature(Tc) was measured with another thermistor inserted about 60 mm into the anus. O2 consumption was measured by the open-circuit method, and values were corrected for metabolic body size (kg0.75). Capsaicin (Sigma) was dissolved in a solution comprising 80% saline, 10% Tween 80, and 10% ethanol, and injected subcutaneously at a dose of 5 mg/kg. Each rat received a single injection of capsaicin because repeated administration of capsaicin renders an animal insensitive to the subsequent administration of capsaicin. Laminectomy was performed at the level of the first and second cervical vertebrae to expose the cervical spinal cord for sectioning. The brain was transected at 4-mm rostral from the interaural line with an L-shaped knife. Results After administration of capsaicin, O2 consumption increased from 13.5 +/- 0.4 mL/min/kg0.75 at 0 min to a peak of 15.9 +/- 0.4 mL/min/kg0.75 at 71 min and gradually declined but remained higher than the basal value until the end of the 4-h observation period. Ts also immediately increased from 27.7 +/- 0.2 degrees C to 31.9 +/- 0.3 degrees C at 39 min, and it returned to the baseline level within 90 min after the capsaicin administration. Tc initially decreased from 37.1 +/- 0.1 degrees C to 36.8 +/- 0.2 degrees C at 43 min and then gradually increased over the baseline level and remained at 37.6 +/- 0.2 degrees C until the end of the experiment. In spinalized rats, the capsaicin-induced increases in O2 consumption was largely attenuated, while the basal O2 consumption was similar to that of control rats. The basal Ts of spinalized rats was 32.4 +/- 0.3 degrees C, which was higher than that of control rats. Capsaicin increased Ts by less than 1 degree C, and Tc did not change after the capsaicin administration. O2 consumption of decerebrated rats was statistically higher than that of control rats after the injection of capsaicin. However, capsaicin did not increase Ts, showing a lack of a vasodilatory response. Decerebration between the hypothalamus and midbrain prevented the capsaicin-induced heat loss but not the heat production response. Conclusion These results show that the capsaicin-induced heat production and heat loss are controlled separately by the brainstem and by the forebrain, respectively, and suggest that the body temperature regulation is performed without an integrative center.

Dietary administration of ovalbumin (OVA) antigen (Ag) into OVA-specific T cell receptor alphabeta-transgenic (TCR-Tg) mice resulted in the induction of activated CD4+ Th cells expressing CD69 early activation Ag. However, the number of CD4+ Th cells rather decreased by dietary administration of OVA antigen. The production of Th1-cytokines such as IFN-gamma and IL-2 markedly reduced in spleen of OVA-fed mice compared to mice fed with normal diet. In sharp contrast, the production of Th2-cytokine, IL-4 greatly increased in spleen of OVA-fed mice though the number of CD4+ T cells decreased to less than 10% of control mouse spleen. The decrease of IFN-gamma production and the increase of IL-4 production by CD4+ T cells was demonstrated at a single cell level by intracellular cytokine staining analysis. Moreover, such a polarized cytokine production pattern was also demonstrated using highly purified CD4+ T cells obtained from mice fed with OVA. In addition to the decrease of Th1-cytokine production, TCR-Tg mice fed with OVA-containing diet showed greatly reduced in vivo generation of NK cells, LAK cells and CTL. These results suggested that dietary protein antigen caused the polarization of Th1/Th2 balance into Th2-dominant immunity and inhibited cellular immunity.

Unilateral microinjection of calcitonin gene-related peptide (CGRP, 1.6 pmol; 0.2 microl) into the ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH) immediately increased oxygen consumption (VO2), heart rate (HR), colonic temperature (Tco), and temperature of interscapular brown adipose tissue (TIBAT) in urethane-anesthetized rats, whereas vehicle saline injection into the VMH and CGRP injection into other hypothalamic regions such as the preoptic area, lateral hypothalamic area, paraventricular nucleus, and bed nucleus of the stria terminalis had no effect. The effects of CGRP injection into the VMH were dose-dependent over the range of 0.016-1.6 pmol. CGRP administration to the lateral ventricle (LV) required 16-320 pmol to elicit similar degrees of responses that were observed after the injection into the VMH. The increase in TIBAT was always higher than that in Tco after CGRP injection. Injection of [Cys(ACM)2,7]hCGRPalpha, a selective CGRP2 receptor agonist, did not induce any thermogenic effects. Human CGRP8-37, a proposed CGRP1 receptor antagonist, by itself induced heat production responses with no signs of inhibition of CGRP-induced responses. Thus, the receptor subtype of the thermogenic effect of CGRP could not be determined by the available pharmacological tools. The present results show that centrally administrated CGRP induces heat production in the BAT specifically through the VMH or DMH.

We examined the function of putative sensory fibers that are contained in intercostal nerves and innervate interscapular brown adipose tissue (IBAT) in urethane-anesthetized rats. Warming the IBAT to 40-44 degrees C with two small heaters placed bilaterally on the skin above it attenuated the subsequent noradrenaline-induced thermogenesis (NIT) of the IBAT. In this range of warming, higher IBAT temperatures resulted in more attenuation. Denervation of IBAT blocked the effect of thermal stimulation on the NIT. Thus, activation of nerve fibers in IBAT that are sensitive to warmth or to the nociceptive effects of heat probably attenuated the NIT. Since the putative sensory fibers in the IBAT contain calcitonin gene-related peptide (CGRP) and substance P, which are thought to act in peripheral tissues, we tested the effects of injection of these neuropeptides into the IBAT. Administration of 5.2 nmol CGRP but not substance P or vehicle saline mimicked the effect of thermal stimulation of IBAT. As the neuropeptide-containing primary sensory neurons are characterized by their sensitivity to capsaicin, we also tested its effects (1 mg/kg, s.c.) and found that it also attenuated the NIT. Denervation of the IBAT or pretreatment with capsazepine, a capsaicin receptor antagonist, blocked the effect of capsaicin. We propose that temperature- and capsaicin-sensitive nerve fibers release CGRP to attenuate the NIT of brown adipocytes.

We have investigated whether a hydrophilic photosensitizer, chlorin e6Na (Ce6Na), can sensitize cells to ionizing radiation. When V79-1 cells were pretreated with Ce6Na for 2 hr before receiving a dose of 2-14 Gy of irradiation, the cells became sensitive to X-irradiation. The sensitizing effect of Ce6Na depended on the dose of Ce6Na. The sensitizing effect also depended on the length of the treatment period before X-irradiation up to 4 hr, but not on the length of a treatment period after X-irradiation. Intracellular concentrations of Ce6Na were increased linearly after incubation with Ce6Na for periods of up to 4 h. The dose-modifying factor calculated from the survival curve was 1.25.

The distributions of phylloquinone (PK) and menaquinone-4 (MK-4) in various tissues were assessed after the oral administration of phylloquinone. Wistar rats were fed a vitamin-K-deficient diet for nine days, fasted for 24 h and then given phylloquinone orally at 4 mg/kg body weight. Rats were sacrificed 0, 6, 12 and 24 h after the administration, and an analysis was made of the vitamin K analogues in the plasma, liver, brain, testis, kidney and spleen. The phylloquinone concentration in plasma and the tissues reached a peak 6 h after the oral administration of phylloquinone. By contrast, the concentration of MK-4 peaked in the liver, plasma, kidney and spleen at 12 h, and in brain and testis at 24 h. This data suggests that the ingested phylloquinone was probably converted into MK-4 within the tissues themselves, rather than via hepatic metabolism. The evidence for this is that, after phylloquinone administration, (i) in each of the tissues, the MK-4 concentration increased much more slowly than that of phylloquinone, and (ii) the MK-4 concentration in the plasma and liver reached only much lower levels than those seen in other tissues.

Single-fiber preparations of the rat chorda tympani (CT) nerve were used to study the mechanism of action of capsaicin on salt-taste transduction. Capsaicin selectively suppressed the responses to NaCl of the CT nerve fibers (N-fibers) that are sodium-specific (insensitive or poorly sensitive to potassium). Among the more broadly responsive, cation-sensitive fibers (E-fibers) there are two subtypes, both of which responded to capsaicin but in different ways ('enhanced' type and 'suppressed' type). In both N- and E-fibers, 5% ethanol (the vehicle for capsaicin) slightly reduced the response to 100 mM NaCl. The suppressive effect of capsaicin on the response of the N-type fibers to 100 mM NaCl was significantly stronger than the effect of 5% ethanol. The suppression lasted for at least 20 s after the simultaneous application of 100 p.p.m. capsaicin-100 nM NaCl. These results indicate that 100 p.p.m. capsaicin can modify the response of CT fibers to NaCl. The observed effect of capsaicin on gustatory fibers could be the net result of opposite suppressive and enhancing processes in the taste buds cells and excited intra- or extragemmal trigeminal nerve endings.