Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Surface nanostructures on Nb-doped SrTiO3irradiated with swift heavy ions at grazing incidence.

A single crystal of SrTiO3doped with 0.5 wt% niobium (Nb-STO) was irradiated with 200 MeV Au32+ions at grazing incidence to characterize the irradiation-induced hillock chains. Exactly the same hillock chains are observed by using atomic force microscopy (AFM) and scanning electron microscopy (SEM) to study the relation between irradiation-induced change of surface topography and corresponding material property changes. As expected, multiple hillocks as high as 5-6 nm are imaged by AFM observation in tapping mode. It is also found that the regions in between the adjacent hillocks are not depressed, and in many cases they are slightly elevated. Line-like contrasts along the ion paths are found in both AFM phase images and SEM images, indicating the formation of continuous ion tracks in addition to multiple hillocks. Validity of preexisting models for explaining the hillock chain formation is discussed based on the present results. In order to obtain new insights related to the ion track formation, cross-sectional transmission electron microscopy (TEM) observation was performed. The ion tracks in the near-surface region are found to be relatively large, whereas buried ion tracks in the deeper region are relatively small. The results suggest that recrystallization plays an important role in the formation of small ion tracks in the deep region, whereas formation of large ion tracks in the near-surface region is likely due to the absence of recrystallization. TEM images also show shape deformation of ion tracks in the near-surface region, suggesting that material transport towards the surface is the reason for the absence of recrystallization.

Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.

OBJECTIVE: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression. DESIGN: High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated through RT-qPCR and western blotting analyses. Additionally, 10-week-old mice were subjected to destabilization of the medial meniscus (DMM) surgery to induce OA and were sacrificed 12 weeks post-surgery for pathological examination. OA was evaluated using the OARSI scoring system. RESULTS: Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered mice with DMM presented significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% confidence interval (CI) of difference: 0.1651-3.035) and significantly lower synovial membrane inflammation scores (adjusted P: 0.0243, mean difference: 0.6, 95% CI of difference: 0.06158-1.138) than mice with DMM. IPA further revealed that components of the Rho signaling pathways are regulated by cytokines and colchicine. IL-1ß and TNF-α activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-γ1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, leading to the induction of MMP13 expression. CONCLUSIONS: Colchicine is a potential DMOAD candidate that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCγ1-Ca2+ signaling pathway.

Development of a fast response neutron detector for the supersonic FRC collision process.

The collisional merging experiments of the field-reversing configuration (FRC) at supersonic/Alfvénic velocities have been performed in the FRC Amplification via Translation-Collisional Merging device only in Japan. This experiment may excite shockwaves and cause particle acceleration. To obtain supporting evidence of particle acceleration by shockwaves, we have proposed to observe neutrons originating from the D-D fusion reaction of accelerated non-thermal particles. A plastic scintillation detector has been developed for the supersonic/Alfvénic collision/merging FRC experiment. The developed neutron detector has sufficient performance of neutron sensitivity and nanosecond response time. In the collisional merging process, we obtained a signal that could be considered a neutron, which is not predicted by the adiabatic compression process in the two-dimensional magnetohydrodynamics simulation.

Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling.

OBJECTIVE: Exostosin-1 (EXT1) and EXT2 are the major genetic etiologies of multiple hereditary exostoses and are essential for heparan sulfate (HS) biosynthesis. Previous studies investigating HS in several mouse models of multiple hereditary exostoses have reported that aberrant bone morphogenetic protein (BMP) signaling promotes osteochondroma formation in Ext1-deficient mice. This study examined the mechanism underlying the effects of HS deficiency on BMP/Smad signaling in articular cartilage in a cartilage-specific Ext-/- mouse model. METHOD: We generated mice with a conditional Ext1 knockout in cartilage tissue (Ext1-cKO mice) using Prg4-Cre transgenic mice. Structural cartilage alterations were histologically evaluated and phospho-Smad1/5/9 (pSmad1/5/9) expression in mouse chondrocytes was analyzed. The effect of pharmacological intervention of BMP signaling using a specific inhibitor was assessed in the articular cartilage of Ext1-cKO mice. RESULTS: Hypertrophic chondrocytes were significantly more abundant (P = 0.021) and cartilage thickness was greater in Ext1-cKO mice at 3 months postnatal than in control littermates (P = 0.036 for femur; and P < 0.001 for tibia). However, osteoarthritis did not spontaneously occur before the 1-year follow-up. matrix metalloproteinase (MMP)-13 and adamalysin-like metalloproteinases with thrombospondin motifs(ADAMTS)-5 were upregulated in hypertrophic chondrocytes of transgenic mice. Immunostaining and western blotting revealed that pSmad1/5/9-positive chondrocytes were more abundant in the articular cartilage of Ext1-cKO mice than in control littermates. Furthermore, the BMP inhibitor significantly decreased the number of hypertrophic chondrocytes in Ext1-cKO mice (P = 0.007). CONCLUSIONS: HS deficiency in articular chondrocytes causes chondrocyte hypertrophy, wherein upregulated BMP/Smad signaling partially contributes to this phenotype. HS might play an important role in maintaining the cartilaginous matrix by regulating BMP signaling.

An analysis of osteoporosis in patients with hereditary multiple exostoses.

We analyzed osteoporosis in 20 HME patients. According to the T-score of BMD, 30% and 67.5% of the patients fell in the range of osteopenia in the lumbar spine and femoral neck. Our results indicate HME patients have low bone mass. They do not have abnormal bone metabolism. INTRODUCTION: There are few reports of osteoporosis in hereditary multiple exostoses (HME) patients. Therefore, the purpose of this study was to analyze osteoporosis in HME patients. METHODS: This retrospective cohort study included 20 patients diagnosed with HME. Patients underwent bone mineral density (BMD) measurement of the lumbar spine (n = 20) and femoral neck (n = 40). Bone metabolic parameters, including serum osteocalcin and urinary cross-linked N-telopeptide of type 1 collagen (NTx), were analyzed in all subjects. EXT1 and EXT2 genes were sequenced using genomic DNA. We also examined the correlation between genotype and BMD Z-score and T-score. RESULTS: The mean BMD values of the lumbar spine were 1.085 ± 0.116 g/cm2 (n = 11) in male and 1.108 ± 0.088 g/cm2 (n = 9) in female. The mean BMD values of the femoral neck area were 0.759 ± 0.125 g/cm2 (n = 22) in male and 0.749 ± 0.115 g/cm2 (n = 18) in female. Z-score of most HME patients show < 0, indicating that these patients tend to have low bone mass compared with the age-matched population. According to the T-score of BMD, 30% (6 of 20) and 67.5% (27 of 40) of the patients fell in the range of osteopenia in the lumbar spine and femoral neck areas, respectively. Serum osteocalcin and urinary NTx were in the normal range in most patients. There was no significant correlation between genotypes and Z-score. CONCLUSION: HME patients have low bone mass, especially in the femoral neck area. They do not have abnormal bone metabolism, and there was no correlation between genotypes and Z-score.

The relationship between sucrose intake in coffee or tea, and root or coronal caries in an elderly Japanese population.

OBJECTIVES: Few studies have examined the effect of sucrose intake in coffee or tea (SCT) on dental caries, especially root caries, in elderly people. The purpose of the present study was to examine the associations between SCT and the prevalence of root or coronal caries in community-dwelling elderly Japanese. METHODS: Participants were 370 elders aged 75 years from a larger cohort study of elders in Niigata City, Japan. Dietary habits during the preceding month were assessed with a validated brief self-administered diet history questionnaire (BDHQ). The caries examination was conducted using mirror and ball-pointed periodontal probes under artificial light. Poisson regression analysis was performed to analyze the prevalence-rate ratios (PRRs) between SCT and the root or coronal caries. The number of root or coronal caries was selected as the dependent variable for the analysis. Then, SCT (tertiles labeled low, medium and high) and other 4 variables were selected as independent variables. RESULTS: The PRRs between the number of root caries lesions and SCT were signifi cantly higher in the second (medium intake, 1.38, p ⟨ 0.001) and third tertiles (high intake, 2.07, p ⟨ 0.001). Similar tendencies were seen for the number of coronal caries lesions (PRRs in the second and third tertiles 1.74 and 2.46, respectively, both p ⟨ 0.001). CONCLUSION: A significant positive relationship was observed between sucrose in coffee and tea and the number of coronal or root caries lesions in community-dwelling elderly Japanese.

Phase Angle Is a Useful indicator for Muscle Function in Older Adults.

AIM: Phase angle (PhA) can be determined through bioelectrical impedance analysis and is a unique variable for skeletal muscle. The objective of this study was to evaluate the relationship between PhA and muscle mass/quality in older adults. In addition, we attempted to determine the cutoff value of PhA for poor muscle function. METHODS: Community-dwelling Japanese older men (n=285, 81.1±7.1 years) and women (n=724, 80.4±6.8 years) participated in this study and were classified into four groups based on the Asian Working Group for Sarcopenia (normal, presarcopenia, dynapenia, and sarcopenia). We measured PhA using bioelectrical impedance analysis, muscle quantity and quality indicators using ultrasonography, muscle strength, and physical performance and compared them in four groups. We also tried to determine the cutoff value of PhA for poor muscle function. RESULTS: We found a significant difference in PhA among the four groups in men (P<0.05), and the dynapenia (3.61±0.75°) and sarcopenia groups (3.40±0.74°) showed significantly lower values than the normal group (4.50±0.86°) (P<0.05), but not the presarcopenia group (4.12±0.85°). In women, a significant difference was also observed among the four groups (P<0.05), and the dynapenia (3.41±0.65°) and sarcopenia groups (3.31±0.66°) showed significantly lower measures than the normal group (4.14±0.71°) (P<0.05), but not the presarcopenia group (4.07±0.51°). The receiver-operating characteristic curve analysis indicated the best cutoff value of PhA (men: 4.05°, women: 3.55°) to discriminate sarcopenia and dynapenia from normal and presarcopenia. CONCLUSION: These findings suggest that PhA is a useful indicator for muscle function.

Relationships between blood pressure lowering therapy and cardiovascular events in hypertensive patients with coronary artery disease and type 2 diabetes mellitus: The HIJ-CREATE sub-study.

OBJECTIVE: The effects of intensive blood pressure (BP) lowering for hypertensive patients with coronary artery disease (CAD) and diabetes mellitus on their clinical outcomes have not been fully evaluated. The aim was to explore the optimal systolic BP target in such patients in a substudy of a prospective, randomized trial. METHODS: Of a total of 2049 hypertensive patients with CAD who were enrolled in the HIJ-CREATE study, type 2 diabetes was diagnosed in 780 (38.1%). Titration of antihypertensive agents was performed to reach the target BP of <130/85 mmHg. The primary endpoint was the occurrence of a first major adverse cardiovascular event (MACE). Achieved BP was defined as the mean value of systolic BP in patients who did not develop MACEs and as the mean value of systolic BP prior to MACEs in those who developed MACEs during follow-up. RESULTS: During a median follow-up of 4.2 years, the primary outcome occurred in 259 (33.2%) diabetic patients and in 293 (23.1%) non-diabetic patients (p < 0.0001). The diabetic patients were divided into quartiles based on the mean systolic BP during follow-up. The relationships between achieved BP and the incidence of MACEs did not follow a J-shaped curve. Intensive systolic BP lowering to less than 120 mmHg did not correlate with an increased risk of MACEs. CONCLUSIONS: Our results suggest that the intensive BP lowering may not impair patients' clinical courses even in a high-risk population. The establishment of an optimal management strategy for hypertensive patients with diabetes and CAD is essential.

A combined mathematical model linking the formation of amorphous solid dispersions with hot-melt-extrusion process parameters.

Hot-melt extrusion allows for the continuous production of amorphous solid dispersions, which are used to enhance bioavailability of poorly soluble drugs in pharmaceutical drug delivery. To facilitate formulation and extrusion process development, we propose a mathematical model describing the formation of amorphous solid dispersions in the context of this process. The model is based on the calculation of two key process values: (1) time to dissolution of solid drug particles in molten polymer during extrusion and (2) mean residence of material in the extruder. We suggest that their linking allows for rational process design. Experimental data support the validity of our model for both key process values as well as the overall process. This modeling approach allows for fast and cost-effective formulation and extrusion process development as well as feasibility estimations in early stages of drug development.

Plasma Amino Acid Concentrations Are Associated with Muscle Function in Older Japanese Women.

BACKGROUND: Although several previous studies have found benefits for amino acid supplementation in terms of muscle function, the role of plasma amino acid concentrations on sarcopenia are not well addressed yet. OBJECTIVE: The aim of this study was to compare the amino acid concentrations at each stage of sarcopenia (normal, pre-sarcopenia, dynapenia, and sarcopenia) in community-dwelling older Japanese adults. SETTING AND SUBJECTS: Community-dwelling older Japanese women (n=232, 79.4±7.0 years) participated in this study. MEASUREMENTS: We measured plasma amino acid concentrations, 5-m walking speed, grip strength, and skeletal muscle mass using a bioelectrical impedance data acquisition system and compared them among participants at each stage of sarcopenia. RESULTS: The proportions of normal, pre-sarcopenia, dynapenia, and sarcopenia patients were 40.5% (n=94), 12.1% (n=28), 26.3% (n=61), and 21.1% (n=49), respectively. Significant differences were observed for concentrations of leucine, branched-chain amino acid (BCAAs), and essential amino acid (EAAs) among the four groups (p<0.05), and the dynapenia and sarcopenia groups showed significantly lower concentrations of leucine than the normal group (p<0.05). CONCLUSIONS: This study indicated a positive relationship between plasma leucine, BCAA and EAA concentrations and muscle function. A longitudinal study is needed to determine the causal relationship between leucine/BCAA concentrations and muscle function.

Real-time detection and discrimination of visual perception using electrocorticographic signals.

OBJECTIVE: Several neuroimaging studies have demonstrated that the ventral temporal cortex contains specialized regions that process visual stimuli. This study investigated the spatial and temporal dynamics of electrocorticographic (ECoG) responses to different types and colors of visual stimulation that were presented to four human participants, and demonstrated a real-time decoder that detects and discriminates responses to untrained natural images. APPROACH: ECoG signals from the participants were recorded while they were shown colored and greyscale versions of seven types of visual stimuli (images of faces, objects, bodies, line drawings, digits, and kanji and hiragana characters), resulting in 14 classes for discrimination (experiment I). Additionally, a real-time system asynchronously classified ECoG responses to faces, kanji and black screens presented via a monitor (experiment II), or to natural scenes (i.e. the face of an experimenter, natural images of faces and kanji, and a mirror) (experiment III). Outcome measures in all experiments included the discrimination performance across types based on broadband γ activity. MAIN RESULTS: Experiment I demonstrated an offline classification accuracy of 72.9% when discriminating among the seven types (without color separation). Further discrimination of grey versus colored images reached an accuracy of 67.1%. Discriminating all colors and types (14 classes) yielded an accuracy of 52.1%. In experiment II and III, the real-time decoder correctly detected 73.7% responses to face, kanji and black computer stimuli and 74.8% responses to presented natural scenes. SIGNIFICANCE: Seven different types and their color information (either grey or color) could be detected and discriminated using broadband γ activity. Discrimination performance maximized for combined spatial-temporal information. The discrimination of stimulus color information provided the first ECoG-based evidence for color-related population-level cortical broadband γ responses in humans. Stimulus categories can be detected by their ECoG responses in real time within 500 ms with respect to stimulus onset.

Co-circulation of multiple genotypes of African swine fever viruses among domestic pigs in Zambia (2013-2015).

During 2013-2015, several and severe outbreaks of African swine fever (ASF) affected domestic pigs in six provinces of Zambia. Genetic characterization of ASF viruses (ASFVs) using standardized genotyping procedures revealed that genotypes I, II and XIV were associated with these outbreaks. Molecular and epidemiological data suggest that genotype II ASFV (Georgia 2007/1-like) detected in Northern Province of Zambia may have been introduced from neighbouring Tanzania. Also, a genotype II virus detected in Eastern Province of Zambia showed a p54 phylogenetic relationship that was inconsistent with that of p72, underscoring the genetic variability of ASFVs. While it appears genotype II viruses detected in Zambia arose from a domestic pig cycle, genotypes I and XIV possibly emerged from a sylvatic cycle. Overall, this study demonstrates the co-circulation of multiple genotypes of ASFVs, involvement of both the sylvatic and domestic pig cycle in ASF outbreaks in Zambia and possible trans-boundary spread of the disease in south-eastern Africa. Indeed, while there is need for regional or international concerted efforts in the control of ASF, understanding pig marketing practices, pig population dynamics, pig housing and rearing systems and community engagement will be important considerations when designing future prevention and control strategies of this disease in Zambia.

Involvement of multiple Chlamydia suis genotypes in porcine conjunctivitis.

Chlamydia suis has been detected in numerous disease conditions of pigs, particularly in eye infections. This study examined recurring conjunctivitis cases in five commercial pig farms in Japan. 40.5% of the cases were identified as Chlamydia positive using impression cytology of ocular smears and a genus-specific direct fluorescent antibody. C. suis was detected in 59.5% of the samples using PCR tests targeting 16S-23S rRNA intergenic spacer region (ISR) and ompA gene. Genetic analysis of PCR amplicons revealed nine sequence variants of 16S-23S rRNA ISR and 20 sequence variants within ompA gene. Among C. suis-positive conjunctivitis cases, 36.4% showed concurrent infection with 2-4 varied ompA sequence types and 9.1% showed multiple 16S-23S rRNA ISR sequence types of C. suis. Multiple genotypes were found circulating in four of five farms. All 20 detected strains and 25 previously reported C. suis strains were grouped into four clusters. Japanese C. suis strains were closely related to American and European strains indicating wide distribution of these genetically variant strains. This study is the first to show multiple and genetically diverse C. suis strain associations in pig conjunctivitis.

Passive functional mapping guides electrical cortical stimulation for efficient determination of eloquent cortex in epilepsy patients.

Electrical cortical stimulation (ECS) is often used in presurgical evaluation procedures for patients suffering from pharmacoresistant epilepsy. Real-time functional mapping (RTFM) is an alternative brain mapping methodology that can accompany traditional functional mapping approaches like ECS. In this paper, we present a combined RTFM/ECS system that aims to exploit the common ground and the advantages of the two procedures for improved time/effort effectiveness, patients' experience and safety. Using the RTFM and ECS data from four patients who suffer epilepsy, we demonstrate that the RTFM-guided ECS procedure hypothetically reduces the number of electrical stimulations necessary for eloquent cortex detection by 40%.

Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin.

The density of intraepidermal nerve fibres has been shown to be higher in itchy dry skin than in healthy skin, suggesting that epidermal hyperinnervation is at least partly involved in peripheral itch sensitization. We investigated whether oral administration of milk-derived phospholipids (MPLs) would inhibit epidermal hyperinnervation in a mouse model of dry skin. We found that the number of intraepidermal nerve fibres was significantly lower in the MPL group than in the control group. Expression of nerve growth factor (NGF) levels in the epidermis was significantly decreased by oral administration of MPLs, whereas expression of semaphorin (Sema)3A, a nerve repulsion factor, was increased in the MPL group. These results suggest that dietary MPLs attenuate the penetration of nerve fibres into the epidermis by reducing epidermal NGF levels and increasing Sema3A level. Thus, dietary MPLs may have beneficial effects in the prevention and/or alleviation of dry skin-induced itch by reducing intraepidermal nerve fibre density.

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation.

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P<0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P<0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P<0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾180 mg/kg, ganciclovir ⩾10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P=0.044; ganciclovir, 84% vs 58%, P=0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.