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Background: The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood. Methods: We developed a Markov model to describe health states of 6-year-old children with medulloblastoma after treatment with proton or X-ray radiotherapy. The risks of hearing loss were calculated on cochlear dose for each treatment. Three types of health-related quality of life (HRQOL) of EQ-5D, HUI3 and SF-6D were used for estimation of quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for proton beam therapy compared with X-ray radiotherapy was calculated for each HRQOL. Sensitivity analyses were performed to model uncertainty in these parameters. Results: The ICER for EQ-5D, HUI3 and SF-6D were $21 716/QALY, $11 773/QALY, and $20 150/QALY, respectively. One-way sensitivity analyses found that the results were sensitive to discount rate, the risk of hearing loss after proton therapy, and costs of proton irradiation. Cost-effectiveness acceptability curve analysis revealed a 99% probability of proton therapy being cost effective at a societal willingness-to-pay value. Conclusions: Proton beam therapy with cochlear dose reduction improves health outcomes at a cost that is within the acceptable cost-effectiveness range from the payer's standpoint.

Background Recent evidence suggests that erythromycin (EM), a major macrolide antibiotic, has many biological functions in addition to the anti-bacterial actions, including anti-inflammatory and free radical scavenging actions. However, the effects of the drug upon inflammatory myocardial diseases are unknown. We tested the hypothesis that EM ameliorates experimental autoimmune myocarditis in rats attributing to the suppression of superoxide production. Methods We administered EM, 3.3mg/kg/day and 33mg/kg/day, intraperitoneally for 3weeks, to rats with experimental autoimmune myocarditis (EAM) produced by immunization by porcine myosin. Results EM treatment reduced the severity of myocarditis compared with the untreated group in a dose-dependent manner by comparing the heart weight/body weight ratio, pathologic scores, and myocardial macrophage, CD4 + , and CD8 + infiltrations. Echocardiographic study showed that increased left ventricular posterior wall thickness produced by myocardial inflammation was reduced by EM treatment. Myocardial superoxide production, determined by dihydroethidium staining, was significantly reduced by the treatment. Western blotting showed that the expression of myocardial interleukin-1β was reduced by EM treatment compared with untreated groups. The in vivo dorsal air pouch model showed that EM significantly suppressed leukocyte chemotaxis in a dose-dependent manner. Conclusion Irrespective of a well-known classic antibiotic, EM attenuated EAM not only by the anti-inflammatory action but by the suppression of superoxide production.

Summary FcγRIIB contains a unique immunoreceptor tyrosine-based inhibition motif (ITIM) and functions as a negative feedback regulator of leucocyte activation and antibody production. We have previously reported FcγRIIB-nt645+25A/G gene polymorphism to be associated with prevalence and severity of periodontitis, FcγRIIB expression level on peripheral B lymphocytes and the serum IgG level against periodontopathic bacteria. Previous studies have reported maternal periodontal disease to be associated with an increased risk for preeclampsia. Therefore, FcγRIIB-nt645+25A/G gene polymorphism may be associated with preeclampsia by affecting immune response to periodontopathic bacteria in pregnant women. To elucidate whether FcγRIIB-nt645+25A/G gene polymorphism has associations with preeclampsia and/or periodontitis in pregnant Japanese women, a case–control study was carried out on women with preeclampsia (n = 13) and without preeclampsia (n = 106). Maternal periodontal parameters and bacterial data of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia in subgingival plaque were collected within 5 days of delivery. FcγR genotypes of each woman were determined using the genomic DNA isolated from peripheral blood. Serum IgG levels specific for each bacteria were determined. There was a significant association between FcγRIIB-nt645+25A/G polymorphism and preeclampsia (P = 0.013). The frequency of the FcγRIIB-nt645+25AA genotype was higher in the preeclampsia group compared with the nonpreeclampsia group (P = 0.007). The DNA level of A. actinomycetemcomitans from subgingival plaque was shown to be higher in the preeclampsia group (P = 0.017). In conclusion, maternal FcγRIIB-nt645+25A/G polymorphism and subgingival DNA level of A. actinomycetemcomitans were significantly associated with the prevalence of preeclampsia in a limited number of Japanese women independently with periodontal infection. Further investigations should be performed to confirm this association in a larger population and to determine the biological process of the association.

Sucrose nonfermenting-1 (SNF1)-related protein kinases (SnRKs) form a major family of signalling proteins in plants and have been associated with metabolic regulation and stress responses. They comprise three subfamilies: SnRK1, SnRK2, and SnRK3. SnRK1 plays a major role in the regulation of carbon metabolism and energy status, while SnRKs 2 and 3 have been implicated in stress and abscisic acid (ABA)-mediated signalling pathways. The burgeoning and divergence of this family of protein kinases in plants may have occurred to enable cross-talk between metabolic and stress signalling, and ABA-response-element-binding proteins (AREBPs), a family of transcription factors, have been shown to be substrates for members of all three subfamilies. In this study, levels of SnRK1 protein were shown to decline dramatically in wheat roots in response to ABA treatment, although the amount of phosphorylated (active) SnRK1 remained constant. Multiple SnRK2-type protein kinases were detectable in the root extracts and showed differential responses to ABA treatment. They included a 42 kDa protein that appeared to reduce in response to 3 h of ABA treatment but to recover after longer treatment. There was a clear increase in phosphorylation of this SnRK2 in response to the ABA treatment. Fractions containing this 42 kDa SnRK2 were shown to phosphorylate synthetic peptides with amino acid sequences based on those of conserved phosphorylation sites in AREBPs. The activity increased 8-fold with the addition of calcium chloride, indicating that it is calcium-dependent. The activity assigned to the 42 kDa SnRK2 also phosphorylated a heterologously expressed wheat AREBP.

Iwanaga R, Sugita N, Hirano E, Sasahara J, Kikuchi A, Tanaka K, Yoshie H. FcγRIIB polymorphisms, periodontitis and preterm birth in Japanese pregnant women. J Periodont Res 2011; 46: 292–302.©2011 John Wiley & Sons A/S Background and Objective: Recently, numerous studies have investigated the association of preterm birth with periodontitis. FcγRIIb is a human low-affinity receptor for immunoglobulin G (IgG). We have previously demonstrated single nucleotide polymorphisms (SNPs) of FcγRIIb to be associated with periodontitis and the serum-specific IgG level against periodontopathic bacteria. In this study, we investigated whether FcγRIIB gene polymorphisms were associated with periodontitis and/or pregnancy outcome. Material and Methods: We assessed the periodontal conditions of 122 Japanese pregnant women within 5 d of delivery, and polymorphisms in FcγRIIB and in other Fcγ receptors were detected from the genomic DNA. Using clinical and genomic data, we analyzed the relationship between periodontitis, preterm birth and Fcγ receptor polymorphisms. Results: A significant difference was observed in the distribution of FcγRIIB-nt645+25A/G (rs2125685) between preterm and term birth groups, with a higher prevalence of nt645+25AA in the preterm birth group (p = 0.032). Additionally, the FcγRIIB-nt645+25GG carrier showed significantly higher results for the prevalence of periodontitis (p = 0.048), mean pocket depth (p = 0.021), mean clinical attachment level (p = 0.010), percentage of sites with pocket depth ≥ 4 mm (p = 0.005) and percentage of sites with clinical attachment level ≥ 3 mm (p = 0.007) than the AA carrier. An association between preterm birth and periodontitis was not observed in this study. Conclusion: These findings suggest that FcγRIIB-nt645+25AA carriers are more likely to experience preterm birth than FcγRIIB-nt645+25AG and GG carriers. Also, women with FcγRIIB-nt645+25G exhibited a greater tendency to have periodontitis than those with nt645+25A.

A reversible spectroscopic change in chlorophyll (Chl) d has been demonstrated for the first time, using reduction with sodium dithionite and oxidation with potassium ferricyanide in an aqueous solution of detergent micelles. Chl d treated with a low concentration of NaBH4 in methanol showed the same results. The chemical structure of the reduced Chl d was determined by mass spectrometry to be 3-desvinyl-3-hydroxymethyl Chl a. These findings lead to a new hypothesis for the biosynthetic pathway of Chl d, being that Chl d is synthesized by oxidation of 3-desvinyl-3-hydroxymethyl Chl a, which is first formed enzymatically from Chl a.

Pigment exchanges among photosystem reaction centers (RCs) are useful for the identification and functional analysis of chromophores in photosynthetic organisms. Pigment replacement within the spinach Photosystem II RC was performed with Chl d derived from the oxygenic alga Acaryochloris marina, using a protocol similar to that reported previously [Gall et al. (1998) FEBS Lett 434: 88-92] based on the incubation of reaction centers with an excess of other pigments. In this study, we analyzed Chl d-modified monomeric RC which was separated from Chl d-modified dimeric RC by size-exclusion chromatography. Based on the assumption of a constant ratio of two Pheo a molecules per RC, the number of Chl a molecules in Chl d-modified monomeric RCs was found to decrease from six to four. The absorption spectrum of the Chl d-modified monomeric RC at room temperature showed a large peak at 699.5 nm originating from Chl d and a small peak at 672.5 nm orignating from Chl a. Photoaccumulation of the Pheo a- in Chl d-modified monomeric RC, in the presence of sodium dithionate and methyl viologen, did not differ significantly from that in control RC, showing that the Chl d-modified monomeric RC retains its charge separation activity and photochemically active Pheo a.

The purpose of this study was to find whether the concentration of N-acetylglutamate and ornithine transport into mitochondria would regulate urea synthesis when the dietary protein quality was manipulated. Experiments were done on three groups of rats given diets containing 10 g of gluten, 10 g of casein, or 10 g of whole egg protein/100 g for 10 days. The plasma concentration and urinary excretion of urea, the liver concentration and synthesis of N-acetylglutamate, the liver concentrations of glutamate and lysine, and the liver ornithine transport into mitochondria increased with the decrease in quality of dietary protein. A reverse correlation was observed between the activities of urea cycle enzymes, the plasma concentration of arginine, and urinary excretion of urea under these conditions. N-Acetylglutamate concentration and ornithine transport into mitochondria in the liver were closely correlated with the excretion of urea. These results suggest that greater N-acetylglutamate concentration and ornithine transport into isolated mitochondria in the liver of rats, given the lower quality of protein, stimulate urea synthesis and that the concentrations of glutamate and lysine in the liver are at least partly related to the hepatic N-acetylglutamate synthesis and ornithine transport, respectively.

The purpose of this study was to determine whether genistein affects the rate of brain protein synthesis in ovariectomized female rats. Experiments were conducted on three groups of 12-wk-old female rats: those in group 1 were ovariectomized to reduce the level of plasma sex hormone; those in group 2 were ovariectomized and fed diets containing 0.01% genistein; and those in group 3 were sham-operated controls. The fractional rates of protein synthesis in the brain of ovariectomized rats fed genistein were significantly greater than those in ovariectomized rats without genistein treatment. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA.d)] significantly correlated (r > 0.86, P < 0.001) with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. The results suggest that the addition of genistein to the diet of ovariectomized female rats is likely to increase the rate of protein synthesis in the brain, and that RNA activity is at least partly related to the fractional rate of brain protein synthesis.

The purpose of this study was to determine whether the quantity and quality of dietary protein affected the polysome profile of the brain in aged rats. Two experiments were done on three groups of aged rats (30 wk) given the diets containing 20% casein, 5% casein, or 0% casein (experiment 1), and 20% casein, 20% gluten, or 20% gelatin (experiment 2) for 10 d. The aggregation in brain ribosomes declined with a decrease of quantity and quality of dietary protein except in the hippocampus. The RNA concentration (mg RNA/g protein) did not differ among the three groups varying the dietary protein in any brain regions. The results suggest that the higher quantity and quality of dietary protein improves the polysome profile in the brain of aged rats, and that the polysome profile is at least partly related to the mechanism by which the dietary protein affects brain protein synthesis in aged rats.

RIG-I-like receptor (RLR) plays a pivotal role in the detection of invading pathogens to initiate type I interferon (IFN) gene transcription. Since aberrant IFN production is harmful, RLR signaling is strictly regulated. However, the regulatory mechanisms are not fully understood. By expression cloning, we identified Pumilio proteins, PUM1 and PUM2, as candidate positive regulators of RIG-I signaling. Overexpression of Pumilio proteins and their knockdown augmented and diminished IFN-β promoter activity induced by Newcastle disease virus (NDV), respectively. Both proteins showed a specific association with LGP2, but not with RIG-I or MDA5. Furthermore, all of these components were recruited to NDV-induced antiviral stress granules. Interestingly, biochemical analyses revealed that Pumilio increased double-stranded (ds) RNA binding affinity of LGP2; however, Pumilio was absent in the dsRNA-LGP2 complex, suggesting that Pumilio facilitates viral RNA recognition by LGP2 through its chaperon-like function. Collectively, our results demonstrate an unknown function of Pumilio in viral recognition by LGP2., Author Summary Mammals utilize innate immune system to counteract viral infections. The host pattern-recognition receptors, such as RIG-I-like receptors (RLRs), sense invading pathogens and initiate innate immune responses. RLRs are composed of three RNA helicases, RIG-I, MDA5 and LGP2, and detect a series of RNA viruses, such as influenza or hepatitis C virus, in the cytoplasm. Upon RNA virus infection, RLRs transmit signals through mitochondrial adaptor protein, IPS-1, to activate transcription factor IRF-3/7, resulting in the production of type I interferon (IFN). Type I IFN plays a crucial role in innate immune system by inducing a hundreds of interferon-stimulated genes and its induction is tightly controlled at transcriptional and translational steps. Pumilio proteins are originally identified as translational repressor through direct binding to specific sequence motifs in the 3′ untranslated regions of specific mRNA, and regulate critical biological processes, such as development and differentiation. In this report, we identified human Pumilio proteins, PUM1 and PUM2, as candidate regulators of IFN signaling. Our results demonstrated an unknown function of Pumilio in viral recognition by LGP2.

It has been shown that oxidative stress may play an important role in the development of atherosclerosis, and carvedilol has the capacity of reducing oxidative stress. Accordingly, we assessed the hypothesis that carvedilol may reduce the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice in addition to its hemodynamic effects. Atherosclerosis was induced in apoE-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were orally treated with propranolol (30 mg/kg/day), metoprolol (75 mg/kg/day) and carvedilol (10 mg/kg/day) over eight weeks (each group n = 7−9). Fatty streak plaque developed in apoE-deficient mice, and was suppressed in mice treated with all three drugs. The accumulation of macrophages and expression of CD4+ and CD8+ cells in the lesions were decreased by the treatment of the drugs, of which carvedilol was the most effective. In addition, carvedilol reduced superoxide production in aortic walls detected by ethidium staining. There were no significant changes in blood pressure among the study groups. The heart rates in the treated groups were decreased by 4%–12% compared with the control group, with carvedilol yielding the highest suppression of heart rate. The β-blocker treatment did not significantly modify the serum lipid profiles. Carvedilol may suppress atherosclerosis via reducing superoxide production, in addition to the hemodynamic modifications in this animal model.

Aim To determine whether periodontitis and three prominent members of the periodontal flora are associated with the development of preeclampsia (hypertension plus proteinuria) Materials and Methods The samples were composed of 127 systemically healthy women. Within 5 days after labour, clinical periodontal parameters and Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia in subgingival plaque were evaluated. Maternal serum IgG antibody specific for each bacteria was determined by enzyme-linked immunosorbent assay. Multivariate logistic regression analysis was used to control for confounders (maternal age, body mass index before pregnancy, parity, and smoking). Results Eighteen women were affected with preeclampsia. The number of A.actinomycetemcomitans was shown to be significantly associated with preeclampsia in the logistic regression model (odds ratio; 1.7, 95% confidence interval; 1.1–2.7). There were statistically significant differences between the preeclamptic and control groups in body mass index before pregnancy, pre-term birth and low birthweight (respectively, p = 0.014, p = 0.010 and p

Many studies have reported an association between periodontal disease and preterm birth, although this remains controversial. Cytokines and antibodies produced to give resistance to infection can enter the bloodstream and cause preterm labor. We analyzed maternal genetic polymorphisms in various immunoregulatory genes that could affect both preterm birth and periodontitis. A total of 1099 women referred to the Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital were candidates for participation, 424 of whom refused, and 553 were excluded. The final number of subjects was 122 (51 with preterm birth, 71 with term birth). Genomic DNA was isolated from venous blood, and 22 polymorphisms were determined: IL-1A, IL-1B, IL-1RN, IL-2, IL-4, IL-6, IL-10, TNFA, TNFRI, TNFRII, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB, and FcαR. Within five days of labor, periodontal parameters were evaluated, and bacteria from subgingival plaque were detected using real-time PCR. There was no difference in the prevalence and degree of periodontitis between term and preterm births. Chi-squared tests showed that an age33 years and FcαR(+56)T/C alleles were associated with preterm birth. Multiple logistic regression analysis represented a model with significant fitness in which four variables were associated with preterm birth: maternal age, number of Aggregatibacter actinomycetemcomitans, IL-6(-572)G/C, and FcαR(+56)T/C. In conclusion, there was no association between preterm birth and periodontitis in this study. A. actinomycetemcomitans, IL-6, and FcαR were suggested to be associated with preterm birth. Multiple logistic regression models with both genetic and environmental factors would be useful for evaluating susceptibility to preterm birth.

Recent studies suggest an association between maternal periodontitis and preterm birth, although the association remains controversial. It was suggested that mechanisms such as a genetic predisposition for a hyperinflammatory response cause periodontitis and preterm births. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor and ligand-dependent transcription factor. PPARgamma inhibits the transcriptional activity of the genes that produce proinflammatory mediators and repress periodontitis. Recently, a common polymorphism, proline(PRO)-to-alanine(ALA) mutation at codon12 in exonB (Pro12Ala: rs 1801282) PPARgamma, was reported to reduce the ability to transactivate responsive promoters. In this study, we tested whether the PPARgammaPro12Ala polymorphism was associated with maternal periodontitis and/or preterm birth.Genomic DNA was isolated from the venous blood of pregnant Japanese women (term birth: n = 72; preterm birth: n = 58). The PPARgammaPro12Ala genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Within 5 days after labor, clinical periodontal parameters were evaluated, and periodontopathic bacteria from the subgingival plaque were detected by species-specific PCR.The mean clinical attachment level (P = 0.012), mean probing depth (P = 0.031), mean gingival index (P = 0.037), and percentages of sites with bleeding on probing (P = 0.041) in women with the PPARgammaPro12Ala genotype were significantly higher than in women with the PPARgammaPro12Pro genotype. However, there was no association between preterm birth and periodontitis.We suggest that the PPARgammaPro12Ala polymorphism may represent a genetic susceptibility factor for the clinical measurements of periodontitis in a limited number of pregnant Japanese women, but it probably cannot influence the relationship between periodontitis and preterm birth.

A deficiency of sex hormones affects brain function in mammals, including the decrease of protein synthesis. Recently, we have shown that the protein synthesis in the brain depended on the quality of dietary protein in ovariectomized female rats. The methionine is the first limiting amino acid for the recommended dietary allowance of amino acids in soy protein. The purpose of this study was to determine whether the addition of dietary methionine affected the rate of brain protein synthesis in ovariectomized female rats fed on the soy protein diet. Experiments were conducted on two groups of ovariectomized female rats (24 week) given the diets containing 5% soy protein or 5% soy protein + 0.2% methionine for 10 d. The fractional rates of protein synthesis in cerebral cortex and cerebellum significantly increased with an addition of dietary methionine. In the brain, the RNA activity [g protein synthesized/((g RNA) x d)] was significantly correlated with the fractional rate of protein synthesis. The RNA concentration (mg of RNA/g of protein) was not related to the fractional rate of protein synthesis in any organ. The results suggest that the addition of limiting amino acid for the low soy protein elevates the rate of protein synthesis in the brain of ovariectomized female rats, and that RNA activity is at least partly related to the fractional rate of brain protein synthesis.

The purpose of this study was to determine whether genistein affects the rate of brain protein synthesis in ovariectomized female rats. Experiments were conducted on three groups of 12-wk-old female rats: those in group 1 were ovariectomized to reduce the level of plasma sex hormone; those in group 2 were ovariectomized and fed diets containing 0.01% genistein; and those in group 3 were sham-operated controls. The fractional rates of protein synthesis in the brain of ovariectomized rats fed genistein were significantly greater than those in ovariectomized rats without genistein treatment. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA.d)] significantly correlated (r0.86, P0.001) with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. The results suggest that the addition of genistein to the diet of ovariectomized female rats is likely to increase the rate of protein synthesis in the brain, and that RNA activity is at least partly related to the fractional rate of brain protein synthesis.

The purpose of this study was to determine whether the quantity and quality of dietary protein affected the polysome profile of the brain in aged rats. Two experiments were done on three groups of aged rats (30 wk) given the diets containing 20% casein, 5% casein, or 0% casein (experiment 1), and 20% casein, 20% gluten, or 20% gelatin (experiment 2) for 10 d. The aggregation in brain ribosomes declined with a decrease of quantity and quality of dietary protein except in the hippocampus. The RNA concentration (mg RNA/g protein) did not differ among the three groups varying the dietary protein in any brain regions. The results suggest that the higher quantity and quality of dietary protein improves the polysome profile in the brain of aged rats, and that the polysome profile is at least partly related to the mechanism by which the dietary protein affects brain protein synthesis in aged rats.

The purpose of this study was to determine whether 17-ss-estradiol affects the rate of brain protein synthesis in ovariectomized female rats. Experiments were conducted on three groups of 12-wk-old female rats: group 1 were ovariectomized to reduce the level of plasma estradiol, group 2 were ovariectomized and treated with estradiol and group 3 were sham-operated controls. The fractional rates of protein synthesis in brain of ovariectomized rats treated with estradiol were significantly greater than that in ovariectomized rats without estradiol treatment. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA. d)] significantly correlated (r > 0.87, P < 0.001) with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. The results suggest that estrogen treatment of ovariectomized female rats is likely to increase the rate of protein synthesis in the brain and that RNA activity is at least in part related to the fractional rate of brain protein synthesis.